The possible role of sirtuins and MiRNAs in gastrointestinal cancers: special focus on Sirt1

Abstract

This review comprehensively examines the role of Sirtuins and microRNAs (miRNAs) in gastrointestinal cancers (GICs) with a particular focus on Sirt1. Gastrointestinal malignancies, comprising a wide range of tumors within the digestive tract, represent an essential health challenge worldwide, and are distinguished by high incidence and mortality rates. Emerging evidence implies that Sirtuins, particularly SIRT1, act as a double-edged sword in cancer biology, acting as either tumor promoters or suppressors, depending on the cellular milieu. miRNAs also have been identified as critical regulators of gene expression, impacting cancer progression through their interaction with Sirtuins. A comprehensive literature search was conducted in PubMed, Scopus, Web of Science, and Google Scholar to identify relevant studies on the topic. This review highlights the complex relationships between Sirtuins and miRNAs in GICs, exploring their potential as biomarkers for early detection and targets for therapeutic intervention. The regulatory mechanisms of miRNAs in the Sirtuin family, specifically in human GICs, are examined to identify their influence on cancer diagnosis, progression, and management. The results may ultimately serve as a basis for developing diagnostic markers for the early detection of GICs.

Introduction

Gastrointestinal (GI) malignancies are a leading cause of morbidity and mortality worldwide, accounting for nearly one-fourth of all cancer cases and one-third of cancer-related deaths. Their incidence and mortality are projected to rise significantly by 2040 [1, 2]. Despite many studies on GI tumors, our current understanding of the molecular mechanisms involved in the initiation, progression, and development of GI cancers is indeed limited, since they are known to be multifactorial [3]. GI cancers arise from complex mechanisms involving chronic inflammation, genetic mutations, and disrupted signaling pathways that promote uncontrolled cell growth and metastasis. Environmental and metabolic factors, including oxidative stress, microbiota imbalance, diet, and obesity, further shape the tumor microenvironment and disease progression.

Biological markers, including microRNAs (miRNAs), DNA, RNA, antibodies, cytokines, and circulating proteins, have been proposed as potential aids for the early detection of cancer and monitoring tumor progression. Among these molecular regulators, Sirtuins and miRNAs have gained considerable attention for their intertwined roles in tumor biology [4].

Sirtuins, also known as Silent information regulator 2 (SIR2) proteins, are a group of enzymes that belong to the family of histone deacetylases (HDACs). Their primary function is to facilitate the removal of acetyl groups from lysine residues on both histone and non-histone proteins. In mammals, Sirtuins are a family of proteins identified as SIR2 that exist in seven homologs (SIRT1-SIRT7). These proteins are crucial because they are involved in developing critical human diseases, including cardiovascular and neurodegenerative diseases, diabetes, and cancer [5, 6]. SIRT1, as the most prominent member of the SIRTUIN family, is widely studied in different diseases. SIRT1 belongs to the class 3 histone deacetylases, and it is involved in regulating various cellular functions, including cell cycle, proliferation, metabolism, senescence, and apoptosis [7]. There are different ways to regulate the expression of SIRT1 during translation, and in cancer cells, several potential mechanisms can disrupt SIRT1 expression [8].

The role of SIRT1 in cancer is complex, as it can have both tumor-promoting and tumor-suppressing effects depending on the specific oncogenic pathway involved in a particular type of cancer. Despite its significance, the role of SIRT1 in cancer has not been thoroughly explored [9]. In human gastrointestinal cancers, SIRT1 is observed to have high expression levels and acts as an oncogene and epigenetic regulator. Its ability to promote anti-apoptotic activity is linked to its involvement in tumorigenesis. Consequently, an elevated expression of SIRT1 is related to increased proliferation, migration, and invasion of tumor cells [5, 7].

microRNAs (miRNAs) are small molecules and are usually 18–25 nucleotides long that help regulate biological processes. miRNAs affect the central dogma of molecular biology by attaching to their specific target messenger RNA (mRNA) molecules and inducing their degradation, which leads to the downregulation of the translation process. This interaction occurs at the 3’-untranslated regions of genes [10]. The targeting of miRNAs usually involves a group of genes rather than a single gene, and each miRNA has the capacity to target numerous genes [11].

Deregulation of miRNAs are connected to cancer initiation, development, and advancement. miRNAs that are associated with cancer are referred to as oncomiRs, which can function as either oncogenes or tumor suppressors in case of their upregulation and downregulation, respectively. They influence various pathways, such as apoptosis, autophagy, angiogenesis, senescence, cell proliferation, metastasis, and differentiation [12, 13]. In addition, the regulation of SIRT1 is believed to be significantly impacted by miRNAs (Fig. 1) [14]. However, the interplay between Sirtuins and miRNAs in gastrointestinal cancers remains insufficiently characterized, and published findings often report contradictory roles for SIRT1 as either a tumor suppressor or promoter. These seemingly conflicting findings probably reflect the complex, context-dependent nature of SIRT1 biology rather than just experimental variability. SIRT1, an NAD⁺-dependent deacetylase, links metabolic status with DNA repair and responses to inflammatory or low-oxygen stress. It can either help maintain genome stability and trigger cell death or, alternatively, enhance survival, induce EMT, and increase drug resistance depending on factors such as tumor type, genetic background (e.g., TP53 status), disease stage, and microenvironmental signals. Moreover, many studies rely on a limited number of cell lines and use overexpression or knockdown approaches, which can exaggerate certain pathways and make SIRT1 seem either consistently oncogenic or tumor-suppressive. These biological complexities and methodological limitations must be taken into account when interpreting the research and comparing different models.

Fig. 1.

SIRT1 and MicroRNAs collaboration; the mechanisms in Gastrointestinal (GI) neoplasms. MicroRNAs could play a vital function in the development of GI neoplasia through various mechanisms such as metastasis, angiogenesis, and proliferation, acting as either tumor promoters or suppressors. MicroRNAs regulate cancer progression through the targeting of SIRT1. These relationships between miRNAs and SIRT1 in GI cancers are illustrated in this figure. AGO: Argonaute protein; DGCR8: DiGeorge syndrome critical region 8; EMT: Epithelial–mesenchymal transition; miRNA: MicroRNA; mRNA: Messenger RNA; Pol II: RNA polymerase II; RISC: RNA-induced silencing complex; SIRT1: Sirtuin 1; TRBP: TAR RNA-binding protein. →: Activation, ⊣: Inhibition

This review aims to address this gap by summarizing current evidence on Sirtuin–miRNA interactions in gastrointestinal malignancies, with a particular focus on SIRT1-centered regulatory networks and their potential diagnostic and therapeutic relevance. It also highlights the regulatory mechanisms of miRNAs in the sirtuin family in human cancers, specifically GI neoplasms, which ultimately may provide promising strategies for the early detection of GI cancers. To accomplish this, a thorough literature search was conducted across databases such as PubMed, Web of Science, Scopus, and Google Scholar. The search utilized keywords such as “Gastrointestinal cancers,” “Sirtuins,” “miRNA,” “SIRT1,” “pathogenesis,” “diagnosis,” and “treatment.” Articles were chosen based on the relevance of their findings and their suitability for this review.

SIRT1 regulation by MiRNAs in GI cancers

Several studies have revealed that various miRNAs regulate the expression of SIRT1. This regulation can either promote or suppress carcinogenesis. In the context of tumor suppression, abnormal expression of the miRNAs can lead to increased cancer development, while in the case of oncogenesis, this dysregulated expression is favorable and can limit cancer development. This section, Table 1, summarizes the findings in this area.

Table 1.

MicroRNAs and SIRT1: the mechanisms involved in the modulation of GI cancer development

Cancer	MicroRNAs	SIRT1	Mechanism(s)	Outcome(s)	Ref.
Esophageal Cancer	↑ miR-34a	↓	↓ PI3k/AKT/mTOR Pathway	Decreased Radiation therapy Resistance	[18]
	↑ miR-34a	↓	↑ Caspase-3	Increased Apoptosis Decreased Drug Resistance Decreased Proliferation	[28]
	↑ miR-34a	↓	NA	Decreased Invasion and Proliferation	[20]
	↑ miR-34a	↓	↑ P53	Increased DNA Damage Decreased Tumor Growth	[193]
Gastric Cancer	↑ miR-181a-5p	↓	↓ E-cadherin ↑ N-cadherin, Twist, Slug	Increased EMT, Migration, and Invasion	[48]
	↑ miR-1301-5p	↓	↑ Cyclin D1, c-Myc, CDK4 ↓ P21	Increased Proliferation	[194]
	↑ miR-34a	↓	NA	Decreased Multi Drug Resistance (MDR)	[37]
	↑ miR-204	↓	↑ E-cadherin ↑ NF-κB ↓ Vimentin	Increased Apoptosis Decreased EMT, Invasion, Proliferation	[49]
	↑ miR-132-3p/ miR-212-3p	↓	NA	Increased Migration, Invasion, and Proliferation	[39]
	↓ miR-138	↓	↑ STAT3	Decreased Proliferation and Invasion	[195]
	↑ miR-543	↓	↑ N-cadherin, Vimentin, Snail ↓ E-cadherin ↓ LC3, P62	Increased EMT, Invasion, Migration, and Proliferation Decreased Autophagy	[41]
	↑ miR-21 ↓ miR-451	↑	NA	Increased Drug Resistance	[51]
	↑ miR-34a	↓	NA	Increased Apoptosis Decreased Proliferation	[196]
	↑ miR-132	↓	↑ ABCG2	Increased Chemoresistance	[43]
	↑ miR-543	↓	NA	Increased Proliferation	[44]
	↑ miR-204	↓	↑ E-cadherin ↓ Vimentin	Decreased EMT, Invasion, and Metastasis Decreased Anoikis Resistance	[46]
	↑ miR-449	↓	↑ P53, PARP, Caspase-3	Increased Apoptosis	[47]
	↓ miR-204	↑	↑ Vimentin ↓ E-cadherin	Increased EMT, Proliferation, and Invasion	[49]
	↑ miR-181-5p	↓	↑ GPX4, SLC7A11 ↑ P-gp ↓ Caspase-3, Bax ↑ BCRP/ABCG2 ↓ E-cadherin ↑ N-cadherin, Slug, Twist	Increased Ferroptosis Increased Lipid Peroxidation Increased EMT, Migration, Invasion, and Proliferation Decreased Apoptosis	[48]
Colorectal Cancer	↓ miR-20b-3p	↑	↑ DEPDC1	Increased Drug Resistance	[59]
	↑ miR-34a	↓	↑ B7-H3	Increased pro-inflammatory Effect	[61]
	↓ miR-34a	↑	↑ Bax, mTOR ↓ Bcl-2, Beclin 1 ↓ LC3-II	Increased Apoptosis Decreased Autophagy	[63]
	↓ miR-138	↑	NA	Increased Migration, Invasion, and Proliferation	[64]
	↑ miR-34a	↓	↑ Bax, Cytochrome c ↓ Bcl-2, Beclin 1 ↓ LC3-II	Increased Apoptosis Decreased Autophagy	[67]
	↑ miR-141	↓	↓ Caspase-3,8	Decreased Apoptosis Increased Proliferation	[70]
	↑ miR-1185-1	↓	↓ CD24	Decreased CSCs Self-renewal Decreased Tumor Growth	[72]
	↑ miR-29b	↓	↑ ROS, JNK ↑ Caspase-3,7,9	Increased Apoptosis Decreased Drug Resistance	[74]
	↑ miR-34a	↓	↓ Wnt/β-catenin Axis	Decreased Metastasis and Proliferation Decreased Tumor Growth	[76]
	↑ miR-34a	↓	NA	Increased Cell Cycle Arrest Decreased Proliferation	[78]
	↑ miR-128	↑	↑ ROS, JNK	Increased Apoptosis	[80]
	↑ miR-135a-5p	↓	↑ Caspase-3	Increased Apoptosis Increased Cell Cycle Arrest Decreased Migration, Invasion, and Proliferation	[81]
	↑ miR-194-5p	↓	↑ P62 ↓ LC3-II	Decreased Autophagy Increased Chemoresistance	[83]
	↑ miR-34a	↓	↑ P53, PARP, Caspase-3,9  ↓ Wnt	Increased Apoptosis Decreased Cell Viability, Migration, and Invasion	[84]
	↓ miR-15b-5p	↑	↑ ACOX1	Decreased Metastasis	[86]
	↑ miR-199b	↓	↑ E-cadherin ↑ CREB, KISS1 ↓ Vimentin, MMP-2, MMP-9	Increased Drug Sensitization Decreased EMT, Migration, and Invasion	[88]
	↑ miR-34a	↓	↑ P53, P21	Increased Apoptosis Increased Drug Sensitization Decreased Proliferation, Invasion, and Migration	[90]
	↑ miR-34a	↓	↓ E2F1	Decreased Drug Resistance Decreased Proliferation and Tumor Growth	[91]
	↑ miR-22	↓	↑ RARβ, NUR77	Increased Apoptosis Decreased Tumor Growth	[197]
	↑ miR-34a	↓	↑ PARP, Caspase-8,9 ↓ Bcl2	Increased Chemosensitization Increased Apoptosis Decreased Tumor Growth	[198]
Liver Cancer	↑ miR-4669	↑	↓ CD80, TNF-α	Decreased M1 Macrophage Activity and increased Immunosuppressive Tumor Microenvironment Increased Metastasis Increased Drug Resistance	[100]
	↑ miR-34a	↑	↑ P53	Increased Liver Regeneration After Partial Hepatectomy	[103]
	↑ miR-4461	↓	NA	Decreased Chemoresistance Decreased Metastasis Decreased CSCs Self-renewal	[104]
	↑ miR-124-3p	↓	↓ AKT2, FOXO3a	Increased Drug-induced Apoptosis Decreased Drug Resistance	[107]
	↑ miR-148a	↓	↑ P53 ↓ PXR	Decreased Drug Resistance	[108]
	↓ miR-425	↑	↑ LC3-II	Increased Lipophagy Decreased Proliferation, Migration, and Invasion	[110]
	↓ miR-601	↑	NA	Increased Migration, Invasion, and Proliferation	[111]
	↑ miR-124-3p/ miR-506-3p	↓	NA	Decreased Migration, Invasion, and Proliferation Decreased Tumor Growth	[112]
	↑ miR-34a	↓	↓ NLRP3, Caspase-1, IL-1β	Decreased Pyroptosis Decreased HCC Progression	[114]
	↑ miR-22-3p	↓	↑ P53, P21, P16, pRb, ↑ E-cadherin ↓ Vimentin, N-cadherin, Fibronectin, ZEB1, ZEB2	Increased HCC Cellular Senescence Decreased EMT, Proliferation, and Migration	[115]
	↑ miR-34a	↓	↑ P53 ↓ Bcl-2, ↓ Cyclin D1, CDK4, CDK6 ↓ MDR1	Increased Apoptosis Increased Cell Cycle Arrest Decreased Chemoresistance	[116]
	↑ miR-34a	↓	↑ P53 ↓ Bcl-2	Increased Apoptosis Decreased Radiosensitization	[118]
	↑ miR-124	↓	↑ ROS, JNK	Increased Apoptosis Increased Drug Sensitization	[120]
	↑ miR-486-5p	↓	↓ CD13	Decreased Proliferation and Invasion Decreased CSCs Self-renewal	[121]
	↑ miR-34a	↓	↑ P53	Increased Apoptosis	[122]
	↑ miR-22	↓	↑ ROS, Cytochrome c, Caspase-3,9 ↓ Bcl-2	Increased Apoptosis	[124]
	↑ miR-34a	↓	↑ Acetyl-P53	Decreased Metastasis	[125]
	↑ miR-138	↓	NA	Decreased Proliferation and Invasion	[126]
	miR-204	↓	NA	Decreased Migration and Invasion	[127]
	↑ miR-133b	↓	↑ E-cadherin ↓ Bcl-2, Bcl-xl, Mcl-1, Glypican-3 (GPC3) ↓ Wnt/β-catenin Axis	Increased Apoptosis Decreased EMT, Proliferation, and Invasion	[129]
	↑ miR-204-5p	↓	NA	Increased Apoptosis Increased Drug Sensitization Decreased Cell Survival and Invasion	[130]
	↑ miR-29c	↓	NA	Decreased Proliferation	[132]
	miR-29c	↓	↓ E2F1, Cyclin A, CDK2, CDK6	Increased Cell Cycle Arrest Decreased Proliferation	[133]
	miR-34a	↓	↓ Bcl-2	Decreased Tumor Growth	[136]
	↑ miR-6845-5p/ miR-6886-3p/ miR-6825-5p	↓	↓ USP22 ↓ LC3-ll ↑ Atg5, Atg7 ↑ Caspase-3, PARP P62	Increased Ubiquitination Increased Chemosensitization Decreased Autophagy Decreased HCC Growth	[199]
	↑ miR-185	↓	↓ c-Myc	Increased Cell Cycle Arrest Decreased Proliferation	[200]
	↑ miR-106a/b	↓	NA	Increased Chemosensitization	[201]
Pancreatic Cancer	↑ miR-30b-5p	↓	↑ NLRP1, NLRP3, ASC, Caspase-1	Increased Pyroptosis Decreased PC Cell Viability	[141]
	↑ miR-23b-3p	↓	↓ HIF-1α	Decreased Glycolysis Decreased Drug Resistance Decreased Proliferation	[144]
	↑ miR-373	↓	↑ ROS, Bax, Caspase-8,9,3 ↓ Bcl-2, PARP ↓ PGC-1α/Nrf2 Axis	Increased Apoptosis Decreased Proliferation	[145]
	↑ miR-138-5p	↓	↓ FOXO1/Rab7 Axis ↓ LC3-ll, P62 ↓ HIF-1α	Decreased Autophagy Decreased Tumor Growth	[146]
	↑ miR-601	↓	↑ E-cadherin ↓ N-cadherin ↓ AKT	Decreased EMT, Proliferation, and Invasion	[147]
	↑ miR-494	↓	↓ MMP-2, MMP-9 ↓ Bcl-2, Cyclin D1 ↑ Bax, P21	Increased Apoptosis Decreased Proliferation and Invasion Decreased Chemoresistance	[149]
	↑ miR-217	↓	↑ E-cadherin ↓ N-cadherin, Snail, ZEB1	Decreased EMT and Metastasis	[150]
	↑ miR-34a	↓	↓ CD44 ↓ Aldehyde Dehydrogenase (ALDH)	Increased Apoptosis Decreased Proliferation Decreased Tumor Growth	[151]
	↑ miR-34a	↓	↓ Bcl-2, Caspase-3,7 ↓ CDK6, VEGF ↑ P53, P21 ↓ Notch ↑ E-cadherin ↓ N-cadherin, Snail, ZEB1, Slug	Increased Apoptosis Increased Cell Cycle Arrest Decreased CSCs Self-renewal Decreased EMT, Invasion, and Proliferation	[152]

