Abnormal levels of miRNA in pancreatic cancer are linked to tumor progression by regulating the translation of tumor-associated mRNA

Abstract

Background

Pancreatic cancer remains one of the most malignant tumors, characterized by limited treatment efficacy.

Main Findings

microRNAs (miRNAs) play a crucial role in regulating the proliferation, invasion, migration, drug resistance, apoptosis, and cell cycle progression of pancreatic cancer cells by inhibiting tumor-associated proteins. Metscape analysis revealed that miRNA-targeted proteins associated with pancreatic cancer are enriched in processes such as cell proliferation, mitosis, and cell migration, and participate in multiple signaling pathways. These proteins primarily localize to classical pathways, including JAK/STAT, PI3K/AKT, and Wnt/β-catenin. Furthermore, gene mutations or abnormal alternative poly(A)denylation (APA) within miRNA-targeted regions can disrupt base pairing to the 3’-Untranslated Region (3′-UTR), thereby enhancing the translation of oncogenic mRNA translation.

Future Directions

Collectively, these findings indicate that multiple miRNAs act cooperatively to influence pancreatic cancer progression. Consequently, therapeutic strategies aimed at restoring the balance of the miRNA system are essential to disrupt the ‘mRNA-oncogene’ vicious cycle.

1. Background

Pancreatic cancer is one of the most aggressive types of tumors. Unfortunately, most patients’ cancer had metastases when diagnosed, making surgical removal impossible [1]. Treatment modalities include surgical resection, adjuvant chemotherapy, and radiotherapy [2,3]. Pancreatic cancer progresses rapidly, surgical opportunities are few, surgical resection is complex, and the therapeutic effect is not ideal. Therefore, more reviews are needed to explore how to highlight unmet therapeutic needs.

A hallmark of pancreatic cancer is the aberrant stability of oncogenic mRNAs and instability of tumor suppressor mRNAs [4]. microRNA(miRNA) expression is dysregulated in this malignancy, generally promoting tumorigenesis. Key mechanisms include: (1) Downregulation of miRNAs targeting oncogenes and upregulation of miRNAs targeting tumor suppressors [5,6]. (2) Most miRNAs inhibit mRNA translation by binding 3′-Untranslated Region (3′-UTR) [5,6], while a few miRNAs enhance mRNA translation by binding 3′-UTR [7–10]. (3) Gene mutation or abnormal selective poly(A)denylation(APA) of mRNA 3′-UTR in tumor tissues can affect miRNA binding, resulting in high stability of oncogene mRNA.

It has been reported that miRNA has strong tumor therapeutic potential, involving tumor proliferation, invasion, and other aspects [6,11,12]. At the same time, miRNA is also engaged in various classical tumor pathways, including JAK/STAT [13], PI3K/AKT [14], Wnt/β-catenin [15], and other classical tumor pathways. miRNA can trigger the breakdown of oncogene mRNA, and its external model has the potential for anticancer effects. This paper reviews the potential clinical value of miRNA in regulating the translation of oncogene mRNA in pancreatic cancer. The low expression of miR-141 and miR-133a in tissues was significantly associated with a poorer prognosis [16,17], meanwhile, the survival time of the miR-200c low-expression group was longer [18] (All miRNA-related information listed in Supplementary Table 1).

2. Mechanism of mRNA transcription inhibition induced by miRNA

miRNAs are tiny, endogenous non-coding RNAs, typically between 21 and 23 nucleotides in length, that regulate gene expression at the translational level [19]. Mature miRNAs are loaded onto Argonaute(AGO) proteins and bind to form an active RNA-inducing silencing complex (RISC) complex [20]. A single mRNA can recognize multiple mRNA targets, and various miRNAs can recognize an mRNA target. Based on the conserved 5′-end ‘seed’ sequence homology search analysis of miRNAs, it is speculated that about two-thirds of protein-coding genes in the human genome are regulated by miRNAs. The process of miRNAs targeting complementary mRNAs 3 ‘UTR, leading to the degradation of target mRNA is called transcriptional gene silencing (PTGS) [21,22]. miRNA can guide RISC to down-regulate gene expression at the post-transcriptional level, mRNA degradation or translation inhibition [23]. When mRNA perfectly complements miRNA, it succumbs to degradation by the RNA-induced silencing complex (RISC). However, in instances where the mRNA is only partially complementary to the miRNA, it skillfully prevents the mRNA from acting as a translation template, thereby rendering it powerless to synthesize proteins [23].

