miRNA regulation of the Akt/mTOR pathway in oral squamous cell carcinoma: a focused review

Abstract

Oral squamous cell carcinoma (OSCC) contributes significantly to global cancer mortality, characterized by a progression from hyperplasia to invasive cancer through a series of genetic and epigenetic alterations. Central to this progression is the Akt/mTOR signaling pathway, which regulates cell proliferation and survival. This review examines the role of microRNAs (miRNAs) in modulating the Akt/mTOR pathway and their implications for OSCC. The Akt/mTOR pathway, activated by receptor tyrosine kinases and involving the PI3K/AKT/mTOR complexes, is crucial for tumor cell growth and metabolism. Dysregulation of this pathway is frequently observed in OSCC, leading to increased proliferation, survival, and metastasis. miRNAs, such as miR-21, miR-99, and miR-145, play significant roles in regulating this pathway by influencing key components like Akt and mTOR. These miRNAs can act as oncogenes or tumor suppressors, affecting cancer progression and response to therapy. The review highlights the potential of targeting miRNAs for OSCC treatment, including strategies to restore normal miRNA levels or inhibit aberrant miRNAs. Such targeted therapies offer promise for improving treatment outcomes and overcoming drug resistance in OSCC.

Graphical abstract

Introduction

Oral squamous cell carcinoma (OSCC), the most common malignancy of the oral epithelium, was estimated to affect approximately 400,000 individuals globally in 2020, resulting in around 178,000 deaths. This places OSCC 16th in both incidence and cancer-related mortality worldwide [1]. The pathogenesis of OSCC is marked by a development of carcinoma is driven by both genetic and epigenetic alterations that disrupt the balance between oncogenes and proto-oncogenes. The histopathological evolution of OSCC typically progresses from hyperplasia to dysplasia, advancing to severe dysplasia, and ultimately leading to invasion and metastasis. This progression is driven by an interplay of genetic and epigenetic events. Central to the pathogenesis of OSCC is the Akt/mTOR signaling pathway, an essential intracellular signaling cascade involved in regulating critical cellular processes such as growth, proliferation, and survival [2]. Dysregulation of the Akt/mTOR pathway has been implicated in various malignancies, including OSCC, where it contributes to tumor progression and resistance to treatment. miRNAs are small, non-coding RNAs that regulate gene expression at the post-transcriptional level by targeting messenger RNAs (mRNAs) for degradation or translational repression. miRNAs have been found to directly interact with key components of the Akt/mTOR pathway, modulating its activity and contributing to the oncogenic processes in OSCC. Additionally, the aberrant expression of these miRNAs often correlates with clinical features such as tumor stage, lymph node involvement, and patient survival. This review aims to explore the emerging relationship between miRNAs involved with Akt/mTOR pathway in the context of OSCC, highlighting the implications for diagnosis, prognosis and treatment.

Importance of miRNAs in OSCC

miRNAs control gene expression by attaching to the 3’ untranslated regions (3’ UTR) of target mRNAs, which results in either the degradation of the mRNAs or the inhibition of their translation [2]. In OSCC, miRNAs can act as oncogenes (oncomiRs) or tumor suppressors, influencing crucial processes like cell proliferation, apoptosis, and metastasis. For example, the overexpression of certain oncomiRs can downregulate tumor suppressor genes, promoting cancer progression, while reduced levels of tumor-suppressive miRNAs can result in the upregulation of oncogenes. This dual role highlights the complex involvement of miRNAs in OSCC pathogenesis [3–5].

Beyond their role in tumorigenesis, miRNAs have significant potential as diagnostic and prognostic biomarkers. Specific miRNA expression patterns can distinguish OSCC from dysplastic and healthy tissues, aiding in early detection and prognosis [6–8]. Furthermore, miRNAs offer novel therapeutic avenues, with strategies like miRNA mimics or inhibitors providing targeted approaches to restore tumor-suppressive functions or block oncogenic activities [9]. Additionally, miRNAs influence the tumor microenvironment, affecting processes like angiogenesis and immune response [10], thereby offering insights into developing comprehensive treatment strategies for OSCC.