ABCG2: ATP-binding cassette sub-family G member 2; ACOX1: Acyl-CoA oxidase 1; ALDH: Aldehyde dehydrogenase; ASC: Apoptosis-associated speck-like protein containing a CARD; CREB: cAMP response element-binding protein; CSC(s): Cancer stem cell(s); DEPDC1: DEP domain-containing protein 1; EMT: Epithelial–mesenchymal transition; FOXO1/FOXO3a: Forkhead box O1/O3a; GPC3: Glypican 3; GPX4: Glutathione peroxidase 4; HCC: Hepatocellular carcinoma; HIF-1α: Hypoxia-inducible factor 1 alpha; IL-1β: Interleukin 1 beta; JNK: c-Jun N-terminal kinase; KISS1: KiSS-1 metastasis suppressor; MDR/MDR1: Multidrug resistance/protein 1; miR: MicroRNA; mTOR: Mechanistic target of rapamycin; NA: Not applicable or not available; NF-κB: Nuclear factor kappa-light-chain-enhancer of activated B cells; NLRP1/NLRP3: NOD-like receptor family pyrin domain-containing 1/3; NUR77: Nuclear receptor subfamily 4 group A member 1; PARP: Poly (ADP-ribose) polymerase; PC: Pancreatic cancer; PGC-1α: PPAR gamma coactivator 1-alpha; PI3K: Phosphoinositide 3-kinase; P62: Sequestosome 1; pRb: Retinoblastoma protein; PXR: Pregnane X receptor; RARβ: Retinoic acid receptor beta; ROS: Reactive oxygen species; SIRT1: Sirtuin 1; SLC7A11: Solute carrier family 7 member 11; STAT3: Signal transducer and activator of transcription 3; TNF-α: Tumor necrosis factor alpha; USP22: Ubiquitin-specific peptidase 22; VEGF: Vascular endothelial growth factor. ↑: Upregulation, ↓: Downregulation

Esophageal cancer

Overview of esophageal cancer epidemiology and diagnostic challenges

Esophageal cancer (EC) is the seventh most common cancer worldwide and causes the sixth highest number of deaths, with a 5-year survival rate of merely 15–20% [15, 16]. It comprises two main subtypes: esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC), with ESCC accounting for approximately 80% of cases. Most patients are diagnosed at advanced stages due to the absence of specific and reliable biomarkers, underscoring the need for early molecular diagnostics [17–19].

Roles of MiRNAs and SIRT1 in EC

Mounting evidence shows that epigenetic and post-transcriptional regulators are key in EC development. SIRT1, a type of histone deacetylase (class III), often has increased expression in tumor tissues and is a crucial factor in EC. Tumors of ESCC with high SIRT1 levels are associated with poorer survival, suggesting that SIRT1 may act as an oncogenic driver in these cases [20]. MiRNAs, small non-coding RNAs, are similarly critical: their dysregulation contributes to cancer initiation and progression. They can serve as oncogenes or tumor suppressors (oncomiRs in the context of cancer), depending on their targets [21, 22]. In EC, many miRNAs regulate pathways involved in cell proliferation, apoptosis, and metastasis by targeting essential genes like Sirt1. Besides miR-34a, several other miRNAs, such as miR-132, miR-204, miR-125b, miR-29b, and miR-181a, have also been reported to influence Sirt1 expression or its downstream pathways in ESCC, contributing to changes in tumor cell survival, invasion, and therapy responsiveness [23–25]. The involvement of these additional miRNAs suggests that SIRT1 regulation in EC is not limited to a single miRNA, but rather arises from a broader network of miRNA-mediated control. Recent comprehensive reviews on ncRNAs and GC further support the significance of this regulatory network and highlight the wider relevance of Sirt1-associated miRNAs in GI cancer biology [26]. For example, loss of tumor-suppressing miRNAs or increased levels of oncogenic miRNAs can impair normal Sirt1 regulation, leading to abnormal cell growth and survival. Profiling studies have also identified miRNAs as potential prognostic biomarkers in EC. Overall, the interaction between miRNAs and SIRT1 plays a central role in EC biology, influencing tumor behavior and patient prognosis [18].

Mechanisms of miRNA-Mediated SIRT1 regulation in EC

One of the best-characterized mechanisms connecting miRNAs to SIRT1 in esophageal cancer involves the TP53/miR-34a/SIRT1 axis. TP53 is a tumor suppressor gene that transcriptionally activates MIR34A; in EC cells with wild-type p53, DNA damage induces miR-34a expression, which then directly binds to the 3′ untranslated region (3′ UTR) of SIRT1 mRNA and inhibits SIRT1 protein production [20, 27]. Through this direct targeting, miR-34a effectively downregulates SIRT1, resulting in the reactivation of p53’s downstream effector p21 and promoting cell-cycle arrest in cancer cells. Additionally, by reducing SIRT1 levels, miR-34a disrupts pro-survival signaling pathways; for example, restoring miR-34a was shown to inhibit the PI3K–AKT–mTOR pathway in radioresistant ESCC cells, thereby increasing their sensitivity to radiotherapy [16, 18]. Beyond direct interactions with the 3′UTR, miRNA activity on SIRT1 can also be influenced by other non-coding RNAs. A notable example is the long non-coding RNA MNX1-AS1, which is significantly upregulated in ESCC. MNX1-AS1 acts as a competitive endogenous RNA sponge for miR-34a, binding to and sequestering miR-34a, thereby preventing it from downregulating SIRT1. As a result, overexpression of MNX1-AS1 correlates with increased SIRT1 levels and enhanced tumor cell proliferation, migration, and invasion in ESCC [20]. Another layer of mechanistic insight comes from therapeutic modeling: Fang et al. demonstrated that a polyethylene glycol-coated nano-carrier co-encapsulating miR-34a and doxorubicin could overcome cisplatin resistance in EC by reactivating apoptosis and suppressing SIRT1 signaling [27, 28]. Treated cells displayed restored drug sensitivity, attributed to miR-34a-mediated Sirt1 suppression, and the approach was proposed as a potential therapeutic strategy to improve chemotherapeutic efficacy. Collectively, these mechanistic studies illustrate how miRNAs (exemplified by miR-34a) exert tumor-suppressive effects in esophageal cancer by directly or indirectly downregulating SIRT1 and its pro-tumorigenic pathways.

Mechanisms of miRNA-Mediated Sirt1 regulation in EC

In summary, the dynamic interplay between miRNAs and SIRT1 plays a vital role in the progression of esophageal cancer. miR-34a functions as a crucial tumor suppressor in this cancer type, with consistent evidence indicating that increasing its levels can inhibit Sirt1, thereby reducing tumor growth and improving treatment response [20, 27, 28]. Overexpression of Sirt1, often due to miRNA deregulation, contributes to therapy resistance and more aggressive tumor behavior in ESCC. However, the current body of evidence is largely descriptive and often centered on single miRNA–target interactions, which may oversimplify a more complex regulatory network involving multiple miRNAs with context-dependent effects. Variability across different ESCC cell lines and experimental conditions also suggests that Sirt1 regulation may not follow a uniform pattern in all settings. Therefore, targeting the miRNA–SIRT1 pathway offers promising potential for better EC management. Restoring or mimicking the activity of downregulated tumor-suppressor miRNAs, particularly miR-34a, or directly inhibiting Sirt1 may help overcome resistance to radiotherapy and chemotherapy, induce apoptosis, and inhibit proliferation. Additionally, unique miRNA expression patterns could serve as clinical biomarkers; for instance, altered tissue or circulating miR-34a and other Sirt1-targeting miRNAs might be useful for early detection or prognosis in EC. Despite these advances, most available studies rely on in vitro models, small patient cohorts, or lack robust clinical validation, limiting the generalizability of current findings. Conflicting mechanistic results across different studies further indicate the need for comprehensive in vivo experiments and larger, well-designed clinical investigations. Further research is needed to deepen these molecular insights and develop effective treatments.

Gastric cancer

Overview of gastric cancer

Gastric cancer (GC) is prevalent and impacts over one million individuals globally annually, with the most significant incidence occurring in South America and Asia [29]. According to reports from 2020, despite the decline in the prevalence of GC worldwide, in the last five years, it remained amongst the top three regarding the mortality rate [30]. In many countries, despite significant progress in innovative treatment approaches and early detection techniques, the five-year survival is less than 30% in the majority of patients [31]. The etiology of GC is complex and involves multiple factors such as Helicobacter infections, environmental aspects, and genetic and epigenetic alterations [32–34]; the significance of these genetic aberrations in the genesis of GC has led to many studies on miRNAs and signaling pathways [35, 36]. Therefore, it seems necessary to develop new biomarkers for the early diagnosis and management of this malignancy.

Roles of MiRNAs and SIRT1 in GC

A 2021 study by Luo et al. documented that miR-1301-3p is overexpressed in GC cells and tissues, promoting cancer cell growth and tumor formation. The study also found that miR-1301-3p directly targets and reduces the levels of SIRT1, a protein that controls cell growth. When SIRT1 level is reduced, cell proliferation increases even when miR-1301-3p is inhibited. These findings suggest that miR-1301-3p may be a promising diagnostic and therapeutic target for GC also been investigated by inhibiting the expression of SIRT1 and two protein factors that contribute to MDR by pumping chemotherapy drugs out of cancer cells, including MRP1 (Multidrug resistance-related protein 1) and P-gp (P-glycoprotein). The results showed that the expression of SIRT1, P-gp, and MRP1 was promoted by the low expression of hsa-miR-34a, which led to the development of MDR in GC cells. Based on this result, miR-34a is proposed as a potential therapeutic target for reversing MDR in GC cells [37].

An investigation in 2021 revealed that miR-132-3p and miR-212-3p play significant roles in the formation and progression of GC by influencing the relationship between circ-sirt1 and Sirt1. Circ refers to circular RNAs, which are a type of non-coding RNA that form a closed-loop structure. The role of circRNAs in cancer is still being studied, but they have been shown to function in regulating gene expression and may have potential as biomarkers or therapeutic targets. circ-sirt1 identifies a circular RNA molecule that is transcribed from the sirt1 host gene in the human genome and has a negative impact on miR-132-3p/miR-212-3p, while it has a positive effect on sirt1. The study showed that increasing the level of circ-sirt1 in vitro led to a reduction in the expression of miR-132-3p and miR-212-3p, which resulted in an increased expression of sirt1 at both the mRNA and protein levels. However, when miR-132-3p/miR-212-3p was overexpressed, the high sirt1 expression was counteracted. In general, overexpression of circ-sirt1 upregulates sirt1 expression at both mRNA and protein levels and inhibits tumor growth and invasion, probably by sponging miR-132-3p/miR-212-3p and upregulating sirt1 expression in GC. Therefore, sirt1 may act as a tumor suppressor in the development of GC [38, 39]. In addition to these findings, recent work has shown that miRNAs in GC regulate key oncogenic pathways such as Wnt/β-catenin, HMGA2/mTOR/P-gp, PI3K/AKT/c-Myc, VEGFR, and TGF-β, contributing to tumor proliferation, metastasis, and chemoresistance [40].