In addition to mature miRNAs, the miRISC complex also contains AGO2, VIG, dFXR, Dmp68, and other proteins [24]. When miRNA and mRNA are complementary and paired, AGO2 protein can directly cause mRNA degradation through cutting, thus completing gene silencing regulation [23]. By recruiting the 3′-UTR of the target mRNA to miRNA, AGO2 competitively binds the m7G cap with the initiation complex eIF4E/G and finally exerts the inhibitory effect on the translation initiation complex [25]. It is also suggested that by influencing the deadenylation of target mRNA, the poly(A) tail is shortened [26]. Thus, mRNA and poly(A)-binding protein (PABP) are blocked, affecting protein translation initiation [27]. The Ago protein is localized in RNA granules, such as processing bodies (P-bodies), which contain enzymes that degrade mRNA [28].

3. Multiple miRNAs jointly affect tumor progression (Figure 1)

Figure 1.

miRNA regulates tumor proliferation, migration, invasion, treatment resistance, cell cycle, and apoptosis by regulating mRNA stability.

3.1. miRNA involves proliferation and migration

It has been reported that the regulation of miRNAs on the proliferation and migration of pancreatic cancer is complex, and a few miRNAs promote proliferation and migration by targeting tumor suppressor mRNA [6,7,9,29–44]. miR-629 regulates FOXO3 at the post-transcriptional level, leading to enhanced cell proliferation and pancreatic cancer invasion [35], and the Overall Survival (OS) and Disease-Free Survival (DFS) of patients with high expression of miR-629 were significantly shorter than those of the low-expression group [45]. By targeting SOCS3 3′-UTR, miR-203 regulates JAK/STAT pathway activity and promotes cell proliferation [36], as the survival time in the miR-203 high expression group was significantly shortened [46]. Most miRNAs inhibit proliferation and migration by targeting oncogene mRNA in pancreatic cancer [5,8,10–12,14,15,47–84]. Over-expression of miR-142-5p inhibits the proliferation of pancreatic cancer cells by targeting RAP1A [5], as miR-142-5p is a predictive marker of gemcitabine response in patients undergoing pancreatic cancer resection [85]. miR-211-5p can target the 3′-UTR of BMP2 and down-regulate its expression, thereby inhibiting the proliferation of pancreatic cancer [48]. Meanwhile, miR-506 may inhibit tumor proliferation by inhibiting the translation of PIM3 [74].

3.2. miRNA involves invasion

Research has indicated that miRNAs play a crucial role in regulating the tumor invasion of pancreatic cancer cells, and a select group of miRNAs has been found to facilitate the invasion of pancreatic cancer by targeting specific proteins [6,7,30,31,33,35,39,42,43,86,87]. Notably, up-regulating miR-186 can boost the invasive potential of pancreatic cancer cells through its impact on NR5A2 translation [30], and miR-186 predicts poor survival [86]. miR-629 enhances invasion by post-transcriptionally regulating FOXO3, and miR-1178 increases tumor invasion by acting on CHIP [35,39]. On the contrary, most miRNAs inhibit the invasion of pancreatic cancer [12,14,15,47,50,51,53,55,60–64,66,69,71–73,76,77,79,80,82,83]. For instance, The invasion of pancreatic cancer is suppressed by miR-557 through its targeting of EGFR [50]. miR-509-5p targeted to the MDM2 gene to hinder Panc-1 cell invasion [14]. miR-9-5p regulates GOT1 translation by targeting the mRNA 3 ‘UTR, impeding invasion, glutamine metabolism, and redox homeostasis [47]. There is a negative association between miR-205-5p/ZEB1 and the invasion of pancreatic cancer cells [62]. Further, miR-29c impedes cell invasion through targeting the MMP2 3′-UTR [71].