Overview of the Akt/mTOR pathway

The Akt/mTOR pathway is activated in response to nutrient levels, hormones, and growth factors, playing a significant role in tumor cell proliferation. The central component is the PI3K heterodimer, composed of a regulatory subunit (p85) and a catalytic subunit (p110). These subunits are encoded by different genes: PIK3CA, PIK3CB and PIK3CD for the catalytic subunits (p110α, p110β, p110δ) and PIK3R1, PIK3R2 and PIK3R3 for the regulatory subunits. Upon activation by receptor tyrosine kinases (RTKs), PI3Ks convert PIP2 into PIP3, leading to the activation of Akt, a serine/threonine kinase that influences cell survival, growth and proliferation [11]. PTEN, a tumor suppressor, counteracts this by dephosphorylating PIP3 back to PIP2. Mutations involving PTEN and PIK3CA, particularly in exons 9 and 20, are common in various cancers, including breast cancer. Additionally, Akt-independent activation has been observed in some cancers, suggesting alternative pathways for tumorigenesis.

Downstream of Akt is mTOR, a serine/threonine kinase that forms two complexes, mTORC1 and mTORC2. mTORC1, better studied and targeted by rapamycin, regulates cell growth by affecting proteins like S6K1 and 4EBP1. mTORC2, although less understood, regulates cellular metabolism and cancer growth. Activation of mTORC1 by Akt involves the inhibition of the TSC1/2 complex, a tumor suppressor, which normally suppresses mTORC1 activity [12]. mTORC1 composed of Raptor, mLST8, and proline-rich Akt substrate 40 (PRAS40). Akt activates mTORC1 by inhibiting the tumor suppressor complex TSC1/2, which consists of tuberin and hamartin and functions as a guanosine triphosphatase activating protein for Ras homolog enriched in brain (Rheb)-GTP. Akt achieves this by phosphorylating TSC2 at specific sites (serine 939 and threonine 1462), thereby suppressing TSC1/2 activity. Additionally, Akt phosphorylates PRAS40, further promoting mTORC1 activation. Once activated, mTORC1 influences cellular metabolism and promotes cell anabolism by acting on proteins such as 40 S ribosomal protein S6 kinase 1 (S6K1) and eukaryotic initiation factor 4E binding protein (4EBP1) [11]. Dysregulation of the Akt/mTOR pathway is frequently associated with numerous diseases, particularly cancer, making it a central focus of therapeutic research [13, 14].

Interactions and signaling

Activated Akt translocates to the plasma membrane, where it is activated by phosphorylation at threonine 308 and serine 473 by PDK1 and mTORC2. Once fully activated, Akt regulates various cellular processes by phosphorylating a range of target proteins. Key substrates of Akt include tuberous sclerosis complex 2 (TSC2) and glycogen synthase kinase 3β (GSK3β). Akt-mediated phosphorylation of TSC2 inhibits its activity, thereby reducing its ability to suppress the Ras-Rheb GTPase. This inhibition results in the activation of mTORC1, which consists of mTOR, Raptor, mLST8, and PRAS40, regulates protein synthesis and cell growth by phosphorylating key targets such as 40 S ribosomal protein S6 kinase 1 (S6K1) and 4EBP1. These phosphorylation events lead to enhanced protein translation and cell cycle progression. Additionally, mTORC2, which includes mTOR and components such as Rictor and Sin1, regulates Akt activation and cellular metabolism, further influencing cell survival and proliferation. The Akt/mTOR pathway is tightly regulated through feedback mechanisms and interactions with other signaling networks [15]. For instance, the tumor suppressor PTEN (phosphatase and tensin homolog) counteracts the pathway by dephosphorylates PIP3 back to PIP2, thus attenuating Akt activation. Other feedback mechanisms involve the modulation of pathway components through various post-translational modifications and interactions with additional signaling proteins, which help maintain cellular homeostasis and prevent excessive activation.

Akt/mTOR pathway in OSCC

The Akt/mTOR pathway is often aberrantly activated in OSCC due to genetic mutations or overexpression of pathway components. The Cancer Genome Atlas (TCGA) study revealed that 37% of head and neck squamous cell carcinoma (HNSCC), including 34% of HPV-negative and 56% of HPV-positive patients, exhibit mutations or overexpression in PIK3CA, a gene encoding a component of the PI3K/AKT/mTOR network [16]. In OSCC, these alterations lead to somatic copy number changes in the genes that encode elements of this pathway, further enhancing its activity. Activation of the AKT/mTOR pathway is associated with phosphorylation of AKT and mTOR, which triggers a cascade of downstream biological processes. These include enhanced cell metabolism, proliferation, protein synthesis, and transcription, all of which contribute to the malignant behavior of OSCC cells. Additionally, extracellular ATP can stimulate this pathway via the P2Y2-Src-EGFR axis, promoting metastasis. Other mechanisms, such as the circEPSTI1/miR-942-5p/LTBP2 axis, also phosphorylate components of the pathway, facilitating epithelial-mesenchymal transition (EMT) and further driving OSCC metastasis and proliferation [17].