Mechanisms of miRNA-mediated SIRT1 regulation in GC

Studies have demonstrated that the upregulation of human cytomegalovirus protein UL136 leads to a decrease in the expression of SIRT1 in GC cells. Moreover, the inhibition of SIRT1 expression and increased STAT3 phosphorylation levels were observed in GC cells when treated with miR-138 mimics. These results suggested that miR-138 is functionally relevant in regulating the expression of SIRT1 in GC cells and can effectively activate the STAT3 signaling pathway [39].

That miR-543 has an impact on SIRT1 and autophagy in H. pylori-associated GC was also shown. The findings demonstrated that miR-543 specifically targets SIRT1, resulting in decreased levels of autophagy. Autophagy is a vital cellular mechanism that takes place in lysosomes and plays a key role in the degradation of damaged organelles and proteins. By engaging in autophagy, cells can effectively recycle these materials and uphold a harmonious internal environment, also called cellular homeostasis.

The reduction in autophagy was linked to the promotion of epithelial-mesenchymal transition (EMT), associated with increased cell migration and invasion in GC. EMT is a biological process during cancer when epithelial cells lose their cellular nature and take on a mesenchymal phenotype. The Western blot analyses revealed that miR-543 significantly suppressed the expression of SIRT1 at both the mRNA and protein levels in GC cells. The study highlighted the regulatory mechanism involving miR-543 and SIRT1 in GC, where miR-543 targets SIRT1 to suppress autophagy, promoting EMT, cell migration, and invasion [41, 42]. This confirmed that miR-34a targets SIRT1 in GC cells. This targeting reduced mRNA and protein expression of SIRT1, which causes decreased cell proliferation and increased apoptosis in GC cells. Overall, the study revealed that miR-34a may act as a tumor suppressor gene in GC by targeting SIRT1. The data provides insights into the regulatory mechanism of miR-34a and SIRT1 in GC cells [42].

Lgr5 + cells are GC stem cell-like (GCSC) cells that display stem cell-like features. They have been identified as a potential biomarker for sorting GCSCs, and additionally, it has been demonstrated that miR-132 is increased in stem cells associated with Lgr5 + GC. This upregulation of miR-132 contributes to the resistance of cisplatin, a chemotherapy drug, through a cellular signaling pathway involving SIRT1, CREB, and ABCG2. CREB is a transcription factor that plays a crucial role in regulating gene expression in response to various extracellular signals. Thus, the findings of this study clarify that SIRT1 modifies CREB by removing acetyl groups, resulting in its inactivation through phosphorylation. Additionally, ABCG2 belongs to the ATP-binding cassette (ABC) transporter family, and SIRT1 can lower its expression by promoting CREB de-acetylation. CREB, on the other hand, activates ABCG2 by binding to its promoter and stimulating its transcription.

In GC tissues, the expression of SIRT1 is lower than that of non-cancerous tissues, whereas miR-132 expression is higher. The data indicate that miR-132 negatively controls SIRT1 in samples of GC tissue, and it suggests that decreased miR-132 levels could lead to an elevated SIRT1 protein expression, potentially enhancing cisplatin resistance in GC [43].

It has also been confirmed that miR-543 can downregulate the expression of SIRT1 in GC cells by binding to specific sites on the mRNA of SIRT1. This interaction promotes increased cell proliferation and progression through the cell cycle in GC cells. Interestingly, the study also found that the expression of miR-543 is elevated in GC patients, and there is an inverse correlation between miR-543 levels and SIRT1 expression. valuable insights into how miR-543 regulates SIRT1 in GC, suggesting that targeting this pathway could be a promising therapeutic approach for managing the disease [44]. Based on work published by Zhang and colleagues, miR-204 is less active in GC tissues, and its direct target is SIRT1.

Vimentin and E-cadherin are proteins that are involved in the EMT process that is associated with metastasis. E-cadherin is typically expressed in epithelial cells and is involved in cell adhesion. At the same time, Vimentin is a protein that is commonly expressed in mesenchymal cells and is involved in cell motility. Loss of E-cadherin expression and gain of Vimentin expression are hallmarks of the EMT. When miR-204 is overexpressed, or SIRT1 is suppressed in metastatic GC cells, there is a shift towards a more normal cell structure with increased levels of E-cadherin and decreased levels of Vimentin. The control of the EMT process by miR-204 involves cooperation with LKB1, a protein that regulates the EMT and is a known tumor suppressor gene on human chromosome 19p13. The reduced activity of miR-204 suppresses LKB1 through SIRT1, which promotes the invasion of human GC cells. So, based on this study, miR-204 plays a significant role in regulating the spread of GC by repressing SIRT1 through post-transcriptional mechanisms [45, 46].

This research also demonstrated that miR-449 has decreased activity levels in GC. Based on this study, MET, GMNN, CCNE2, SIRT1, and HDAC1 are genes that are involved in cell cycle regulation and have been linked to the pathogenesis of many malignancies. Therefore, miR-449 was found to directly target MET, GMNN, CCNE2, SIRT1, and HDAC1 genes by binding to their 3’UTRs (Untranslated region). The study suggested that miR-449 induces apoptosis by inhibiting the histone deacetylase (HDAC1) and SIRT1, leading to the p53 pathway activation; thus, the induction of apoptosis markers cleaved CASP3 and PARP.

miR-449 expression was also confirmed in human gastric tumors compared with normal tissues [47]. In 2023, Qu et al. reported that DACT3-AS1, a type of non-coding RNA, acts as a tumor suppressor in GC. This RNA regulates cell proliferation, invasion, and migration by interacting with miR-181a-5p and controlling the expression of SIRT1. The results discovered that a decrease in DACT3-AS1 and SIRT1 expression in GC tissues correlates with an increase in miR-181a-5p expression [48].

Additionally, circNOP10, a circular RNA, functions in GC progression. The study in question revealed that circNOP10 engages with miR-204, hindering its ability to control the expression of SIRT1. This interaction results in elevated levels of SIRT1, which in turn enhances the invasion, proliferation, EMT, and apoptosis resistance of GC cells [49].

Cancer stem cells (CSCs) are a small population of cells within a tumor. These cells possess the unique ability to self-renew and differentiate into various cell types that make up the tumor. They are believed to play a role in the initiation, resistance to chemotherapy, and development of tumors [50]. Based on a study in 2019, it was found that SIRT1 and specific miRNAs, such as miR-34a, miR-451, and miR-21, play significant roles in two crucial aspects of GC: preserving the stem-like features of CSCs and their chemotherapy resistance, specifically Docetaxel (DOC). The authors noted that the expression of SIRT1 and miR-21 increased in DOC-treated cells compared to non-treated cells, indicating a possible positive regulatory relationship between SIRT1 and miR-21 in GC. However, the expression of miR-34a and miR-451 decreased in DOC-treated cells, implying a negative regulatory relationship between SIRT1 and these miRNAs. Therefore, these alterations in the expression of genes can potentially contribute to the survival and proliferation of cancer stem cells, enhancing their ability to withstand the effects of chemotherapy treatment [51].

Summary and therapeutic implications

In summary, these studies highlight that SIRT1 is intricately regulated by various miRNAs and ncRNAs in GC. Some pathways promote tumor growth and resistance to chemotherapy, while others act to suppress tumors. Most of the data are from in vitro studies, animal models, or small patient groups, which limits how broadly the findings can be applied. Additionally, some research presents opposing roles for SIRT1—either as promoting cancer or suppressing it—indicating its function might depend on tumor type, stage, or microenvironment. Nonetheless, the evidence suggests that targeting the SIRT1–miRNA axis could be a promising approach for GC diagnosis and treatment, especially in overcoming MDR, reducing EMT, and targeting CSCs.

Colorectal cancer

Overview of colorectal cancer

Colorectal cancer (CRC) is a common neoplasm that affects the digestive system and is one of the leading causes of death globally. It is ranked in the top five deadliest types of cancer and is considered a significant form of malignancy. In 2018 alone, approximately 862,000 individuals lost their lives due to this disease [52]. Even though there have been remarkable advancements in treating CRC with chemotherapy, radiotherapy, and surgical procedures, the probability of survival for patients is still not optimal. Hence, CRC continues to be a considerable threat to the health and well-being of any community [53]. The development of CRC is associated with various factors, including harmful diet and genetic predisposition. However, the precise molecular mechanisms responsible for the progress of this neoplasm in humans are still poorly understood [54]. Multiple studies have demonstrated the crucial involvement of miRNAs in the advancement and growth of CRC. Moreover, their interactions with diverse signaling pathways, such as SIRT1, significantly impact the malignancy of this type of cancer [55–57]. Continuing research is required to find alternative biomarkers that can be employed for the early detection and improved management of CRC.

Roles of MiRNAs and SIRT1 in CRC

Multiple functional studies have demonstrated that SIRT1 acts as a key regulator in CRC, influenced by various miRNAs that affect tumor cell growth, survival, invasion, metabolism, and response to treatments. miR-20b-3p, miR-34a, miR-138, miR-141, miR-29b, miR-128, miR-194-5p, miR-135a-5p, miR-15b-5p, miR-199b, miR-222-3p, miR-132-3p, miR-1185-1, and others regulate SIRT1 either directly or indirectly, impacting critical signaling pathways such as NF-κB, Wnt/β-catenin, SIRT1/ROS/JNK, SIRT1/CREB/KISS1, and SIRT1/p53. Additionally, several lncRNAs and circRNAs including GAS5, NEAT1, H19, HNF1A-AS1, and FOXD3-AS1 serve as competing endogenous RNAs that bind miRNAs, thereby modulating SIRT1 expression. Collectively, these networks connect SIRT1 to resistance against oxaliplatin and 5-FU, sensitivity to TRAIL, ferroptosis, autophagy, immune evasion, and the maintenance of cancer stem cells in CRC.

Mechanisms of miRNA-mediated SIRT1 regulation in CRC

Oxaliplatin (L-OHP) is a common chemotherapy drug used to treat CRC, but drug resistance can limit its effectiveness [58]. A study conducted by Zhao and colleagues in 2022 documented that SIRT1 contributes to L-OHP resistance in CRC by controlling a pathway involving miR-20b-3p and DEP domain containing 1 (DEPDC1). DEPDC1 is a protein that affects cancer cell migration, invasion, and proliferation. The study showed that there is an inverse relationship between SIRT1 and miR-20b-3p, meaning that SIRT1 levels were higher in L-OHP-resistant CRC tissues and cells. However, when SIRT1 was reduced, CRC cells became more sensitive to L-OHP by decreasing DEPDC1 levels through miR-20b-3p binding [59, 60]. Based on a 2021 study, miR-34a is a molecule that prevents the protein SIRT1 from inhibiting the production of molecules that weaken the immune system’s ability to fight against CRC. The results demonstrated that this occurs through the activation of a signaling pathway called NF-κB, which leads to the production of B7-H3 and TNF-α in the tumor environment. Unfortunately, these molecules help the cancer cells evade the immune system and promote tumor growth. Thus, miR-34a aids CRC cell growth by blocking SIRT1 and activating the NF-κB/B7-H3/TNF-α pathway, which impairs the immune system’s capacity to fight the tumor [61, 62]. Also, researchers have investigated the connection between a lncRNA called GAS5, miR-34a, mTOR, and SIRT1 in CRC in-vitro. The study revealed that miR-34a controls both apoptosis and autophagy by regulating the mTOR/SIRT1 pathway, which was found to be more active or increased in tumor cells [63].

With the aid of a dual-luciferase reporter assay, it has been demonstrated that SIRT1 is a new goal of miR-138 in CRC. The study indicated that miR-138 levels were significantly reduced in vitro in CRC cells, while SIRT1 levels were increased in the same cells. The report showed that miR-138 can hinder CRC cells’ migration, invasion, and proliferation by directly targeting SIRT1. In summary, these findings suggest a new and promising approach to managing CRC [64]. Other miRNAs consistently inhibit colorectal tumor growth by targeting essential survival pathways. Recent studies identified miR-509-5p as a strong tumor suppressor in CRC. Like miR-138, which curtails proliferation by downregulating SIRT1, miR-509-5p promotes ferroptosis—a form of iron-dependent cell death characterized by lipid peroxidation—by directly targeting SLC7A11, a cystine transporter that blocks ferroptosis. Its suppression of SLC7A11 disrupts redox balance, inducing ferroptotic death in CRC cells. Therefore, the miR-509-5p/SLC7A11 pathway presents a promising therapeutic target for CRC management [65].

Catalpol, which is derived from Rehmannia glutinosa, a traditional Chinese medicine, inhibits the progression of different types of neoplasms by modulating miRNAs [66]. In CRC, treatment with catalpol reduced autophagy, triggered apoptosis, decreased cell viability, and regulated SIRT1 expression by increasing miR-34a levels both in-vivo and in-vitro. The results revealed a significant decrease in miR-34a expression and overexpression of SIRT1 in all CRC cell lines and the majority of CRC tissues. Hence, it was proposed that the upregulation of SIRT1 and the downregulation of miR-34a may contribute to the progression of CRC [67].

The competing endogenous RNA (ceRNA) hypothesis suggests that RNA molecules can regulate the expression of genes by competing with miRNAs. In this scenario, RNA molecules function as sponges, effectively binding and sequestering microRNAs, leading to changes in other RNA molecules’ expression levels. This mechanism highlights the complex and dynamic interaction between RNA molecules and miRNAs in the intricate process of gene expression regulation [68]. Additionally, the control of apoptosis, cell proliferation, and differentiation is administered by the Wnt/β-catenin signaling pathway. When there are disruptions in this pathway, it has been linked to the onset of different forms of neoplasia, such as CRC [69].

A previous report suggested that the lncRNA SNHG15 might promote CRC progression by functioning as a competing endogenous RNA that modulates the miR-141/SIRT1/Wnt/β-catenin axis. However, the study proposing this mechanism has since been retracted, and the validity of these findings is therefore uncertain. As a result, this pathway should be interpreted with considerable caution. At present, no reliable or independently validated evidence supports a regulatory role for SNHG15 in the miR-141–SIRT1 axis in CRC, and the original observations may reflect experimental or methodological limitations rather than a true biological interaction. A separate study has shown that miR-141 can regulate SIRT1 in cancer cells, influencing proliferation and apoptosis [70]. miR-141 interacts with the SIRT1 protein to regulate the growth and survival of CRC cells. Using a luciferase reporter assay, the study revealed that elevated levels of miR-141 facilitated cellular growth and suppressed apoptosis. Conversely, reduced levels of miR-141 had the opposite impact on cell death and cell proliferation. Furthermore, a reduction in miR-141 levels was associated with increased SIRT1 expression. These results highlight the crucial role of miR-141 in controlling CRC cell growth and survival through interaction with SIRT1. The study suggests that targeting miR-141 may have potential implications for developing new therapies for treating CRC [70]. Importantly, the miR-141/SIRT1 interaction presents potential for targeted therapy. Therapeutically manipulating this axis may sensitize cancer cells to chemotherapy by inhibiting cell proliferation pathways and enhancing apoptosis. For instance, the use of miR-141 mimics or SIRT1-specific inhibitors in combination with conventional therapies might improve clinical outcomes by disrupting oncogenic signaling cascades associated with tumor survival and immune evasion.