3.3. miRNA involves therapeutic resistance

Multiple miRNAs jointly affect therapeutic resistance in pancreatic cancer. Certain miRNA has been found to promote treatment resistance in pancreatic cancer [9,30,38,88–90], and miR-21-5p binds to the 3′-UTR of DSCR9 and BTG2, leading to reduced Gemcitabine-induced apoptosis [30], as it is a significant unfavorable prognostic factor [91]. Additionally, miR-330-5p targeting RASSF1 has been shown to promote Gemcitabine resistance in pancreatic cancer cells [88]. Conversely, certain miRNAs have been discovered to enhance the sensitivity to treatment in pancreatic cancer [12,58,64,65,69,92–100], Decreased miR-203 expression and increased DJ-1 translation in pancreatic cancer cells are linked to drug resistance [58]. Furthermore, miR-146a-5p has been shown to sensitize pancreatic cancer to Gemcitabine by targeting the 3′-UTR of TRAF6 [92]. miR-20a-5p regulates the sensitivity of gemcitabine chemotherapy by targeting RRM2 in pancreatic cancer cells, and it can be used to Evaluate the application value of gemcitabine chemotherapy [90]. While miR-124 inhibits pancreatic cancer cell resistance to Erlotinib by directly targeting EphA2 mRNA [99], low serum miR-124 levels were significantly associated with postoperative lymph node metastasis, tumor lymph node metastasis stage, and shorter survival time [101].

3.4. miRNA involves cell cycle

The regulatory role of miRNA in the cell cycle of pancreatic cancer is two-fold. Certain miRNA facilitate the progression of the cell cycle [6,39], with an elevation in miR-887-3p levels diminishing STARD13 translation and thereby leading to the inhibition of the S/G2 checkpoint transition [6]. The miR-1178 leads to an increase in G1/S checkpoint transition [39], as miR-1178 is an independent poor prognostic indicator for patients with pancreatic cancer [102]. Conversely, a significant number of miRNAs act to hinder the pancreatic cancer cell cycle [11–13,75,81,83,103,104]. For instance, miR-217 targets ATAD2 directly, leading to an increase at the G1/S checkpoint [11]. miR-488 targets ERBB2 directly, leading to a halt at the G2/M phase of the cell cycle [13]. Low expression of miR-431-5p in pancreatic cancer relieved the inhibition of HCAR1, increasing G1/S checkpoint transition [75]. miR-491-5p is implicated in inducing cell cycle arrest through TP53, indirectly down-regulating DTYMK, and contributing to the progression of pancreatic cancer [104]. miR-431-5p inhibits tumor growth in pancreatic cancer cells by impacting the cell cycle, particularly in BxPC-3 cells [75]. In conclusion, miRNA regulates checkpoint transitions in the cell cycle of pancreatic cancer cells (including S/G2, G1/S, and G2/M) through various proteins.

3.5. miRNA involves cell apoptosis

The regulation of apoptosis of pancreatic cancer cells by miRNA is complex. Certain miRNAs have the ability to prevent the apoptosis of pancreatic cancer cells [6,36]. The miR-887-3p decreases the translation of STARD13 and inhibits the apoptosis of pancreatic cancer cells [6]. miR-203 decreases the level of SOCS3 in pancreatic cancer, increases the expression of p-JAK2 and p-STAT3 proteins, and inhibits cell apoptosis [36]. On the other hand, some miRNA induces apoptosis of pancreatic cancer cells [5,11,12,49, 53,55, 58,59,72,81,97,103,105,106], and miR-142-5p regulates the translation of RAP1A negatively by binding to its 3′-UTR and promoting apoptosis [5]. miR-373 targets the 3′-UTR of SIRT1 and induces apoptosis [49], and PC patients with lower serum miR-373 level had shorter 5-year overall survival [107]. By inhibiting PRR11, miR-144-3p can increase the expression of Caspase-3 and then induce pancreatic cancer cycle arrest and apoptosis [103]. Additionally, over-expression of miR-142-3p directly binds to the 3′-UTR of HSP70 and induces apoptosis (Table 1, Supplementary Table 2) [106].

Table 1.

Multiple miRNAs jointly affect tumor proliferation, migration, invasion, treatment resistance, cell cycle, and apoptosis.