Moreover, cancer-associated fibroblasts (CAFs) with high ITGB2 expression can activate the PI3K/AKT/mTOR pathway through NADH oxidation, promoting OSCC progression. Numerous factors, including ZNF703, PDGF-D, CCL18, and Muc1, also contribute to the activation of this pathway, leading to increased cell survival, invasion, and resistance to therapy [18, 19]. Given its central role in OSCC pathogenesis, targeting the PI3K/AKT/mTOR pathway represents a promising strategy for preventing and treating this malignancy.

miRNAs involved in the Akt/mTOR pathway

The interactions of miRNA along with mRNA can either lead to mRNA degradation or inhibit translation, thereby influencing the activity of critical signaling pathways, including Akt/mTOR. Understanding the role of miRNAs in this pathway is crucial for elucidating their impact on cancer progression and identifying potential therapeutic targets. The discovery of miRNAs involved in the Akt/mTOR pathway involved a systematic approach, beginning with an extensive literature review to identify miRNAs that have been documented to interact with key components of this signaling cascade [20–22]. Recent advancements in next-generation sequencing (NGS) and microarray analysis, have facilitated the identification of miRNAs with regulatory roles in Akt/mTOR signaling. Studies have highlighted miRNAs such as miR-21, miR-29, miR-99 and miR-100 as significant modulators of this pathway [23–25]. Comprehensive reviews and meta-analyses of the literature integrate findings from diverse studies to provide a robust understanding of how specific miRNAs affect the Akt/mTOR pathway [26, 27].

miRNA function: role in regulating the Akt/mTOR pathway

miRNAs are integral to regulation of Akt/mTOR pathway. The intricate interplay between miRNAs and the Akt/mTOR pathway significantly influences various physiological and pathological processes, including cancer development. The Akt/mTOR pathway as previously discussed, is triggered by RTKs and includes the phosphorylation of multiple downstream targets that control cell proliferation and metabolism. miRNAs affect this pathway by influencing the expression levels of critical molecules such as Akt, mTOR and their upstream regulators. For example, miR-21 has been shown to upregulate components of the Akt/mTOR pathway by targeting and suppressing several tumor suppressors, thereby enhancing cellular proliferation and survival [28]. Conversely, miR-29 has been involved in downregulation of mTOR signaling, affecting cell response to external stimuli [29]. miRNAs like miR-99 and miR-100 specifically target components of the mTOR complex, modulating its activity and influencing cellular processes such as protein synthesis and metabolism. The commonly involved miRs have been summarized in Table 1.

Table 1.

MicroRNAs (miRNAs) involved in the Akt/mTOR pathway in OSCC and HNSCC

miRNA	Role	Target gene(s)/protein(s)	Function	Pathway impacted	Cancer type	References
miR-99	Tumor suppressor	mTOR	Downregulates mTOR, involved in AKT/mTOR signaling	Akt/mTOR	OSCC, HNSCC	[31]
miR-218	Tumor suppressor	RICTOR	Inhibits AKT S473 phosphorylation	mTORC2, Akt/mTOR	OSCC	[32]
miR-27a (miR-27a-5p)	Oncogenic	AKT1, mTOR	Downregulates AKT1 and mTOR	Akt/mTOR	HNSCC	[33]
miR-491-3p	Tumor suppressor	RICTOR	Inhibits mTORC2 activity, sensitizes cells to chemotherapy	mTORC2, Akt/mTOR	OC (general), drug-resistant OC	[34]
miR-21	Oncogenic	PTEN, PDCD4, TPM1	Promotes proliferation, invasion, metastasis	PI3K/Akt	OSCC	[35]
miR-24	Oncogenic	p27, Bim	Enhances proliferation, inhibits apoptosis	Cell cycle regulation, apoptosis	OSCC	[36]
miR-143	Tumor suppressor	ERK5	Inhibits proliferation, promotes apoptosis	MAPK/ERK	OSCC	[37]
	Tumor suppressor	FSCN1	Suppresses migration, invasion, proliferation	Cytoskeletal dynamics, cell motility	OSCC	[38]
miR-146a	Tumor Suppressor	TRAF6, IRAK1	Inhibits inflammation, tumorigenesis	NF-κB signaling	OSCC	[39]
miR-155	Oncogenic	PI3K/AKT Pathway Genes	Promotes tumor growth, immune evasion	PI3K/Akt, immune response	OSCC	[40]
miR-199a-3p	Tumor suppressor	mTOR	Inhibits proliferation, metastasis	mTOR	OSCC	[41]
miR-200c	Tumor suppressor	ZEB1, ZEB2	Inhibits EMT, invasion, metastasis	EMT pathway, cell adhesion	OSCC	[42]
miR-222	Oncogenic	p27, p57	Promotes proliferation, invasion	Cell cycle regulation	OSCC	[43]
miR-34a	Tumor Suppressor	Bcl-2, SIRT1, CDK6	Induces apoptosis, cell cycle arrest	p53 pathway, apoptosis	OSCC	[44]