CD24 protein is commonly detected in different human cancers, including CRC. The expression of CD24 in CRC is closely linked to the advancement of the disease, and it is utilized as a surface marker to identify the cancer stem cells that are present within the tumor [71]. miR-1185-1 plays a critical role in regulating the progression of CSCs in CRC. Research has shown that miR-1185-1 and SIRT1 have contrasting impacts on the formation of CSCs in CRC, such that SIRT1 decreases the levels of miR-1185-1, leading to an elevation in CD24 expression and augmentation in CSCs [72]. JNK, a member of the MAPK (mitogen-activated protein kinase) family, controls cell growth, apoptosis, and differentiation during cellular stress. Reactive Oxygen Species (ROS) are oxygen-containing molecules that aid cell signaling and stability. However, excess ROS leads to oxidative stress, activating JNK and causing cellular damage and diseases like neoplasia [73]. miR-29b overcomes oxaliplatin resistance in CRC by targeting the SIRT1/ROS/JNK pathway. In-vitro experiments using OR-SW480 cells treated with oxaliplatin showed that overexpression of miR-29b decreased the upregulation of SIRT1. This reduction led to an increase in ROS production and JNK phosphorylation, ultimately resulting in the activation of caspase 3, 7, and 9 and promoting apoptosis [74].

In 2018, Luo and colleagues used miR-34a agomir to treat xenograft tumors generated from in-vitro experiments. Agomir is a chemically modified, double-stranded RNA molecule that mimics the function of endogenous miRNAs. It is used to increase the expression of specific miRNAs in cells and tissues. The study showed that a specific lncRNA called NEAT1 acts as a ceRNA and regulates the expression of miRNA-34a. This regulation represses the miR-34a/SIRT1 axis and activates the Wnt/β-catenin signaling pathway. Nonetheless, treatment with miR-34a agomir decreased the levels of SIRT1 and members of the Wnt/β-catenin signaling pathway, inhibiting tumor growth [75, 76].

Paclitaxel is a chemotherapy medication that is generally used to treat several types of neoplasms, including CRC. It works by preventing the growth and division of cancer cells, ultimately leading to their death [77]. miR-34a decreased the mRNA expression of the SIRT1 and BCL2 (involved in regulating apoptosis) genes. However, combining paclitaxel with miR-34a caused a minor alteration in the levels of SIRT1 and Bcl2. In summary, miR-34a regulated SIRT1 expression, while paclitaxel did not significantly affect SIRT1 [78].

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is an anti-tumor cytokine that selectively induces apoptosis in cancer cells by binding to death receptors 5 (DR5), which is known to promote apoptosis and is located on the surface of tumor cells [79]. It was found that miR-128 can directly regulate the expression of SIRT1 in CRC cells. Elevated miR-128 levels in CRC cells result in a decrease in SIRT1 expression and an increase in the production of ROS after being exposed to TRAIL treatment. Notably, this increased ROS production leads to the upregulation of DR5, which enhances TRAIL-induced apoptosis through the SIRT1/ROS/DR5 pathway [80].

FOXD3-AS1 is a lncRNA that promotes colon adenocarcinoma progression. The study observed increased expression of FOXD3-AS1 in both CRC tissues and cells. Subsequent in-vitro experiments illustrated that the knockdown of FOXD3-AS1 resulted in decreased migration, invasion, and cell proliferation. Moreover, it caused cell cycle arrest and enhanced apoptosis in CRC cells. FOXD3-AS1 also functions as a ceRNA by binding to miR-135a-5p and modulating the expression of SIRT1. When the level of FOXD3-AS1 is elevated, it can interact with miR-135a-5p and limit its availability to control SIRT1 expression in CRC cells. Consequently, SIRT1 levels increase due to this interaction, leading to its overexpression in CRC tissues and cells. Therefore, the high expression of FOXD3-AS1 indirectly leads to the upregulation of SIRT1 levels by sequestering miR-135a-5p in CRC [81].

Dysregulation in autophagy is a potential mechanism for chemoresistance, and lncRNA also shows its regulatory role in cancer drug resistance [82]. The research of Wang et al. proposed that a lncRNA called H19 plays a role in promoting resistance to the chemotherapy drug 5-Fluorouracil (5-FU) in CRC cells. H19 achieved this by increasing autophagy through SIRT1. According to the findings, miR-194-5p suppressed the expression of SIRT1 in CRC cells in normal conditions. However, the researchers discovered that the H19 acted as a ceRNA for miR-194-5p, which meant that H19 bound to miR-194-5p instead of SIRT1. This binding interaction prevented miR-194-5p from suppressing SIRT1 expression, which led to increased levels of SIRT1 in CRC cells. Thus, increased levels of SIRT1 expression led to the promotion of autophagy, which played a role in developing resistance to 5-FU treatment in CRC cells [83].

A feedback loop consisting of miR-34a, SIRT1, and p53 is also implicated in the metastasis of CRC. The study’s findings indicated that lncRNA HNF1A-AS1 plays a crucial role in promoting the migration, invasion, and survival of CRC cells both in-vivo and in-vitro. During CRC metastasis, HNF1A-AS1 acted as a ceRNA by binding to miRNA-34a, which reduced its ability to regulate the expression of p53 and SIRT1. This interference disrupted the miR-34a/SIRT1/p53 feedback loop, ultimately suppressing it. Interestingly, the study found that HNF1A-AS1 activates the Wnt signaling pathway, which is also involved in the spread of CRC [84].

Fatty acid oxidation (FAO) is a metabolic process that breaks down fatty acids to generate energy, and ACOX1 is the first rate-limiting enzyme of the fatty acid oxidation pathway found in peroxisomes [85]. ACOX1 is a direct target of miR-15b-5p, and its expression is positively correlated with SIRT1 expression in CRC cells and xenograft models. The research findings indicated that SIRT1 and miR-15b-5p have an opposite relationship, meaning that increased expression of SIRT1 leads to a decrease in the levels of miR-15b-5p within CRC cells. This phenomenon occurs as SIRT1 suppresses the transcription of miR-15b-5p through its deacetylase activity. Overall, the study proposed that the SIRT1/miR-15b-5p/ACOX1 axis is crucial in the metastasis of CRC and could be a hopeful target for improving treatments for metastatic CRC [86].

The growth of tumors is associated with increased expression and activation of the cAMP response element-binding protein (CREB). This suggests that CREB, positioned downstream of multiple growth signaling pathways, has the potential to act as an oncogene in tumor cells [87]. Shen and colleagues found that in CRC cells, miR-199b is involved in regulating the SIRT1/CREB/KISS1 signaling pathway, leading to the activation of CREB/KISS1. The activation of KISS1, a gene that suppresses metastasis and is associated with the prognosis of cancer, through this pathway may have an impact on the spread of CRC. The findings also indicated that miR-199b targets SIRT1 in CRC, and knocking down SIRT1 leads to increased KISS1 expression by promoting CREB acetylation. Therefore, miR-199b could be a potential prognostic marker or a therapeutic target for CRC patients [88, 89]. The research revealed that miR-34a can elevate the sensitivity of SW480 cells to 5-FU treatment by regulating the SIRT1/p53 pathway. miR-34a also affects the expression of several proteins involved in apoptosis, chemotherapy response, and cell proliferation. The results suggest that increasing miR-34a levels can inhibit the invasion and migration of CRC cells by increasing the acetylated-p53 and p21 and decreasing the expression of SIRT1 [90].

Several miRNAs could regulate the expression of SIRT1 in CRC, with miR-34a, miR-222-3p, and miR-132-3p being identified as regulators that can decrease its expression in CRC tissues. The reduced expression of these miRNAs may be linked to the advancement of CRC [91]. The protein E2F3 is associated with drug resistance in DLD-1 cells of human CRC [92]. The study discovered that by increasing the level of miR-34a, the growth of 5-FU-resistant cells was repressed, and their resistance to 5-FU was reduced. This effect was achieved by declining the expression of E2F3 and SIRT1 [93].

Summary and therapeutic implications

Taken together, these studies indicate that SIRT1 is embedded in a dense regulatory network of miRNAs and lncRNAs in CRC, with consequences for proliferation, apoptosis, metabolic adaptation, metastasis, cancer stem cell maintenance, and, particularly, chemotherapy resistance. Many of the described axes converge on clinically relevant drugs such as oxaliplatin, 5-FU, paclitaxel, and TRAIL, suggesting that modulation of specific miRNA–SIRT1 circuits could be exploited to resensitize tumors to treatment or to prevent the emergence of resistant clones. However, most of the available evidence is derived from in vitro systems, xenograft models, or relatively small patient cohorts, and the same miRNA–SIRT1 interaction can participate in multiple pathways, making causal interpretation complex. Some findings also appear context-dependent, with SIRT1 sometimes acting primarily pro-tumorigenic and in other settings contributing to stress responses that may restrain tumor growth. Overall, while the miRNA–SIRT1 axis is a compelling candidate for biomarker development and therapeutic targeting in CRC, larger, well-controlled clinical and translational studies are needed to validate the most robust interactions and to define which patient subsets are most likely to benefit from interventions in these pathways.

Liver cancer

Overview of liver cancer

Liver cancer is the sixth most frequently diagnosed form of neoplasm and ranks as the third leading cause of cancer-related deaths worldwide. In 2020, there were approximately 906,000 new patients with liver cancer and 830,000 deaths attributed to the disease [94]. Hepatocellular carcinoma (HCC) accounts for the majority of primary liver neoplasia cases, and its development involves a mixture of epigenetic alterations and genetic abnormality [95]. HCC is associated with various risk factors such as obesity, viral infection, type 2 diabetes, smoking, alcohol addiction, and fatty liver disease. The most effective curative options for HCC are liver transplantation, surgical resection, and local ablation. However, these treatments demand early detection and a liver that is functioning adequately [96]. HCC is often diagnosed at an advanced stage due to the existence of symptomless pathology in its early stages, despite efforts to improve its detection. Unfortunately, the high rate of recurrence in HCC persists, leading to a poor prognosis even after receiving treatments [97]. Several studies have reported that its initiation, progression, and therapy failure are significantly influenced by various factors, including miRNAs [98]. Herein, we will discuss previous research highlighting the significant involvement of sirtuins in HCC and their relationship with miRNAs as potential biomarkers for diagnosing this type of malignancy [99].

Roles of MiRNAs and SIRT1 in liver cancer

Accumulating evidence indicates that SIRT1 is tightly regulated by a wide range of miRNAs and lncRNAs in HCC and that this regulation influences key malignant traits, including proliferation, apoptosis, metastasis, chemoresistance, radioresistance, metabolic adaptation, stemness, pyroptosis and autophagy. miR-34a, miR-124, miR-138, miR-204-5p, miR-22-3p, miR-29 family members, miR-425, miR-4461, miR-486, miR-148a, miR-601 and others have all been implicated in modulating SIRT1 expression or activity, while multiple lncRNAs (such as MVIH, PP7080, SNHG7, MIAT, MALAT1, SIRT1-AS and others) act as competing endogenous RNAs that fine-tune miRNA–SIRT1 interactions. Through these networks, SIRT1 can either support tumor growth, invasion and therapy resistance or, in specific contexts, contribute to growth inhibition and cell death. Thus, the miRNA–SIRT1 axis represents an important regulatory hub in HCC biology with potential diagnostic and therapeutic relevance.

Mechanisms of miRNA-mediated SIRT1 regulation in liver cancer

Nakano and colleagues found that when miR-4669 is overexpressed in HCC cells, it enhances their migration ability and leads to the development of resistance to sorafenib, a commonly used drug for HCC treatment. This overexpression of miR-4669 is associated with increased levels of SIRT1 protein and MVIH, a lncRNA that is connected to microvascular invasion (MVI) in HCC cells [100]. MVI is a vital factor strongly linked to the metastasis and postoperative recurrence of HCC [101], and MVIH is associated with a predictive value indicating a poor prognosis following hepatectomy [102].

A positive feedback loop involving P53, miR-34a, and SIRT1 contributes to the end of liver regeneration by suppressing cell proliferation and promoting apoptosis. The study results demonstrated that miR-34a exerts a negative control on the expression of SIRT1 by binding to its 3’UTR. This interaction may contribute to the progression of HCC cells by suppressing the activity of the P53/miR-34a/SIRT1 axis [103].

miR-4461 plays a critical role in suppressing the ability of liver CSCs to self-renew and form tumors has also been documented. Moreover, miR-4461 directly targets SIRT1 in liver CSCs, resulting in the reduction of SIRT1 expression. Hence, enhancing the levels of miR-4461 could be a viable therapeutic strategy for both the prevention and intervention of HCC [104].

FOXO3a, a forkhead transcription factor belonging to the FOXO subfamily, is responsible for regulating diverse cellular processes, including DNA damage response, cell cycle progression, apoptosis, and tumorigenesis. In HCC, FOXO3a acts as a significant tumor suppressor, exerting a critical role in inhibiting the growth and advancement of tumors [105]. The underlying mechanisms of sorafenib resistance in HCC were investigated, and it identified approaches to enhance HCC sensitivity to this drug. The study findings demonstrated that miR-124-3p.1 plays a role in the regulation of FOXO3a by negatively targeting AKT2 and SIRT1 proteins, reducing their activity or expression levels. AKT2, a protein kinase B family member, plays a role in regulating apoptosis in cancer cells and is associated with developing drug resistance in various cancers. In summary, these regulatory mechanisms enhance the sensitivity of liver tumor cells to sorafenib treatment, offering a potential novel therapeutic approach for patients with HCC [106, 107].

Rhamnetin, a flavonoid compound, acts as a potent inhibitor of SIRT1. It suppresses the expression of multidrug resistance 1 (mdr-1), a gene downstream of the pregnane X receptor (PXR) pathway. PXR is responsible for mediating sorafenib resistance in HCC. Rhamnetin enhances the transcription of miRNA-148a by suppressing the activation of SIRT1. This reduction leads to an elevation in the acetylation level of residue-373 on the P53 protein, ultimately inhibiting PXR expression. Acetylation at residue-373 of P53 involves adding an acetyl group to the 373rd amino acid residue of the P53 protein. Hence, the treatment with rhamnetin was observed to slow down the metabolic clearance of sorafenib in HCC cells, and this effect was correlated with the expression of miR-148a. Overall, rhamnetin treatment increased the sensitivity of HCC cells to sorafenib, suggesting a potential therapeutic strategy for enhancing the efficacy of sorafenib in HCC treatment [108].