	Cancer-promoting related miRNA	Cancer-suppressing related miRNA
Proliferation and migration	miR-380-3p,miR-21-5p,miR-887-3p,miR-193a-5p,miR-5703,miR-92a-3p,miR-629,miR-125b,miR-135b,miR-1178,miR-107,miR-934,miR-27a,miR-21,miR-367,miR-381	miR-142-5p,miR-217,miR-9-5p,miR-337,miR-211-5p,miR-373,miR-557,miR-4516,miR-204-3p,miR-4299,miR-141,miR-133a,miR-495,microRNA-374,miR-509-5p,miR-143,miR-203,miR-365a-3p,miR-200,miR-218-5p,miR-205-5p,miR-221,miR-140-5p,miR-210,miR-421,miR-218,miR-219-1-3p,miR-377,miR-29a,miR-330-5p,miR-29c,miR-217,miR-132,miR-1247,miR-506,miR-431-5p,miR-148a,miR-133,miR-210-3p,miR-30b,miR-96,let-7miRNA,miR-33a,miR-7-5p,miR-24-3p
Invasion	miR-21-5p,miR-887-3p,miR-193a-5p,miR-125b,miR-203,miR-629,miR-186,miR-1178,miR-107,miR-367,miR-381	miR-9-5p,miR-337,miR-557,miR-4516,miR-4299,miR-141,miR-495,miR-509-5p,miR-200,miR-218-5p,miR-205-5p,miR-140-5p,miR-210,miR-218,miR-29a,miR-330-5p,miR-29c,miR-217,miR-1247,miR-148a,miR-133,miR-30b,miR-96,miR-27a,miR-7-5p,miR-24-3p
Radiation and chemotherapy resistance	miR-21-5p,miR-135b,miR-320a,miR-20a-5p,miR-21	miR-146a-5p,miR-141,miR-203,miR-23B,miR-210,miR-421,miR-29a,miR-330-5p,let-7miRNA,miR30a-3p,miR-124,miR-9,miR-31,miR-153,miR-410-3p
Cell cycle	miR-887-3p,miR-1178	miR-217,miR-488,miR-141,miR-491-5p,miR-144-3p,miR-33a,miR-24-3p
Apoptosis	miR-887-3p,miR-203	miR-142-5p,,miR-373,miR-4299,miR-141,miR-495,miR-203,miR-365a-3p,miR-217,miR-431-5p,miR-9,miR-491-5p,miR-144-3p,miR-33a,miR-142-3p

4. miRNA and tumor-related signaling pathways

Metascape analyses have shown that miRNAs play a crucial role in regulating pancreatic cancer through multiple signaling pathways. miRNAs targeted protein are enriched in various signaling pathways that affect processes such as regulation of epithelial cell proliferation, regulation of the mitotic cell cycle, regulation of growth, negative regulation of cell migration, epithelial to mesenchymal transformation, and epithelial cell development in cancer, epithelial cell development, Epithelial to mesenchymal transition in colorectal cancer, epithelial cell development, epithelial cell migration. Additionally, miRNA may regulate pancreatic cancer through the interleukin-4 and interleukin-13 signaling pathways, VEGFA VEGFR2 signaling pathways, enzyme-linked receptor protein signaling, Photodynamic therapy induced AP 1 survival signaling, EGF/EGFR signaling, Leptin signaling pathway, Photodynamic therapy induced HIF 1 survival signaling, MAPK signaling, NOTCH signaling, and HIF-1 signaling pathways (Figures 2 and 3) [108].

Figure 2.

Metascape analyzes potential pathways involved in pancreatic cancer-associated proteins.

Figure 3.

miRNA and tumor-related signaling pathways.

4.1. JAK/STAT signal pathway

miRNAs play a critical role in the activation of the JAK/STAT signaling pathway via the interaction with proteins such as SIK1 and SOCS3 [33,36,109]. Specifically, miR-203 targets the 3′-UTR of SIK1, which is involved in the phosphorylation of AKT [33,109]. Additionally, miR-203 influences the growth and programmed cell death of pancreatic cancer cells by regulating the translation of SOCS3, subsequently modulating the activity of the JAK/STAT pathway [36]. Moreover, miRNAs are known to inhibit the JAK/STAT signaling pathway by suppressing various proteins, including STAT3, ERBB2, OTX1, LASP1, CDK8, GPx8, and SOX18 [13,15,51,61,63,82,98,110–114]. miR-488 directly binds to the 3′-UTR of the ERBB2 gene, leading to effective inhibition of the JAK/STAT pathway and suppression of cancer cell proliferation, invasion, and migration [13,110]. miR-4516 regulates the translation of OTX1 by binding to the negative 3′-UTR of OTX1, as down-regulation of the targeted protein inhibits cancer progression by inhibiting JAK/STAT signaling [51,111]. miR-218-5p inhibits the translation of LASP1 by binding to the 3′-UTR of LASP1, and significantly increases the expression levels of p-JAK2, p-STAT3 and p-STAT5 [61,115], and low-level expression of miR-218 is significantly associated with a short OS in patients with pancreatic cancer [116]. The JAK/STAT pathway is related to proliferation, invasion, and immune escape. miRNA regulates chemotherapy resistance, EMT, and metastasis through JAK/STAT pathway.