Mechanisms of action

The mechanisms through which miRNAs regulate the Akt/mTOR pathway involve several key processes. miRNAs typically bind to the 3’ UTRs of target mRNAs through complementary base pairing, which leads to the recruitment of RNA-induced silencing complexes (RISCs) [2]. This binding results in the degradation of the target mRNA or inhibition of its translation [30]. The regulatory effects of miRNAs on the Akt/mTOR pathway are also influenced by their ability to interact with multiple target genes and signaling networks simultaneously. This multitarget approach allows miRNAs to fine-tune the pathway’s activity and integrate various extracellular and intracellular signals. Understanding these mechanisms provides insight into how miRNAs contribute to cellular homeostasis and pathology, and underscores their potential as therapeutic targets for modulating the Akt/mTOR pathway in diseases such as cancer [12].

miRNAs regulate the Akt/mTOR pathway not only by direct targeting of core components but also by modulating upstream and downstream signaling cascades. For example, miR-21 suppresses PTEN expression by binding to its 3’ untranslated region, resulting in increased PIP3 accumulation and subsequent hyperactivation of Akt through phosphorylation at Ser473 (via mTORC2) and Thr308 (via PDK1). This enhanced Akt activation promotes phosphorylation and inhibition of TSC2, relieving the suppression of Rheb and leading to robust mTORC1 activation. Moreover, miRNAs such as miR-99a directly target mTOR transcripts, reducing its expression and downstream signaling to S6K1 and 4EBP1, thus impacting protein synthesis and cell cycle progression. Importantly, feedback loops exist wherein excessive mTORC1 activation can inhibit upstream IRS-1, thereby modifying PI3K activation—a complexity often influenced by miRNA regulation. This multilayered control reflects the intricate interplay between miRNAs and the Akt/mTOR signaling network in oncogenesis.

These miRNAs influence various signaling pathways in OSCC, contributing to the regulation of tumor progression through their effects on cell proliferation, apoptosis, migration, invasion, and other critical cellular processes. A critical synthesis of the available data suggests that miRNAs influencing the Akt/mTOR pathway in OSCC predominantly exert their effects at three major levels: upstream regulators (e.g., PTEN, PI3K), core pathway components (e.g., Akt1, mTORC1/mTORC2), and downstream effectors (e.g., S6K, 4EBP1). Notably, oncogenic miRNAs such as miR-221/222 frequently suppress tumor suppressors like PTEN, leading to hyperactivation of the pathway, whereas tumor-suppressive miRNAs like miR-99a/b inhibit mTOR directly. Despite variations in individual miRNAs, the overarching functional consequence revolves around promoting unchecked proliferation, inhibiting apoptosis, and modulating metabolism. Recognizing these shared mechanistic patterns may aid in identifying key regulatory hubs within the pathway that could serve as broader therapeutic targets.

Akt/mTOR and OSCC progression

The Akt/mTOR integrates signals from growth factors to regulate key cellular functions [45]. In OSCC, aberrant activation of this pathway, due to mutations or overexpression of its components, leads to increased cellular proliferation, enhanced survival, and accelerated metastasis. Specifically, the activation of mTORC1 promotes protein synthesis and cell growth, while mTORC2 regulates cell metabolism and motility [46], both of which are crucial for tumor progression and metastasis and illustrated in Fig. 1.