Lipophagy is a specific type of autophagy that selectively targets and breaks down lipids through the autophagic pathway. This process is essential for the tumor’s self-protection and maintenance [109]. In an in-vitro investigation, it was discovered that there is an inverse relationship between the expression of miR-425 and SIRT1. Suppression of miR-425 expression resulted in an upregulation of SIRT1 expression, facilitating the promotion of lipophagy. This induction of lipophagy subsequently led to the inhibition of HCC cell proliferation. As a result, the study proposes that targeting the molecules involved in lipophagy could serve as a novel strategy for managing and treating liver cancer [110].

Furthermore, the luciferase activity assay demonstrated that lncRNA PP7080 functions as a molecular competitor for miR-601 in HCC cells. This interaction leads to the promotion of proliferation, migration, and invasion in the HepG2 cell line. Notably, the expression of lncRNA PP7080 shows a positive correlation with SIRT1 protein levels. Thus, PP7080 upregulates the expression of SIRT1, whereas miR-601 downregulates SIRT1 expression. These findings confirm that miR-601 and PP7080 may have potential diagnostic and therapeutic implications as biomarkers for HCC [111].

Xiang et al. explored the collaborative effect of two miRNAs on the expression of SIRT1 protein in liver cancer. The results demonstrated a significant reduction in SIRT1 protein expression in-vitro upon transfection with miR-124-3p or miR-506-3p mimics. These findings indicate that the miR-124-3p/miR-506-3p-SIRT1 signaling axis could represent a potential therapeutic target for managing HCC [112].

Pyroptosis is a regulated form of cell death that leads to inflammation. It is facilitated by the NLRP3 inflammasome, a component of the NOD-like receptor family, which plays a vital role in activating caspase-1. Activation of caspase-1 triggers the conversion of pro-IL-1β and pro-IL-18 into their active forms [113]. miR-34a has a regulatory role in controlling SIRT1 expression, thereby influencing NLRP3-dependent pyroptosis in HCC cells. Additionally, the investigation demonstrated that the lncRNA SNHG7 acts as a ceRNA for miR-34a, resulting in the upregulation of SIRT1 expression and the inhibition of NLRP3-dependent pyroptosis in in-vitro experiments. Thus, the study provided evidence that the activation of SIRT1 can effectively suppress the cleavage of caspase-1 and the subsequent release of IL-1β caused by the NLRP3 inflammasome. This inhibition of pyroptosis in malignant cells is believed to have a significant role in developing HCC [114].

A type of lncRNA named myocardial infarction-associated transcript (MIAT) appears during HCC cellular senescence, it was found that MIAT functions as a ceRNA that increases the expression of SIRT1 by inhibiting the activity of miR-22-3p. The downregulation of MIAT was shown to hinder the progression of HCC. These findings highlight the role of MIAT as a regulatory molecule in HCC and its potential implications in HCC development by correlation with the miR-22-3p/SIRT1 axis [115].

The impact of miR-34a expression on the growth inhibition of HepG2 cells by DOX has been investigated. The results demonstrated that overexpressing miR-34a can increase the sensitivity of HepG2 cells to DOX treatment. Notably, this increase in sensitivity was positively correlated with the levels of p53 and SIRT1. These findings provide a foundation for potential gene therapy approaches utilizing miR-34a to enhance the chemosensitivity of HepG2 cells to DNA-damaging drugs like DOX [116].

The primary challenges in cancer radiotherapy are the development of resistance to ionizing radiation (IR) and the potential harm to normal cells due to its toxicity [117]. The potential of epigallocatechin gallate (EGCG), a natural antioxidant found in green tea, to enhance the radiosensitivity of mouse hepatoma cells H22 and mitigate the damage caused by IR to normal hepatic cells AML-12. The study revealed that EGCG activates the miR-34a/SIRT1/p53 signaling pathway, resulting in the downregulation of SIRT1, a target gene of miR-34a. This activation of the pathway by EGCG was associated with increased radiosensitivity. Additionally, EGCG was found to downregulate the expression of Bcl-2 and upregulate the expression of Bax and Caspase-3 in H22 cells, further contributing to radiosensitization. These findings highlight the potential of EGCG as a radiosensitizer through its modulation of the miR-34a/SIRT1/p53 signaling pathway and apoptotic protein expression [118].

CD133 is a specific protein on the surface of CSCs and plays a crucial role in their MDR capability [119]. It was observed that CD133 + HCC cells display a notable resistance to cisplatin compared to CD133- HCC cells. The study revealed that the overexpression of miR-124 resulted in inhibiting SIRT1 expression. This, in turn, led to the generation of ROS and the activation of Jun N-terminal kinase (JNK) phosphorylation, a protein that plays a role in cellular responses like apoptosis. As a result, the apoptosis process was amplified in CD133 + HCC cells when treated with cisplatin. Therefore, targeting the miR-124/SIRT1/ROS/JNK pathway could potentially be a valuable approach to decrease cisplatin resistance in CD133 + HCC cells [120].

A separate scientific study observed that SIRT1 played a critical role in supporting the self-renewal abilities of liver CSCs and promoting tumor development in-vivo. Conversely, miR-486 was identified as a direct regulator that targeted the 3’UTR of SIRT1mRNA, effectively suppressing its expression. Based on the obtained results, the overexpression of miR-486 significantly suppresses the self-renewal and invasion capacities of liver CSCs in laboratory experiments. Moreover, it also demonstrated an inhibitory influence on tumor formation in-vivo. Therefore, targeting miR-486 shows potential as a therapeutic strategy for HCC treatment by modulating the expression of SIRT1 [121].

Xia and colleagues conducted a study where they introduced a newly discovered DNA-damaging compound referred to as 0404. The purpose was to investigate its potential application in HCC treatment. The researchers found that 0404 operated through a positive feedback loop involving the p53/miR-34a/SIRT1 pathway to induce cell apoptosis at a nanomolar concentration. The objective of this compound is to impede the growth of liver cancer cells by primarily influencing the p53-associated pathway. The study findings revealed that the responsiveness of HCC cells to the 0404 compound was significantly enhanced by upregulating miR-34a. Consequently, this led to a decrease in SIRT1 protein levels due to miR-34a-mediated modulation. Therefore, the interaction between SIRT1 and miR-34 plays a significant role in mediating the anti-cancer effects of 0404 in liver neoplasm [122].

Butyrate is a short-chain fatty acid generated by the gut microbiota through the anaerobic fermentation process of dietary fibers. Scientists have demonstrated that butyrate possesses the ability to impede the advancement of tumors by inhibiting histone deacetylase activity. Moreover, it can induce apoptosis in cancer cells [123]. In a study focusing on butyrate-mediated apoptosis in HCC cells, the involvement of ROS was found to be crucial. The findings demonstrated that butyrate treatment led to the release of miR-22, a miRNA that has the ability to down-regulate the expression of SIRT1. SIRT1 is a protein known for its protective function against cell ROS damage. The down-regulation of SIRT1 caused an accumulation of ROS within the cells, ultimately initiating apoptosis in HCC cells [124].

In a study examining HCC metastasis, the role of miR-34 was investigated in an in-vitro situation. The results indicated that miR-34 substantially inhibited the invasion and migration of human Hep3B and Huh7 tumor cells. The reduction in cell numbers was directly associated with the overexpression of miR-34, which resulted in the suppression of SIRT1 mRNA and protein levels in the tumor cells. These findings support the idea that miR-34a holds promise as a potential target for diagnosing and treating HCC metastasis [125].

In a study conducted by Luo et al., the role of miR-138 as a tumor suppressor in HCC was investigated. In this report, miR-138 exhibited tumor-suppressive effects by inhibiting cell migration and proliferation in HCC. The expression analysis using real-time PCR and western blot assays demonstrated a downregulation of miR-138 expression, while SIRT1 mRNA expression was found to be upregulated in HCC cells in-vitro. These results suggest that miR-138 plays a crucial role in suppressing tumor progression in HCC by modulating the expression of SIRT1. As a result, the pivotal role of miR-138 in regulating the progression of HCC through its targeting of SIRT1 has been established. Thus, miR-138 holds significant promise as a potential therapeutic target for the clinical management of HCC in the future [126].

How a specific lncRNA named metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) contributes to the invasion and migration of HCC by interacting with the miR-204/SIRT1 axis has been examined. The study findings revealed that MALAT1 competes with miR-204 for binding, alleviating miR-204’s suppressive effect on SIRT1. Consequently, this suppression release leads to the promotion of HCC metastasis in HepG2 cells. Overall, the study highlights the role of MALAT1 in modulating HCC metastasis by modulating the miR-204/SIRT1 axis through competitive binding [127].

The regulatory mechanisms involving Glypican-3 (GPC3) in controlling cell proliferation, invasion, and apoptosis through the miR-133b/SIRT1/GPC3/Wnt β-catenin axis have also been investigated. GPC3 is a cell surface protein known for regulating differentiation and cell growth. The study demonstrated that when miR-133b is overexpressed or SIRT1 is downregulated, the expression of GPC3 is suppressed. Accordingly, the inhibition of GPC3 results in increased levels of anti-apoptotic proteins such as Bcl-2, Bcl-xL, and Mcl-1, while the expression of E-cadherin is reduced. This molecular cascade ultimately leads to enhanced apoptosis.

In summary, the research findings emphasize the significance of the miR-133b/SIRT1/GPC3/Wnt β-catenin axis in modulating apoptosis and metastasis, with GPC3 playing a crucial role in this regulatory pathway. Moreover, the study’s findings demonstrated that the increase in SIRT1 expression led to elevated levels of β-catenin, a transcription factor critical for growth and cell survival. This increase in SIRT1 facilitated the cytosolic accumulation of β-catenin and promoted its translocation into the nucleus [128, 129].

That SIRT1 is a direct and functional target of miR-204-5p in HCC cells, and their expression levels are inversely related has been documented. The overexpression of miR-204-5p in human HCC cell lines resulted in cell survival suppression, increased drug sensitivity, and amplified apoptosis, primarily through the modulation of SIRT1 levels. Hence, the study proposed that targeting miR-204-5p could have therapeutic potential for managing HCC [130].

The involvement of natural antisense transcripts (NATs) in the progression of human cancers has been observed [131]. A study was carried out to explore the influence of SIRT1-AS on the regulation of miR-29, which typically acts as a suppressor of SIRT1 protein production. The study aimed to understand how SIRT1- antisense, an antisense molecule, affects this regulatory process Antisense, which describes the DNA or RNA strand with a sequence that is opposite or complementary to the sense strand. The study’s findings indicated that SIRT1-AS functions as a protective barrier, shielding the binding site of miR-29 on the 3’UTR of SIRT1 mRNA. Consequently, this interference increases SIRT1 protein levels, ultimately resulting in the proliferation of cells in HCC [132].

That HCC cell growth is suppressed by inhibiting SIRT1 through the overexpression of miR-29 was thoroughly studied. The results showed that decreased levels of SIRT1 impacted the activation of pRb, a crucial cell cycle protein, leading to a reduction in its phosphorylation and subsequent inactivation. As a result, the proteins DP1 and E2F, responsible for activating genes involved in cell cycle progression, were deactivated. Overall, the study suggested that miR-29c acts as a tumor suppressor by counteracting the excessive activity of SIRT1 in liver neoplasia [133].

The efficient delivery of miRNAs into different cancer cell types using adenoviral vectors has been reported. This delivery approach exhibited antitumor efficacy through various mechanisms, such as inhibiting cell proliferation and promoting apoptosis [134, 135]. Also, tumor xenografts in nude mice and liver cancer cells were utilized to investigate the therapeutic potential of AdCN205. AdCN205 is an oncolytic adenoviral vector developed for the treatment of HCC. It works by co-expressing IL-24 and miRNA-34, which are recognized as tumor restrainers. This vector is designed to target HCC cells using the adenovirus endogenous E3 promoter specifically. Within the adenovirus genome, the E3 region encompasses genes that encode proteins involved in evading the immune response and altering the functions of host cells. In both in-vitro and in-vivo, it has been shown that introducing miR-34 through AdCN205-miR-34a infection leads to a decrease in the levels of SIRT1 and Bcl-2 proteins. This reduction in SIRT1, facilitated by miRNA-34, contributes to inhibiting tumor growth and promoting apoptosis in liver neoplasm [136].

Summary and therapeutic implications

Overall, these studies show that SIRT1 operates within a complex network of miRNAs, lncRNAs, and NATs in HCC, affecting processes like proliferation, apoptosis, metastasis, metabolic adaptation, cancer stem cell maintenance, pyroptosis, lipophagy, and resistance to treatments such as sorafenib, cisplatin, doxorubicin, and radiotherapy. Many of these pathways converge on key clinical targets like p53, Wnt/β-catenin, ROS/JNK, NLRP3 inflammasomes, and PXR-driven drug metabolism, emphasizing SIRT1’s central role in balancing stress responses and survival signals in liver cancer. However, most evidence comes from in vitro and xenograft studies with small sample sizes, and SIRT1’s function varies depending on the context, showing both tumor-promoting and tumor-suppressing effects based on the upstream miRNA/lncRNA environment and experimental setup. These limitations hinder direct application to patients and highlight the need for larger translational and clinical research to confirm the key miRNA–SIRT1 circuits. Despite these challenges, the existing data suggest that targeting miRNAs, their lncRNA partners, or SIRT1 through drugs or genetic approaches could offer promising strategies for diagnosis, overcoming drug resistance, and customizing combination therapies in HCC.

Pancreatic cancer

Overview of pancreatic cancer

Pancreatic cancer (PC) is a malignancy that manifests frequently and is distinguished by a notable fatality rate and comparatively brief periods of survival. PC symptoms are not clearly distinctive, leading to late-stage diagnosis in clinical situations where conventional treatments like chemotherapy are ineffective [137]. Although there has been some progress since the 1950 s, the survival rate for PC patients after five years has enhanced modestly, moving from 1% to 7.5%. Nevertheless, this still indicates a challenging and unpromising outlook for individuals affected by this malignancy [138]. Hence, detecting PC at an early stage is crucial for effective management. However, current diagnostic and prognostic markers lack specificity. Therefore, incorporating miRNAs as new biomarkers could provide a non-invasive approach to diagnosing PC more accurately [139]. On the other hand, miRNAs play a dual role in PC, which can promote or suppress tumor growth depending on their interactions with different molecular pathways [140].