4.2. PI3K/AKT signal pathway

miRNA activate the PI3K/AKT signaling pathway through PTEN, BTG2, and Cx43 [29,30,95,117,118]. miR-380-3p targets the 3′-UTR to inhibit PTEN translation and activate the downstream Akt signaling pathway [29]. miR-21-5p can inhibit the translation of BTG2, regulate the apoptosis of cancer cells through the PI3K/AKT signaling pathway, and inhibit cell proliferation, migration, and invasion [30,117]. The interrelation between Cx43 and the PI3K/AKT pathways contributes to epithelial-mesenchymal transition and Tamoxifen resistance [95,118]. miRNA inhibit the PI3K/AKT signaling pathway through ATAD2, DJ-1, ZEB1, MUC4, RRM2, EphA2, PRR11, and lncRNA MIAT protein [11,58,62,67,77,90,94,96,103,119–124]. miR-217 significantly inhibited the translation of ATAD2, regulated the PI3K/AKT signaling pathway, and inhibited cell proliferation [11]. miR-144-3p can inhibit the translation of PRR11, and the PRR11 integrate into the P85α regulatory subunit of PI3K inhibits p85 dimer, thereby participating in the PI3K/AKT signal pathway [103,123]. miR-133 target MIAT 3′-UTR, low expression of lncRNA MIAT significantly inhibits the phosphorylation of PI3K and AKT, and promotes the expression of cMyc and cyclin D1 proteins [77,124]. PI3K/AKT is a key hub for metabolic reprogramming, anti-apoptosis, and chemotherapy resistance.

4.3. Wnt/β-catenin signal pathway

miRNA activate the Wnt/β-catenin pathway by targeting 3′-UTR of PROX1 and FOXO1 mRNA [40,87,125]. The miR-934 directly binds to the 3′-UTR of PROX1, leading to lower expression and subsequent activation of the Wnt/β-catenin signaling pathway [40,125], and up-regulation of miR-934 is associated with a poor prognosis in patients with pancreatic cancer [40]. miR-27a targets the 3′-UTR of FOXO1, increasing Wnt/β-catenin signaling activity, promoting cell proliferation and epithelial-mesenchymal transformation [87]. miRNA inhibit the Wnt/β-catenin pathway through targeted STAT3, MGAT1, OTX1, ROBO1, NR5A2, RCC2, and β-catenin [15,51,52,66,73,81,86,126–130]. The miR-204-3p inhibits MGAT1 translation by targeting its 3′-UTR, thus inhibiting the Wnt/β-Catenin pathway and tumor proliferation [52,126], and miR-218 inhibit the translation of ROBO1 associated with the Wnt/β-catenin pathway [66,128]. The miR-1247 targets chromosome aggregation 2 regulator (RCC2), abnormal expression of RCC2 down-regulates Wnt signaling pathway inducing epithelial-mesenchymal transformation (EMT) [73,130], and high levels of miR-1247 was positively correlated with higher OS and RFS in patients with pancreatic cancer [131]. Activation of Wnt/β-catenin promotes the characteristics, epithelial-mesenchymal transition, and metastasis of cancer stem cells.

4.4. MAPK signal pathway

miRNA can regulate the MAPK pathway, such as miR-203 activating the MAPK pathway by inhibiting SIK1 [33,132]. By controlling the activity of OTX1, ADAM17, and COX-239 proteins, miRNAs play a role in inhibiting MAPK signals [51,57,133]. miR-4516 impacts OTX1 translation by attaching to its 3′-UTR area, thus diminishing the deactivation signals of OTX1 and MAPK [51,133]. miR-143, on another note, plays a role in repressing COX-2 and the activation of MEK/MAPK [57]. MAPK regulates cell proliferation, sustains the inflammatory microenvironment, and contributes to drug resistance.