Fig. 1.

Schematic representation of the EGFR-Akt/mTOR signaling cascade and its regulation by key miRNAs in OSCC. miR-21 and miR-155 promote tumorigenic signaling by downregulating PTEN and enhancing PI3K/Akt activation, while miR-34a exerts tumor-suppressive effects by targeting SIRT1 and Bcl-2. These miRNAs collectively modulate critical nodes within the pathway, influencing cell survival, proliferation, and metastatic potential

Role of MiRNAs in OSCC invasion and metastasis: MicroRNAs (miRNAs) modulate the Akt/mTOR pathway and thereby influence OSCC invasion and metastasis.

• miR-21: Often overexpressed in OSCC, miR-21 promotes invasion and metastasis by targeting and downregulating tumor suppressors like PTEN and PDCD4. This leads to enhanced Akt signaling, driving cellular processes that support metastasis.

• miR-24: Elevated levels of miR-24 are associated with increased OSCC proliferation and reduced apoptosis, facilitating invasion and metastasis. miR-24 targets key regulators of apoptosis, thereby promoting cell survival and tumor spread [47].

• miR-99 and miR-199a-3p: Both act as tumor suppressors by targeting components of the mTOR pathway. miR-99 inhibits mTOR directly, reducing tumor cell proliferation and invasion. Similarly, miR-199a-3p counteracts mTOR signaling, thus curbing tumor growth and metastatic potential [48].

• miR-145: By reducing FSCN1 levels, miR-145 inhibits cell migration and invasion. Its restoration can suppress OSCC metastasis by interfering with the cytoskeletal dynamics crucial for tumor cell motility [49].

• miR-200c: Known for its role in epithelial-mesenchymal transition (EMT), miR-200c inhibits EMT and reduces invasive behavior of OSCC cells, thereby mitigating metastatic spread [50].

• miR-146a: This miRNA modulates inflammation and tumorigenesis through NF-κB signaling. By influencing these pathways, miR-146a can affect the metastatic capabilities of OSCC cells [51].

The involvement of miRNAs in regulating the Akt/mTOR pathway is not unique to OSCC but extends across various malignancies, including lung, breast, and gastric cancers. For instance, miR-21, a well-established oncogenic miRNA in OSCC, also plays a crucial role in activating the Akt/mTOR pathway in colorectal and breast cancers by targeting PTEN, a key negative regulator. Similarly, tumor-suppressive miRNAs such as miR-99a, known to downregulate mTOR in OSCC, exhibit comparable effects in prostate and bladder cancers. Recognizing these parallels highlights conserved oncogenic mechanisms and suggests that therapeutic strategies targeting these miRNAs may have cross-cancer applicability. However, differences in tissue-specific expression and microenvironmental influences must also be considered when extrapolating findings from one cancer type to another.

Targeted therapies based on microRNAs in OSCC

miRNAs have emerged as pivotal regulators in the pathogenesis of OSCC by modulating the Akt/mTOR signaling pathway [52]. The dysregulation of specific miRNAs can significantly impact tumor growth, proliferation, and metastasis. Leveraging this knowledge, targeted therapies are being developed to restore the normal expression levels of these miRNAs or inhibit their aberrant functions. By specifically targeting miRNAs that influence critical components of the Akt/mTOR pathway, these therapies enhance efficacy of the treatment, overcome drug resistance, and improve patient outcomes in OSCC. The following table summarizes various miRNAs involved in the Akt/mTOR pathway and corresponding targeted therapeutic strategies designed to counteract their effects in OSCC.

Although several studies have identified specific miRNAs regulating key components of the Akt/mTOR pathway, it is important to note that therapeutic strategies targeting these miRNAs remain largely at the preclinical or experimental stage. Most available data derive from in vitro studies, animal models, or early-stage investigations, with limited clinical translation so far. The therapeutic targeting of miRNAs, particularly in the context of modulating Akt/mTOR signaling in OSCC, faces challenges including delivery specificity, off-target effects, and miRNA stability. The following table summarizes miRNAs that have been investigated in preclinical studies, highlighting their potential but not yet established clinical applicability (Table 2).

Table 2.