Roles of MiRNAs and SIRT1 in pancreatic cancer

Several studies have shown that SIRT1 is a central effector regulated by different miRNAs and ncRNAs in PC. Depending on the upstream regulator and cellular context, SIRT1 can contribute to chemoresistance, EMT, hypoxia adaptation and survival, or it can be suppressed to promote apoptosis, inhibit autophagy and impair tumor growth. miR-30b-5p, miR-23b-3p, miR-373, miR-138-5p, miR-601, miR-494, miR-217 and miR-34/34a, among others, either directly target SIRT1 or are controlled through ceRNA networks involving lncRNAs and circRNAs. These interactions link SIRT1 to pyroptosis, exosome-mediated drug resistance, EMT, oxidative stress signalling and cancer stem-like properties in PC, highlighting the importance of the miRNA–SIRT1 axis as a regulatory hub and potential biomarker source.

Mechanisms of miRNA-mediated SIRT1 regulation in pancreatic cancer

A recent 2023 study revealed that LINC01133, a lncRNA associated with pyroptosis, is highly expressed in pancreatic adenocarcinoma (PAAD) tissues. This increased expression of LINC01133 is correlated with a poor prognosis for PAAD patients. According to the results, LINC01133 acts as a ceRNA for miR-30b-5p. This interaction prevents miR-30b-5p from binding to SIRT1 mRNA, a gene that inhibits pyroptosis in PAAD. Consequently, LINC01133 prevents the activity of miR-30b-5p, resulting in the inhibition of pyroptosis. Overall, the correlation between the miR-30/SIRT1 axis and LINC01133 could potentially contribute to the development of PAAD [141].

Cells secrete extracellular vesicles (EVs), tiny membrane-bound structures, into the space outside the cell. These vesicles play a crucial role in facilitating communication between cells. EVs transport a diverse range of substances, such as proteins, lipids, and nucleic acids, from one cell to another, enabling the exchange of information and materials between cells. EVs can be classified into various categories according to their dimensions and structural characteristics, including microvesicles, apoptotic bodies, and exosomes [142]. Investigations have shown that PC cells become resistant to chemotherapy when they are in a low-oxygen environment (hypoxia). Furthermore, scientists have discovered that the resistance is associated with exosomes released by hypoxic PC cells [143]. Exosomes containing circZNF91 show a remarkable increase when released in hypoxia compared to when released in normal situations. When cirZNF91 is increased, it encourages chemotherapy resistance in PC cells. Conversely, decreasing its levels counteracts the resistance caused by hypoxic exosomes. Hinged on the results, this circRNA acts as a competitor to miR-23b-3p. As a result, it causes an increase in the expression of the deacetylase enzyme SIRT1. Additionally, it leads to the stabilization of the HIF-1α protein, which is vital for cancer cells to adapt to hypoxia conditions. Also, in low oxygen conditions, HIF-1α regulates the increased presence of circZNF91 in exosomes. Additionally, in experiments involving xenograft models, it was observed that hypoxic exosomes contribute to chemoresistance. However, this chemoresistance can be reversed by either depleting circZNF91 or increasing the levels of miR-23b-3p [144].

The function and process of miR-373 in the apoptosis and proliferation of PC cells through the modulation of SIRT1 were recently studied. Using RT-qPCR and western blotting analysis, the authors demonstrated that the heightened expression of miR-373 or the partial depletion of SIRT1 resulted in decreased cell proliferation and increased apoptosis within the PC cells. These effects were attributed to the accumulation of cleaved caspases-3/8/9 and BAX, which have been shown to induce cell death. It was also discovered that the PGC-1α/NRF2 pathway, responsible for oxidative stress regulation and cellular metabolism, was suppressed, resulting in amplified levels of ROS in the PC cells. Moreover, the downregulation of the anti-apoptotic protein BCL-2 and PARP, which exert a cytoprotective effect by preventing apoptosis, was observed. In summary, the study revealed that miR-373 suppresses SIRT1, increasing apoptosis and decreasing cell proliferation in PC cells. This research suggests that targeting miR-373 could be a promising strategy for managing this type of neoplasia [145].

The role of miR- 138-5p in inhibiting autophagy within PC cells by binding to SIRT1, which regulates autophagy through the FoxO1/Rab7 axis, has been explored. The findings of this in-vivo experiment demonstrated that when miR-138-5p levels were increased, there was a subsequent reduction in the expression of FoxO1 and Rab7 and a decrease in tumor growth. Hence, miR-138-5p holds promise as a potential candidate for future therapeutic strategies aimed at targeting autophagy in PC [146].

That miR-601 expression was notably decreased in PC samples, particularly in those with metastasis, compared to non-metastatic PC tissues is apparent. It was observed that miR-601 acts by inhibiting SIRT1 through the mitigation of EMT and AKT pathways. Consequently, this inhibition decreases the invasion, migration, and proliferation of PC cells. Overall, both SIRT1 and miR-601 have the ability to function as biomarkers that can assist in the early identification and treatment of PC [147].

Small interfering RNA, or SIRNA, is an RNA molecule involved in regulating gene expression. It is used in the laboratory to suppress the expression of certain genes in cells. SiRNA operates by attaching to the mRNA of a targeted gene, creating its degradation and then decreasing protein expression [148]. Liu and their colleagues conducted a study where they employed a co-transfection technique involving c-Myc-RNAi and SIRT1-RNAi to mimic the impression of miR-494 overexpression on the levels of SIRT1 and c-Myc in PC cells. C-Myc is a proto-oncogene that can potentially cause cancer. It produces a transcription factor that affects multiple cellular activities, including the metastatic capabilities of cancer cells. Based on the findings of the research, when co-transfection was performed, it led to a reduction in the levels of SIRT1 and c-Myc expression. This, in turn, resulted in inhibiting migration, invasion, and proliferation of PC cells. Additionally, the research indicated that decreased levels of miR-494 expression were strongly associated with factors such as lymphatic invasion, larger tumor size, and unfavorable prognosis. Therefore, miR-494 could potentially function as a prognostic biomarker in PC by directly modulating the interplay between c-Myc and SIRT1 [149].

In another study, a research investigation regarding the influence of the miR-217/SIRT1 axis on EMT in chronic pancreatitis and pancreas malignancy, it was found that miR-217 displayed a reverse association with its specific target SIRT1. Moreover, the study discovered that increased levels of TGF-β1, a cytokine associated with inflammation, result in the dysregulation of the miR-217/SIRT1 axis and facilitate the progression of EMT. This mechanism probably contributed to the PC progress in-vitro. Overall, miR-217 shows promise as a new diagnostic tool and therapeutic target for preventing and treating PC [150].

The potential tumor-suppressive properties of miR-34 in PC therapy are of major interest. A nanovector system comprising lipid-based nanoparticles to deliver miRNA expression vectors specifically to cancer cells has been developed. Using this technique, the results of the study demonstrated that administering the miRNA nano vectors intravenously had an inhibitory effect on the growth of pancreas tumor xenografts, whether they were located subcutaneously or orthotopically. Furthermore, by elevating the expression of miR-34, the functionality of p53 can be restored through SIRT1 suppression, leading to an increase in active p53 levels. As a result, the proliferation of pancreatic tumors is decreased, and apoptosis is promoted. Hence, this study shows that the use of nano vectors to deliver miR-34 systemically could be a promising method for treating PC [151].

Exploring the impact of miR-34a regulation in PC development by utilizing chromatin modulators, specifically the histone deacetylase (HDAC) inhibitor Vorinostat (SAHA) and the demethylating agent 5-Aza-29-deoxycytidine (5-Aza-dC) is of interest. When performed, the study’s findings indicated that by using 5-Aza-dC and SAHA, the expression of miR-34a can be restored in pancreatic CSCs. This miR-34a upregulation effectively decreases SIRT1 expression and impedes cell proliferation, ultimately leading to CSCs apoptosis. SAHA prevents the HDAC enzyme action that is in charge of eliminating acetyl groups from histone proteins. This action results in alterations in chromatin structure and gene expression. Also, 5-AAO (5a-dC) is a nucleoside analog of cytidine. During replication, 5-AAO binds to DNA and blocks DNA methyltransferase, resulting in DNA hypomethylation. The increased acetylation of p53 resulting from the expression of miR-34a also supports the regulation of SIRT1 mRNA. Overall, the findings of this study demonstrate the crucial role of miR-34a in regulating PC development and propose that its amplified expression could serve as a promising therapeutic procedure in treating pancreatic tumors [152].

Summary and therapeutic implications

Collectively, these studies show that SIRT1 acts as a major regulator of various cancer-promoting and stress-response pathways in pancreatic cancer, influenced by diverse miRNAs and ncRNAs depending on the context. Upstream factors like LINC01133, circZNF91, miR-373, miR-138-5p, miR-601, miR-494, miR-217, and miR-34/34a connect SIRT1 to processes such as pyroptosis, exosome-driven hypoxic chemoresistance, EMT, apoptosis, autophagy, oxidative stress, and cancer stem cell survival. Many of these pathways overlap on key clinical issues like drug resistance, hypoxia adaptation, and CSC maintenance, indicating that targeting miRNA–SIRT1 interactions or their lncRNA/circRNA regulators could improve therapy or help detect the disease earlier. However, most current data come from in vitro experiments, xenograft models, and small patient samples, and SIRT1’s dual roles, promoting survival in some cases and inhibiting growth in others, make clinical application complex. Additionally, many of these pathways are highly interconnected, complicating efforts to attribute specific effects to individual miRNAs or SIRT1-dependent events. Despite these challenges, evidence supports the miRNA–SIRT1 network as a promising source of biomarkers and potential targets to treat pancreatic cancer, especially for overcoming drug resistance, disrupting hypoxia-driven survival mechanisms, and eliminating pancreatic cancer stem cells.

Other sirtuins (SIRT2–SIRT7) in Gastrointestinal cancers

While the primary focus of this review is on SIRT1, other members of the Sirtuin family, such as SIRT7, also contribute significantly to gastrointestinal cancers. SIRT7, similar to SIRT1, is implicated in regulating tumor progression through interactions with microRNAs and epigenetic modulation. In HCC, SIRT7 can either synergize with or antagonize SIRT1 pathways, thus influencing key processes like cell proliferation, apoptosis, and therapeutic resistance. Understanding the relationship between SIRT1 and SIRT7 may therefore enhance the development of targeted therapies and improve prognostic assessments in gastrointestinal malignancies. In the previous sections, we explored how miRNAs and SIRT1 are associated with GI neoplasia. These molecules have shown potential as diagnostic biomarkers and targets for GI management through various mechanisms. Additionally, how miRNAs can influence other members of the Sirtuins family in GI cancer has also been investigated (Fig. 2) [153]. In this part, we will take a closer look at these investigations to better understand their implications. Table 2 summarizes the interactions between Sirtuins family and miRNAs and how these interactions contribute to GI cancers.

Fig. 2.

Various miRNAs can interact with SIRTUIN molecules apart from SIRT1 (SIRT2-SIRT7) to either help or inhibit GI cancers. The correlation between the expression levels of these molecules may be either direct or inverse in GI neoplasia, as illustrated in this model. oncomiRNA: oncogenic microRNA

Table 2.

MicroRNAs and other sirtuins (SIRT2-SIRT7): the mechanisms involved in the modulation of GI cancer development

Cancer	MicroRNAs	SIRTUINS	Mechanism(s)	Outcome(s)	Evidence Type	Ref.
Esophageal Cancer	↑ miR-144-3p	↑ SIRT7	↓ ZEB1, ZEB2 ↑ E-cadherin	Decreased EMT, Proliferation, Migration, and Invasion	Clinical samples, in vitro	[181]
	↑ miR-424-5p	↓ SIRT4	NA	Increased Migration and Proliferation Decreased Tumor Growth	In vitro	[163]
Gastric Cancer	↑ miR-138	↓ SIRT2	NA	Increased Apoptosis Decreased Proliferation	Clinical samples, in vitro	[154]
	↑ miR-421	↓ SIRT3	↑ Notch-1	Increased Proliferation and Invasion Decreased Apoptosis	Clinical samples, in vitro	[157]
	↑ miR-34-a	↓ SIRT7	↓ Bcl-2, Mcl-1 ↑ Caspase-3, Bax, PARP	Increased Apoptosis Decreased Proliferation, Metastasis, and Colony Formation Decreased Tumor Growth	Clinical samples, in vitro	[182]
Colorectal Cancer	↑ miR-15a-5p	↓ SIRT4	↑ STAT3/TWIST1 Axis ↓ PTEN/AKT ↓ PARP, Bax ↑ Bcl-2	Increased Migration, Invasion, and Proliferation Decreased Chemosensitization	In vitro	[164]
	↑ miR-212-5p	↓ SIRT2	↑ Cyclin D1, MMP-2, MMP-9 ↓ Caspase-3	Increased Proliferation, Migration, and Invasion Increased Tumor Growth Decreased Apoptosis Decreased Cell Cycle Arrest	Clinical samples, in vitro	[155]
	↑ miR-25	↓ SIRT6	↑ Lin28b/NRP-1 Axis	Increased Metastasis and CRC Progression	Clinical samples, in vitro	[174]
	↑ miR-34c-5p	↓ SIRT6	↑ JAK2/STAT3 Axis	Increased Proliferation Decreased Apoptosis	Clinical samples, in silico	[176]
Liver Cancer	↑ miR-375	↓ SIRT5	↑ LC3-ll/LC3-l ↓ P62	Decreased Drug Resistance Decreased Autophagy	in vitro	[167]
	↑ miR-656-3p	↓ SIRT5	NA	Decreased Proliferation, Migration, and Invasion	in vitro	[169]
	↑ miR-3677-3p	↓ SIRT5	NA	Increased Migration, Invasion, and Proliferation Increased Tumor Growth	Clinical samples	[170]
	↑ miR-494	↓ SIRT3	↑ SMAD3, α-SMA ↓ TGF-β	Increased EndMT, Proliferation, and Migration	Clinical samples	[158]
	↑ miR-3666	↓ SIRT7	↑ Caspase-3, P53, P21	Increased Apoptosis Decreased Colony Formation and HCC cell Growth	Clinical samples, in vitro	[183]
	↑ miR-125b	↓ SIRT6	↑ Bax, P16, Caspase-3	Increased Apoptosis Increased Senescence Decreased Migration and Invasion	Clinical samples, in vitro	[177]
	↑ miR-299-3p	↓ SIRT5	NA	Decreased Proliferation, Migration, and Invasion	Clinical samples, in vitro	[173]
	↑ miR-21-5p	↓ SIRT7	↑ USP24 ↑ LC3-ll/l, Beclin 1 ↓ P62 ↓ E-cadherin ↑ N-cadherin, Vimentin, Fibronectin	Increased Drug Resistance Increased EMT, Proliferation, and Migration Increased Autophagy Decreased Ubiquitination Decreased Apoptosis	Clinical samples, in vitro	[192]
	↓ miR-125a	↑ SIRT7	NA	Increased HCC Progression	Clinical samples	[187]
	↑ miR-526b	↓ SIRT7	↓ ERK ↓ Cyclin D1, c-Myc, c-Jun ↓ Vimentin, Snail, Slug ↑ E-cadherin	Decreased EMT, Migration, Invasion, and Proliferation Decreased Tumor Growth	Clinical samples, in vitro	[188]
	↑ miR-122	↓ SIRT6	↓ HADH, CPT1	Decreased Fatty Acid β-Oxidation	In vivo	[180]
	↑ miR-125b	↓ SIRT7	NA	Decreased Proliferation	Clinical samples, in vitro	[189]
	↑ miR-125a-5p/ ↑ miR-125b	↓ SIRT7	↑ P21, Beclin ↓ Cyclin D1	Increased Cell Cycle Arrest Decreased Tumor Growth	In vitro	[190]
Pancreatic Cancer	↓ miR-421	↑ SIRT3	↓ HIF-1α	Decreased Proliferation, Invasion, and Migration Decreased Glycolysis	Clinical samples, in vitro	[160]
	↓ miR-708-5p	↑ SIRT3	NA	Decreased Proliferation, Invasion, and Metastasis	Clinical samples, in vitro	[162]