4.5. TGF-β signal pathway

miRNAs play a role in activating the TGF-β signaling pathway by regulating Smad7 and TGF-β2 [8,42]. For example, miR-367 reduces the translation of Smad7 in pancreatic cancer cells, which leads to an increase in transforming growth factor-β [42]. Additionally, miR-132 directly interacts with TGF-β2, enhancing its translation and leading to an increase in luciferase activity [8]. miRNA can also inhibit signaling pathways by targeting proteins like LASP1 and IF5A2 [61,97,134,135]. miR-218-5p inhibits LASP1 translation, epithelial-mesenchymal transformation, and the TGF-β/Smad3 pathway [61,134], Furthermore, miR-9 reduces the translation of eIF5A2 in pancreatic cancer, and inhibition of the TGF-β pathway can lead to resistance to the drug Doxorubicin [97,135]. TGF-β suppresses proliferation in early pancreatic cancer stages, promoting metastasis and immunosuppression in later stages.

4.6. NF-κB signal pathway

miRNA possess the ability to repress NF-κB signaling through interaction with TRAF6, c-Rel, and CMTM4 [32,59,92,136]. miR-146a-5p is known to decrease the activity of the TRAF6/NF-κB p65/P-gp axis. In parallel, miR-365a-3p reduces c-Rel levels thereby dampening NF-κB signaling [59]. miR-5703 specifically targets the 3′-UTR of CMTM4, diminishing its translation [32,136]. miR-365a-3p inhibited c-Rel mRNA translation and then affected c-Rel expression, NF-κB activity, and then affected tumor cell activity [59]. miRNA forms a fine regulatory network for inflammation, immune response and cancer progression by targeting the NF-κB pathway.

4.7. Hippo signaling pathways

miR-133 can bind the 3′-UTR of mRNA to silence the expression of MIAT and activate Hippo signaling, thereby inhibiting tumor growth [77,137]. In addition, miR-218-5p reduces the expression level of LASP1 by binding to its 3′-UTR, promoting the activation of the Hippo signaling pathway (Table 2) [61,138]. The Hippo signaling pathway plays a crucial role in the proliferation, maintenance of tissue integrity, and remodeling of the matrix in pancreatic cancer.

Table 2.

The specific miRNA and tumor-related signaling pathways.

Signal pathway	Inhibitory pathway	Activation pathway
JAK/STAT	miR-337/STAT3 miR-488/ERBB2 miR-4516/OTX1 miR-218-5p/LASP1 miR-140-5p/CDK8 miR-31/GPx8 miR-7-5p/SOX18	miR-203/SIK1 miR-203/SOCS3
PI3K/AKT	miR-217/ATAD2 miR-203/DJ-1 miR-205-5p/ZEB1 miR-219-1-3p/MUC4,let-7, miR-20a-5p/RRM2 miR-124/EphA2 miR-144-3p/PRR11 miR-133/MIAT	miR-380-3p/PTEN miR-21-5p/BTG2 miR30a-3p/Cx43
Wnt/β-catenin	miR-337/STAT3 miR-204-3p/MGAT1 miR-4516/OTX1 miR-218/ROBO1 miR-186/NR5A2 miR-1247/RCC2 miR-33a/β-catenin	miR-934/PROX1 miR-27a/FOXO1
MAPK	miR-4516/OTX1 miR-4299/ADAM17 miR-143/COX-2	miR-203/SIK1
TGF-β	miR-218-5p/LASP1 miR-9/eIF5A2	miR-367/Smad7 miR-132/TGF -β2
NF-κB	miR-146a-5p/TRAF6 miR-365a-3p/c-Rel miR-5703/CMTM4
Hippo	miR-218-5p/LASP1	miR-133/MIAT

5. miRNA and targeted 3’-UTR region jointly determine mRNA translation

5.1. Function of miRNA and mRNA translation

The majority of miRNA repress the translation of their target mRNA (Most of the miRNA list in the article), while a few miRNA can bind to the 3′-UTR region and contribute to high translation level of targeted protein [7,9,10]. Similarly, miR-21 promotes the expression of Bcl-2 by binding directly to the 3′-UTR of Bcl-2 [9], while let-7c up-regulates Numbl translation by targeting the 3′-UTR [10]. The underlying molecular mechanism is still unknown, and the molecular mechanism needs to be further perfected in future work. miR-24-1 can bind to enhancers and recruit RNA Polymerase II, P300/CBP, and AGO2 to the enhancer region. This recruitment leads to changes in chromatin structure and activation of the enhancer, ultimately promoting the transcription of nearby miRNA genes [139]. Additionally, the acetylation levels of H3K4me3 and H4 in the promoter of miR-589, which targets cyclooxygenase 2, increase, resulting in the activation of gene transcription [140].