Preclinical strategies targeting miRNAs to modulate the Akt/mTOR pathway in OSCC

miRNA	Targeted therapy strategy	Expected outcome	References
Tumor suppressor miRNAs
miR-99	miR-99 mimic to inhibit mTOR	Reduce tumor growth, inhibit Akt/mTOR signaling	[53]
miR-218	Restoration to inhibit RICTOR/mTORC2	Sensitize cells to chemotherapy	[54]
miR-491-3p	Therapeutic delivery to inhibit mTORC2	Overcome drug resistance, enhance therapy	[32]
miR-199a-3p	Restoration to inhibit mTOR	Inhibit proliferation, reduce metastasis	[55]
miR-145	Restoration to target FSCN1	Suppress migration and invasion	[56]
miR-143	Enhancement to inhibit ERK5, promote apoptosis	Suppress tumor growth	[57]
miR-146a	Restoration to inhibit inflammation via NF-κB	Improve response to immunotherapy	[58]
miR-200c	Restoration to inhibit EMT	Prevent metastasis, inhibit invasion	[59]
miR-34a	Restoration to promote apoptosis via Bcl-2/SIRT1/CDK6 targeting	Induce apoptosis, cell cycle arrest	[60]
Oncogenic miRNAs
miR-21	Anti-miR-21 therapy to restore PTEN, PDCD4	Reduce proliferation, invasion, metastasis	[61]
miR-24	Anti-miR-24 therapy to enhance apoptosis	Improve treatment efficacy	[62]
miR-27a	Anti-miR-27a oligonucleotides to derepress AKT1/mTOR	Reduce proliferation, improve therapy	[63]
miR-155	Anti-miR-155 therapy to restore tumor-suppressive immune response	Inhibit tumor growth	[40]
miR-222	Anti-miR-222 therapy to restore p27/p57	Reduce proliferation and invasion	[64]

The therapeutic applications listed are based on preclinical data (in vitro or animal models). Clinical translation is yet to be established.

Recent advances in miRNA-targeted therapies have brought promising potential for regulating the Akt/mTOR pathway in OSCC. Several miRNAs, including miR-21, miR-155, and miR-99a, have been identified as key regulators of this pathway, influencing cancer progression by modulating cellular processes such as proliferation, apoptosis, and metastasis. Targeting these miRNAs has shown promising results in inhibiting tumor growth and enhancing the effectiveness of other treatments. miR-21, often overexpressed in OSCC, promotes tumor survival by activating the Akt/mTOR pathway, and its inhibition has been shown to reverse chemoresistance and enhance cell death in preclinical models [47].

Moreover, novel delivery systems are advancing the clinical potential of miRNA therapies. Nanoparticle-based carriers, lipid-based vesicles, and viral vectors are being developed to improve the stability, specificity, and efficiency of miRNA delivery to cancer cells. These delivery methods help overcome challenges such as degradation by nucleases in circulation, ensuring that therapeutic miRNAs reach their intended targets within the tumor microenvironment. With ongoing preclinical studies showing favorable outcomes, the therapeutic application of miRNAs targeting the Akt/mTOR pathway is moving closer to clinical trials, offering a new avenue for OSCC treatment.

Several drugs targeting the Akt/mTOR pathway are being investigated for their potential in treating OSCC. Among these, everolimus has garnered significant attention due to its ability to inhibit mTOR, thereby disrupting key cellular processes such as growth, proliferation, and survival. Clinical trials have demonstrated that everolimus, often used in combination with other agents, can enhance treatment efficacy and improve progression-free survival in OSCC patients [65]. Axitinib, a potent inhibitor of the vascular endothelial growth factor (VEGF) pathway, has also shown promise in targeting the Akt/mTOR axis by blocking angiogenesis, which is crucial for tumor growth and metastasis [66]. Additionally, AZD5363 and MK-2206, selective Akt inhibitors, have been shown to induce cell cycle arrest and apoptosis in OSCC cell lines, with ongoing trials assessing their effectiveness in clinical settings [67, 68]. The potential for combination therapies, leveraging these Akt/mTOR inhibitors alongside traditional chemotherapeutics or immunotherapies, is being actively explored, aiming to enhance overall therapeutic outcomes while minimizing resistance. In light of contemporary literature, it is essential to consider the role of cancer stem cells (CSCs) when discussing therapeutic resistance in oral squamous cell carcinoma (OSCC). CSCs possess self-renewal and differentiation capabilities that contribute to tumor recurrence and resistance to conventional treatments. Among various regulatory factors, microRNAs—particularly miR-21 have been recognized as key modulators of these resistance pathways. miR-21 is known to support the maintenance of CSC populations in OSCC, thereby enhancing their ability to evade therapeutic interventions. As research progresses, these targeted agents may provide more effective and tailored treatment strategies for OSCC patients, particularly those with advanced or recurrent disease. While these preclinical strategies offer promising avenues, the translation of miRNA-based therapies into clinical practice requires overcoming significant hurdles related to delivery, specificity, and safety.