α-SMA: Alpha smooth muscle actin; AKT: Protein kinase B; EMT: Epithelial–mesenchymal transition; EndMT: Endothelial-to-mesenchymal transition; ERK: Extracellular signal-regulated kinase; HADH: Hydroxyacyl-CoA dehydrogenase; HCC: Hepatocellular carcinoma; HIF-1α: Hypoxia-inducible factor 1-alpha; JAK2: Janus kinase 2; LC3-I/II: Microtubule-associated protein 1 light chain 3; miR: MicroRNA; MMP-2/9: Matrix metallopeptidases 2/9; NRP-1: Neuropilin-1; PARP: Poly (ADP-ribose) polymerase; P62: Sequestosome 1; PTEN: Phosphatase and tensin homolog; SIRT2–SIRT7: Sirtuin family members 2 to 7; SMAD3: Mothers against decapentaplegic homolog 3; STAT3: Signal transducer and activator of transcription 3; TGF-β: Transforming growth factor beta; TWIST1: Twist-related transcription factor 1; USP24: Ubiquitin-specific peptidase 24. ↑: Upregulation, ↓: Downregulation

SIRT2

Wang and their team conducted a study to investigate the function of miR-138 in GC as a potential anti-tumor molecule. The study found that a particular lncRNA known as LINC00152 has a reverse impact on the expression of miR-138. This interaction is important because miR-138 is known to control the SIRT2 activity, which plays a role in the progression of GC. In summary, the in-vitro outcomes demonstrated that when miR-138 is overexpressed, it substantially reduces the levels of SIRT2. This reduction in SIRT2 expression leads to apoptosis induction in GC cells, such as MKN45 and HGC27 cells [154].

How miR- 212-5p might play a part in the progression of CRC has been the subject of one report. miR-212-5p acts as a regulator of SIRT2 in CRC by explicitly targeting its 3’UTR. Also, SIRT2 has been shown in both in-vivo and in-vitro experiments to suppress the metastasis and proliferation of CRC cells effectively. The results obtained from the western blot technique indicate that when SIRT2 is excessively expressed, it inhibits migration, invasion, and colony formation in CRC cells. Conversely, these processes are heightened when SIRT2 is reduced through the use of miR-212-5p mimics. In summary, miR-212-5p exhibits potential as a probable therapeutic objective and prognostic biomarker in CRC [155].

SIRT3

Notch-1 is an essential element of the Notch signaling pathway, which plays a role in numerous cellular functions such as development, differentiation, and the formation of tumors. The involvement of the Notch-1 is associated with the advancement and spread of this neoplasia in GC [156]. The results of one study illustrated that a lncRNA known as fetal-lethal non-coding developmental regulatory RNA (FENDRR) exhibited a decline in the levels of invasion and proliferation of GC cells. FENDRR controls miR-421 interaction with SIRT3. The findings showed that FENDRR stops the expression of miR-421, increasing SIRT3 expression. Additionally, the study revealed that if SIRT3 is overexpressed, it can suppress the expression of Notch-1 protein. This, in turn, reduces the metastasis ability of GC cells [157].

Examining how miR-494 impacts the process of HCC metastasis by inducing EMT is of interest. The study also involved evaluating the expression of SIRT3 and numerous markers associated with mesenchymal cells. According to the findings, miR-494 caused a decrease in the SIRT3 expression, leading to the activation of the TGF-β/SMAD signaling pathway. This activation was verified by the increased levels of certain markers associated with mesenchymal cells, including p-SMAD 3, SMAD 3, and a-SMA. It is important to note that TGF-β is a cytokine known for its ability to stimulate SMAD proteins. These proteins act as transcription factors, regulating gene expression and playing a vital role in cellular processes and cancer progression. Overall, blocking miR-494, which affects the SIRT3/TGF-β/SMAD pathway, can be a practical approach for the HCC treatment [158].

Zhou and colleagues investigated the impact of exosomal miR-421, released by cancer-associated fibroblasts (CAFs), on the development of PC both in in-vitro and in-vivo. CAF cells, which can be found in the tumor microenvironment of different cancers like PC, possess a dual role. They both hinder and facilitate tumor invasion, migration, and proliferation. They achieve this by transferring specific miRNAs via exosomes to neighboring cells. Hinged on the study results, when researchers prevented the release of exosomal miR-421 by CAFs, they observed elevated SIRT3 levels in PC cells. This SIRT3 overexpression was confirmed through the analysis of western blotting and qPCR data. Moreover, there was a decline in the HIF-1α levels expression, which SIRT3 facilitated. This process involved a decrease in H3K9Ac, an essential modulator of histones that has the ability to enhance gene expression and contribute to the regulation of transcriptional processes and DNA repair. Hence, SIRT3 plays a significant role in PC metastasis, and its activity is influenced by miR-421 [159, 160].

Although the role of miR-708 has been extensively studied in different types of neoplasia, its exact function in pancreatic ductal adenocarcinoma (PDAC) remains unclear [161]. One report examined how miR-708 affects various aspects of PDAC progression, such as invasion, migration, and cell proliferation. At first, through techniques like luciferase reporter assay, RT-qPCR, and western blotting, the scientists identified SIRT3 as a specific gene regulated by miR-708. Besides, the laboratory information indicated that when miR-708 mimics were added to tumor cells, it caused a decrease in the levels of SIRT3, which in turn promoted the progress of PDAC. Therefore, it can be concluded that miR-708 has the potential to function as a PDAC biomarker and play a significant role in the poor outcome and progression of this type of malignancy [162].

SIRT4

Additional research examined the impact of miR-424-5p on the progression of ESCC. The findings revealed that higher levels of miR-424-5p significantly promote the in-vitro migration, proliferation, and invasion of ESCC cells. Based on laboratory methods involving western blot analysis, qRT-PCR, and dual luciferase reporter assay, it was determined that miR-424-5p exerts its properties in ESCC by SIRT4 targeting. miR-424-5p functioned by downregulating the levels of SIRT4, thereby exerting a negative regulatory influence on its expression. Also, when SIRT4 levels are increased, it counteracts the elevating effect of miR-424-5p on the ability of ESCC cells to metastasis. Hence, identifying miR-424-5p as a biomarker could be helpful for ESCC early detection, and developing interventions that specifically impact the miR-424-5p/SIRT4 pathway could offer an innovative means of treating esophageal neoplasms [163].

Deng et al. published data in which miR-15 a-5p was shown to play a role in the progression of CRC via SIRT4 targeting. The study revealed that miR-15a-5p functions in the SIRT4 downregulation and inhibits its expression in CRC cells. This situation leads to increased invasion, migration, and cell proliferation by influencing numerous signaling pathways. Based on the results, when miR-15a-5p is blocked, it allows SIRT4 to increase, preventing the activation of the STAT3/TWIST1 pathway. This pathway consists of two transcription factors that play a role in controlling the metastasis of cancer cells. TWIST1 is subject to regulation by the activation of STAT3, a transcription factor that acts upstream.

SIRT4 exerts a positive regulatory influence on PTEN, which serves as a negative modulator of AKT, a part of the PI3K pathway, and becomes activated through phosphorylation. AKT activation is critical for the cancer cells’ growth and viability. When miR-15a-5p is excessively expressed, it hinders the production of SIRT4, decreasing PTEN levels and stimulating AKT activity. Thus, miR-15a-5p has a significant impact on CRC progression by collaborating with SIRT4 and two signaling pathways known as PTEN/AKT and STAT3/TWIST1. This study highlights the potential of targeting miR-15a-5p as a hopeful strategy for CRC treatment [164–166].

SIRT5

Explorations of the effects of miR-375 on the development of resistance to sorafenib in HCC cells are ongoing. In an in-vitro experiments, it was observed that miR-375 decreases the levels of the SIRT5 protein, leading to repressed autophagy and amplified apoptosis in HCC cells. The regulation of autophagy markers, including LC3II, LC3I, and p62, is under the control of miR-375. Hence, by manipulating the levels of miR-375, there is a potential for the development of innovative therapeutic approaches targeting HCC patients who have poor responses to sorafenib [167].

SNHG14, a lncRNA, has been discovered to play a significant role in advancing various types of tumors by affecting mechanisms such as cell migration, invasion, differentiation, and proliferation [168]. It has been observed that SNHG14 acted as a ceRNA in HCC cells, specifically MHCC97H and HepG2. Its role involved competing with miR-656-3p to bind to SIRT5 mRNA, influencing its function. Therefore, when miR-656-3p is decreased, it has been detected that there is an increase in the expression of SIRT5, leading to the HCC advancement and metastasis [169].

Yao and colleagues performed a study to investigate the function of a newly discovered miRNA named miR-3677-3p in HCC cells when exposed to a hypoxic condition. The outcomes of their in-vitro tests demonstrated that when liver cancer cells were subjected to hypoxia, there was an observed elevation in the levels of miR-3677-3p. This rise in miR-3677-3p inhibited the SIRT5 expression by binding to its 3’UTR. As a result of this change, there was a stimulation of invasion, migration, and proliferation of HCC cells. In sum, the potential of miR-3677-3p as a biomarker for HCC was recognized, and inhibiting its activity could be viewed as a therapeutic strategy to impede HCC progression [170].

MiR-299-3p has a significant association with the advancement of certain neoplasms, such as lung cancer and CRC. However, its precise role in HCC has not been thoroughly investigated [171, 172]. According to a study by Dang and colleagues that was published in 2018, it was suggested for the first time that the miR-299-3p expression in HCC cells was influenced by its correlation with SIRT5. The study’s findings showed that miR-299-3p played a role in preventing the proliferation, invasion, and migration of HCC cells by downregulating SIRT5. Therefore, miR-299-3p exhibits promising characteristics that make it a viable candidate as a diagnostic indicator and therapeutic target of liver neoplasia [173].

SIRT6

Understanding the role of SIRT6 and miR-25 in the effects of EVs derived from CRC cells on the advancement and spreading of CRC is of major importance. It was observed that EVs obtained from HCT116 cells played a role in enhancing the malignant characteristics of SW620 and SW480 cells. The cause of this effect was attributed to miR-25 translocation via the EVs. Also, the results showed that when miR-25 impedes SIRT6, it causes a decrease in the expression of neuropilin-1 (NRP-1) and lin-28 homolog B (Lin28b). Lin28b is a gene that is involved in the regulation of NRP-1, a protein that is functionally relevant to the metastasis of the CRC and prevents the activity of SIRT6. Overall, EVs derived from CRC cells that are highly miR-24 expressing increase the tumorigenesis and progress of colon neoplasm [174].

In different neoplasms, like CRC, the JAK2/STAT3 pathway is highly active and has a crucial impact on diverse cellular mechanisms such as angiogenesis, migration, invasion, and cell proliferation [175]. When SIRT6 is overexpressed, it impaired the JAK2/STAT3 axis, leading to apoptosis and reduced cell proliferation in CRC cells. This effect is achieved by reducing the phosphorylation of both STAT3 and JAK2. Conversely, hinged on the results of the study, when miR-34 is excessively produced, it has been observed to hinder the function of SIRT6 and its impact by repressing the JAK2/STAT3 signaling pathway [176].

The relationship between SIRT6 and miR-125b in inducing apoptosis in HCC cells has been, in part, clarified. In the laboratory experiment using liver cancer patient samples, researchers found that miR-125b can lower the measure of SIRT6 in HCC cells. The SIRT6 reduction caused by miR-125b leads to a higher apoptosis rate in HCC cells. This can be observed through the elevated levels of BAX and caspase-3, which are well-known markers of apoptosis [177].

Earlier studies have shown that miR-122 is abundantly present in the liver of mammals and plays a fundamental role in regulating various metabolic functions in this organ [178]. In a study carried out in 2016, it was found that miR-122 controls fatty acid β-oxidation by suppressing the activity of genes related to this metabolic pathway. Moreover, a relationship between miR-122 and SIRT6 was recognized in the study. Fatty acid oxidation is a vital metabolic process that breaks down fatty acids to generate ATP, the body’s primary energy source. Clearly, enhancing SIRT6 levels leads to a rise in fatty acid oxidation during the HCC expansion and brings about the regulation of critical genes involved in this metabolic pathway, including IGFBP1, IGFBP2, ACLY, CPT1, CROT, IRS1, and IRS2. Moreover, the study revealed that when miR-122 binds to the SIRT6 mRNA, it contributes to a mitigation in the expression of SIRT6 within liver tumors. Therefore, the association between miR-122 and SIRT6 may be a potential biomarker to assess the HCC prognosis [179, 180].

SIRT7

Dong et al. conducted a study to explore the impact of a particular type of lncRNA called LINC00886 on ESCC. The study examined how the dysregulation of miR-144 and SIRT7 in an in-vitro condition is associated with the role of LINC00886 in ESCC. Based on the results, ELF3, a gene regulated by LINC00886, can attach to the promoter region of miR-144 and inhibit its activity. Consequently, when ELF3 is suppressed, there is an elevation in the miR-144 expression. This increased expression of miR-144, in turn, can potentially reduce the levels of mRNA expression of ZEB1 and ZEB2. ZEB1 and ZEB2 are genes known for their involvement in developing the growth of tumors and their ability to ESCC metastasis. On the other hand, SIRT7 can be activated by Linc00886 to reduce H3K18 acetylation on the promoter region of ELF3, thereby inhibiting the expression of ELF3. Hence, miR-144 affects SIRT7 through the regulatory pathway involving ELF3, which is influenced by LINC00886 in ESCC [181].