5.2. Gene mutations and APA in miRNA-targeted 3’-UTR

Mutations in the 3′-UTR region of pancreatic tumor cells have an impact on tumor prognosis [141,142]. Gene mutations in the 3′-UTR can cause abnormal miRNA binding, preventing miRNA from binding to the 3′-UTR of the target gene, which leads to over-expression of the target gene. The variant genotype rs9224 in the 3′-UTR alters the translation of LUSQ mRNA by affecting miR-22-5p binding [143]. Somatic mutations within miR136-5p targets disrupt miRNA mediated regulation and result in increased gene activity [144]. Introducing a gene mutation in the 3′-UTR of WT sema 4D eliminates the effect miRNA related mRNA instability [145]. Mutation in the ERBB4 3′-UTR gene affect the binding affinity of miR-3144-3p [146].

APA is a crucial post-transcriptional process that can impact gene expression by controlling the length of its 3′-UTR through the utilization of different poly(A) sites [147–152]. Shortening the 3′-UTR of ABCC1 using 3′-UTR-APA eliminates miRNA binding sites in the longer 3′-UTR, thereby removing miRNA regulation [147]. Shortening KHDRBS1 mRNA by 3′-UTR can escape the inhibition of miRNA, resulting in increased expression in cancer [148]. The 3′-UTR shortening of LAMC1 removes the miR-124/506 binding site, thereby alleviating effective miRNA-based inhibition of LAMC1 expression [149]. miR-485-5p targets the 3′-UTR between the distal and proximal poly(A) sites, causing an aging-related phenotype by reducing protein production from longer CDK16 transcripts [150]. APA and optional splicing events in Pax-5 transcripts affect miRNA binding [151]. Abnormal shortening of the 3′-UTR reduces the number of miRNA binding sites, enabling oncogenes to escape miRNA suppression (shown in Figure 4) [152].

Figure 4.

Gene mutations and APA in miRNA-targeted 3′-UTR regions.

6. Conclusion and prospect

In future studies, it may be crucial to focus on over-inhibited miRNA networks within tumors for the future treatment of pancreatic tumors. The expression levels of most miRNAs are lower in the tumor group compared to neighboring or normal tissues. Their low expression leads to the translation of many tumor-associated protein mRNAs, thereby contributing to the progression of pancreatic tumors. In the future, we may aim to enhance the expression of specific miRNA or target the modification of the binding site of proto-oncogene mRNA 3′-UTR to regulate mRNA translation and effectively inhibit the translation of oncogenes in tumors. Numerous miRNAs work together to influence the progression of tumor cells, with our paper focusing on 94 specific miRNAs. The main objective of this review is to illustrate how multiple miRNAs collectively contribute to the advancement of pancreatic cancer. When drugs are designed to target specific miRNAs, other miRNAs can also impact the associated pro-cancer pathways and the abnormal proliferation behaviors of the tumor.

At present, miRNA-related anti-cancer treatments have made good progress.miR-29b is down-regulated in prostate cancer, and overexpression of miR-29b limits the metastasis of prostate cancer. Intratumoral injection of simulated miR-29b can significantly inhibit the growth of prostate cancer xenografts in nude mice [153]. In a mouse stress overloading-induced disease model, in vivo, miR-21 silencing by specific antagomir reduced cardiac ERK-MAP kinase activity, inhibited interstitial fibrosis, and alleviated cardiac dysfunction [154]. In humans, the biosynthesis of miRNA involves highly regulated pathways and four essential enzymes: Drosha, Exportin 5, Dicer, and AGO2. However, mutations in genes associated with the miRNA biosynthesis pathway are found in various types of cancer. This often leads to a reliance on miRNA dysregulation in tumor expression. To address this issue, it is crucial to restore the balance of the miRNA system and break the vicious cycle of ‘mRNA-oncogene.’

Funding Statement

This research was funded by grants from Startup Fund for Scientific Research of Fujian Medical University (No.2022QH2033).

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No new data has been generated during the study.

Disclosure statement

The authors declare no conflicts of interest

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