Conclusion

OSCC remains a formidable clinical challenge, primarily due to its complex and heterogeneous molecular mechanisms, particularly those involving the Akt/mTOR signaling pathway. While recent studies have highlighted the regulatory roles of miRs such as miR-21, miR-99 and miR-145 in modulating key nodes within this pathway thereby influencing tumor growth, survival and metastasis significant gaps still remain. Many current investigations are limited by small sample sizes, lack of longitudinal data, and insufficient in vivo validation. Additionally, the context-specific behavior of miRNAs and their interactions with multiple signaling pathways introduce complexity that is not yet fully understood.

To advance clinical translation, future research must focus on addressing these limitations through robust, large-scale studies and functional validation in diverse populations. Integrating multi-omics approaches combining genomics, transcriptomics, proteomics and epigenomics will be critical in capturing the full landscape of miRNA-mediated regulation. Furthermore, the development of precise and safe delivery systems for miRNA-based therapeutics remains a key hurdle. Emerging platforms such as nanoparticle carriers, hydrogels, and tissue-specific vectors hold promise for improving therapeutic efficacy and minimizing off-target effects. Ultimately, a deeper understanding of miRNA–Akt/mTOR interactions, coupled with technological advancements, will be pivotal in harnessing miRNA modulation as a viable strategy for OSCC diagnosis, prognosis, and therapy.

Abbreviations

OSCC

Oral squamous cell carcinoma

Akt

Protein kinase B

mTOR

Mechanistic target of rapamycin

miRNAs

MicroRNAs

RTKs

Receptor tyrosine kinases

PI3K

Phosphoinositide 3-kinase

mTORC1

Mechanistic target of rapamycin complex 1

mTORC2

Mechanistic target of rapamycin complex 2

PTEN

Phosphatase and tensin homolog

PIK3CA

Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha

PIK3CB

Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta

PIK3CD

Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta

PIK3R1

Phosphoinositide-3-kinase regulatory subunit 1

PIK3R2

Phosphoinositide-3-kinase regulatory subunit 2

PIK3R3

Phosphoinositide-3-kinase regulatory subunit 3

PIP2

Phosphatidylinositol 4,5-bisphosphate

PIP3

Phosphatidylinositol (3,4,5)-trisphosphate

PRAS40

Proline-rich akt substrate of 40 kDa

S6K1

40 S Ribosomal protein S6 kinase 1

4EBP1

Eukaryotic initiation factor 4E-binding protein 1

EMT

Epithelial-mesenchymal transition

NGS

Next-generation sequencing

RISCs

RNA-induced silencing complexes

HNSCC

Head and neck squamous cell carcinoma

CAFs

Cancer-associated fibroblasts

GSK3β

Glycogen synthase kinase 3 beta

Rheb

Ras homolog enriched in brain

ERK5

Extracellular signal-regulated kinase 5

FSCN1

Fascin actin-bundling protein 1

TRAF6

TNF receptor-associated factor 6

IRAK1

Interleukin-1 receptor-associated kinase 1

NF-κB

Nuclear factor kappa B

Bcl-2

B-cell lymphoma 2

SIRT1

Sirtuin 1

CDK6

Cyclin-dependent kinase 6

ZEB1

Zinc finger E-box binding homeobox 1

ZEB2

Zinc finger E-box binding homeobox 2

SOS2

Son of sevenless homolog 2

PDCD4

Programmed cell death protein 4

TPM1

Tropomyosin alpha-1 chain

p27

Cyclin-dependent kinase inhibitor 1B

Bim

Bcl-2-like protein 11

Author contributions

Conceptualization; Data curation; Formal analysis & Methodology - Shazia Fathima J.H; Data curation, Writing– original draft - Mohammad Fareed; Conceptualization, Methodology, Supervision, Visualization, Writing– original draft, Writing– review & editing - Mohmed Isaqali Karobari.

Funding

None.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent to publish

Not applicable.

Competing Interests

The authors declare no competing interests.