SIRT7 and miR-34 were also studied for their effects on GC. SIRT7 induced GC cell viability and proliferation in human GC tissue. Reportedly, Sirt7 diminishes the level of miR-34a in GC cells. On the other hand, when SIRT7 is suppressed, it increases the levels of pro-apoptotic proteins like caspase-3, Bax, and PARP. At the same time, it decreases the levels of anti-apoptotic proteins like Mcl-1 and Bcl-2. In conclusion, this study demonstrates a strong correlation between miR-34a and the survival of GC patients [182].

Li et al. explored the impact of a circRNA called circPVT1 on the HCC progression and its regulatory function. The in-vitro findings revealed that circPVT1 is ceRNA for miR-3666, a miRNA found in lower levels in HCC tissues. Also, the researchers conducted luciferase reporter assays, which presented that miR-3666 directly binds to 3’UTR of the SIRT7 gene and reduces its expression. Briefly, miR-3666 possesses tumor-suppressing abilities in HCC by effectively competing with cirPVT1 and targeting SIRT7 [183].

Early studies have indicated that the regulation of miR-125a plays a pivotal role in a range of tumor types, such as colon, breast, and glioblastoma [184–186]. The levels of miR-125a expression in 55 liver tumor biopsies have been investigated. The outcomes showed a notable decrease in miR-125a expression in 80% of HCC cases. The study also used RT-qPCR analysis to assess the levels of SIRT7, a miR-125a target. The results showed that tumor tissue expressed SIRT7 at a higher level compared to non-cancer liver tissues. These findings indicate that miR-125a may have a role in suppressing tumor growth and progression in cases of HCC [187].

In HCC tissues, a negative correlation was found between SIRT7 and miR-526b. The qRT-PCR showed that low miR-526B expression independently predicts poor prognosis in HCC patients. In addition, it was demonstrated that when miR-526b was excessively expressed, it decreased the invasive potential, migration ability, and proliferation rate of HCC cells in-vitro condition. The data showed that miR-526b is directly bound to the 3’UTR region of SIRT7 mRNA, resulting in the suppression of SIRT7. This occurred by inhibiting the functioning of key EMT markers, including ERK, c-Myc, SNAIL, Cyclin D1, and c-Jun. In summary, the findings recommend that targeting the miR-526b/SIRT7 pathway could be valuable for developing drugs to treat HCC [188].

The tumor suppressor function of miR-125b in HCC has been investigated. The study findings indicated a negative correlation between miR-125b and SIRT7 in an in-vitro environment. It was shown that when miR-125b is upregulated, it impedes the SIRT7 expression. Conversely, when miR-125b is downregulated, it causes an elevate in the expression of SIRT7 in HepG2 cells. In sum, when miR-125a mimics were used, it enhanced miR-125a levels, effectively reducing the growth and augmentation of HCC cells. This proposes that miR-125a could have a considerable therapeutic impact on HCC through its spread inhibition [189].

Insights into the role of SIRT7 in HCC by exploring how it interacts with miR-125b and miR-125a-5p have been provided. The activity of p53 and the administration of a DNA methylation inhibitor called 5-aza-2’-deoxycytidine were found to impact the regulation of these miRNAs. The treatment with 5-aza-2’-deoxycytidine positively impacted HCC cells by enhancing the levels of miR-125a-5p and miR-125b. Also, through qRT-PCR analysis, it was observed that these miRNAs have a function in preventing the translation of SIRT7 mRNA. Consequently, the expression of cyclin D1, a crucial protein for cell cycle regulation, was reduced. This resulted in the arrest of cell cycle progression at the G1/S phase, ultimately inhibiting HCC development. Additionally, miR-125b and miR-125a-5p reduced cyclin D1 levels and induced arrest of cellular division in HCC cells. Overall, elevating the miR-125a-5p and miR-125b levels in both HCC tissues and cells shows promise as a practical approach for managing liver cancer [190].

Hu et al. investigated the relationship between ubiquitination, SIRT7 protein levels, and their implications on sorafenib resistance and the progression of HCC. Ubiquitination refers to a posttranslational mechanism in which a protein called ubiquitin is attached to target proteins. This process is pivotal in regulating various cellular functions, including protein degradation, signal transduction, DNA repair, and cell cycle progression. Furthermore, ubiquitination has been implicated in contributing to drug resistance in neoplastic conditions. Additionally, in certain liver cancer cells such as SNU-449 and Hep3B, researchers have noticed that USP24, a type of enzyme called deubiquitinating enzyme or DUB, has a connection with SIRT7. USP24 has the ability to break down certain proteins that contain ubiquitin. Remarkably, the study discovered that miR-21-5p overexpression inhibits the ubiquitination of SIRT7 by enhancing the expression of USP24. This condition leads to heightened N-cadherin levels and diminished E-cadherin levels, triggering autophagy activation. Consequently, the expression of SIRT7 is boosted, resulting in resistance to the sorafenib. However, the study also has revealed that targeting miR-21-5p could potentially improve the response of liver tumors to sorafenib treatment by reducing vimentin levels [191, 192].

Conclusion and Future Perspectives

A detailed analysis of the complex roles of Sirtuins, especially SIRT1, and miRNAs in GI cancers reveals a highly intricate, dynamic, and context-dependent molecular interactions. This review highlights SIRT1’s dual role, functioning either as a tumor suppressor or promoter depending on the cellular and microenvironmental context, illustrating the multifaceted and sometimes paradoxical nature of epigenetic regulation in cancer. Closer inspection indicates that much of this apparent contradiction can be explained by the role of SIRT1 at the intersection of stress-response and survival pathways. In early lesions or tumors with functioning p53 and lower SIRT1 activity, deacetylation of targets involved in DNA repair, senescence, and apoptosis may help prevent tumor growth. Conversely, in advanced, hypoxic, or genomically unstable tumors with persistent SIRT1 overexpression and oncogenic miRNA/lncRNA networks, the same enzymatic functions tend to promote cell-cycle progression, metabolic adaptation, EMT, and resistance to chemotherapy or radiotherapy. Variations in experimental setups (2D vs. 3D culture, xenografts vs. patient samples), methods of manipulating SIRT1 (pharmacologic inhibitors vs. genetic knockdown/overexpression), and the chosen downstream measurements (proliferation, invasion, stemness, immune evasion) also lead to differing conclusions about SIRT1’s role. Recognizing these context- and method-dependent effects is therefore crucial when developing strategies targeting SIRT1 or interpreting SIRT1–miRNA interactions as biomarkers.

The complex interactions between SIRT1 and various miRNAs, such as miR-34a, miR-141, miR-138, miR-204, miR-132, miR-543, miR-212, miR-29, among others, demonstrate the molecular diversity involved in tumor initiation, progression, metastasis, and therapy resistance.

This review highlights SIRT1 and miRNAs as being part of a complex epigenetic and transcriptional regulation network. This broader network includes interactions with other Sirtuin proteins like SIRT7, epigenetic modifiers, transcription factors, long non-coding RNAs, and ceRNAs. These interactions play a key role in tumor biology in GI cancers by affecting pathways related to cell survival, growth, apoptosis, EMT, cancer stemness, autophagy, oxidative stress, and immune evasion. The intricate crosstalk among these molecules offers significant opportunities for discovering new biomarkers, early detection, precise prognosis, and personalized therapies.

Clinically, understanding the miRNA-SIRT1 axis as a biomarker offers significant potential, presenting new opportunities for early detection, better risk assessment, and more effective treatment choices. Using molecular signatures that combine miRNA and SIRT1 profiling could greatly improve the accuracy of current diagnostics, enabling earlier detection of GI cancers when treatments are most successful. These signatures can also enhance patient prognosis and guide personalized treatment plans based on the specific molecular characteristics of each tumor. Overall, these developments mark a major advance toward precision oncology, where therapies are tailored to increase effectiveness, reduce side effects, and prevent resistance.

From a therapeutic standpoint, targeting the miRNA-SIRT1 axis introduces innovative strategies that could transform GI cancer treatment. Approaches like miRNA mimics, antagomiRs, small molecule modulators of SIRT1, and combination therapies—incorporating chemotherapy, targeted therapy, and immunotherapy—show great promise for enhancing patient outcomes. Preclinical studies demonstrate that adjusting miRNA-SIRT1 interactions can effectively make resistant tumors more sensitive, reverse multidrug resistance, reduce metastasis, and specifically trigger cancer cell death, all while avoiding significant harm to normal tissues. Nonetheless, thorough clinical trials are essential to validate these findings and bring them forward for everyday clinical use.

Despite significant progress, many questions remain unanswered. Future research should aim to elucidate the precise molecular mechanisms of SIRT1-miRNA interactions, differences between normal and cancerous cells, and their effects on cancer traits and treatment responses. Using comprehensive multi-omics studies—encompassing genomics, transcriptomics, proteomics, epigenomics, and metabolomics—will be crucial for uncovering these complex regulatory networks. This integrated approach can lead to the discovery of new therapeutic targets, biomarkers, and diagnostic tools, paving the way for innovative treatments.

Additionally, future studies should explore how genetic predispositions, environmental factors, microbiota composition, diet, lifestyle, and population-specific variables influence the miRNA-SIRT1 axis. Since gastrointestinal cancer incidence, progression, and response to therapy vary widely among different populations, considering these factors will enable the development of personalized prevention and treatment strategies tailored to individual risks and diverse patient groups.

In summary, the complex and evolving interaction among SIRT1 and miRNAs offers a promising avenue for breakthroughs in gastrointestinal cancer research, diagnostics, and treatments. Applying these molecular insights through multidisciplinary, translational research could improve clinical outcomes, boost survival rates, and support personalized cancer therapies. Collaboration among clinicians, researchers, bioinformaticians, and biotech innovators is essential to transform molecular discoveries into effective clinical applications. Ultimately, fully harnessing the potential of SIRT1 and miRNA interactions could significantly reduce the global burden of GI cancers, revolutionize cancer care, and enhance patients’ quality of life.

Abbreviations

5-FU

5-Fluorouracil

ABC

ATP-binding cassette

ABCG2

ATP-binding cassette sub-family G member 2

AKT

Protein kinase B

ALDH

Aldehyde Dehydrogenase

B7-H3

B7 homolog 3

BCRP

Breast cancer resistance protein

Bax

Bcl-2-associated X protein

Bcl-2

B-cell lymphoma 2

CASP3

Caspase-3

CDK2

Cyclin-dependent kinase 2

CDK4

Cyclin-dependent kinase 4

CDK6

Cyclin-dependent kinase 6

CREB

cAMP response element-binding protein

CSC

Cancer stem cell

Cyclin A

Cyclin A protein

Cyclin D1

Cyclin D1 protein

Cytochrome c

Cytochrome c protein

DEPDC1

DEP domain containing 1

DOX

Doxorubicin

DR5

Death receptor 5

E-cadherin

Epithelial cadherin

E2F1

E2F transcription factor 1

E2F3

E2F transcription factor 3

EAC

Esophageal adenocarcinoma

EC

Esophageal cancer

EGCG

Epigallocatechin gallate

EMT

Epithelial-mesenchymal transition

ERK

Extracellular signal-regulated kinase

ESCC

Esophageal squamous cell carcinoma

EndMT

Endothelial-mesenchymal transition

FAO

Fatty acid oxidation

FOXO3a

Forkhead box O3a

GC

Gastric cancer

GCSC

Gastric cancer stem cell-like

GI

Gastrointestinal

GIC

Gastrointestinal cancer

GMNN

Geminin

GPX4

Glutathione peroxidase 4

HCC

Hepatocellular carcinoma

HDAC

Histone deacetylase

HDAC1

Histone deacetylase 1

HIF-1α

Hypoxia-inducible factor 1-alpha

IL-18

Interleukin-18

IL-1β

Interleukin-1 beta

IR

Ionizing radiation

JNK

Jun N-terminal kinase

L-OHP

Oxaliplatin

LC3

Microtubule-associated protein 1 light chain 3

LKB1

Liver kinase B1

Lgr5+

Leucine-rich repeat-containing G-protein coupled receptor 5-positive

MAPK

Mitogen-activated protein kinase

MDR

Multidrug resistance

MDR1

Multidrug resistance 1

MET

Mesenchymal-epithelial transition factor

MMP-2

Matrix metalloproteinase-2

MMP-9

Matrix metalloproteinase-9

MRP1

Multidrug resistance-related protein 1

MVI

Microvascular invasion

MVIH

Microvascular invasion in hepatocellular carcinoma

Mcl-1

Myeloid cell leukemia 1

N-cadherin

Neural cadherin

NF-κB

Nuclear factor kappa-light-chain-enhancer of activated B cells

NLRP1

NOD-like receptor protein 1

NLRP3

NOD-like receptor protein 3

NRP-1

Neuropilin-1

NUR77

Nuclear receptor subfamily 4 group A member 1

P-gp

P-glycoprotein

P16

Cyclin-dependent kinase inhibitor 2 A

P21

Cyclin-dependent kinase inhibitor 1

P53

Tumor protein 53

PARP

Poly (ADP-ribose) polymerase

PGC-1α

Peroxisome proliferator-activated receptor gamma coactivator 1-alpha

PI3K

Phosphoinositide 3-kinase

PTEN

Phosphatase and tensin homolog

PXR

Pregnane X receptor

RARβ

Retinoic acid receptor beta

ROS

Reactive oxygen species

SIRT1

Sirtuin 1

SIRT2

Sirtuin 2

SIRT3

Sirtuin 3

SIRT4

Sirtuin 4

SIRT5

Sirtuin 5

SIRT6

Sirtuin 6

SIRT7

Sirtuin 7

SLC7A11

Solute carrier family 7 member 11

SMAD3

Mothers against decapentaplegic homolog 3

STAT3

Signal transducer and activator of transcription 3

TGF-β

Transforming growth factor beta

TNF-α

Tumor necrosis factor-alpha

TRAIL

Tumor necrosis factor-related apoptosis-inducing ligand

TWIST1

Twist-related protein 1

USP22

Ubiquitin-specific peptidase 22

USP24

Ubiquitin-specific peptidase 24

VEGF

Vascular endothelial growth factor

Vimentin

Vimentin protein

Wnt

Wingless-related integration site

ZEB1

Zinc finger E-box binding homeobox 1

ZEB2

Zinc finger E-box binding homeobox 2

c-Myc

Cellular myelocytomatosis oncogene

ceRNA

Competing endogenous RNA

lncRNA

Long non-coding RNA

mTOR

Mammalian target of rapamycin

miRNA

microRNA

α-SMA

Alpha-smooth muscle actin

Author contributions

SMM: Conceptualization, Investigation, Writing – Original draft. FB, KK, and RJR: Writing – review and editing. NR: Supervision, Writing – review and editing.

Funding

The authors did not receive any financial support for any part of this article.

Data availability

Not applicable, as this is a review article based on previously published literature. All relevant data are available within the cited publications.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.