The role of microRNAs in gastritis, intestinal metaplasia, and gastric cancer: a narrative review

Introduction

Mammalian genomes harbor an abundant number of non-coding RNA genes that have emerged as crucial regulators of various physiological and pathological processes, including cell development, differentiation, growth and survival, and apoptosis. Among these, microRNAs (miRNAs or miRs) are pivotal rheostats of cellular functions and have been extensively studied in multiple contexts (1). MiRNAs are a class of endogenous non-coding single-stranded RNA molecules, typically 20–22 nucleotides in length, which play a crucial role in the development of precancerous lesions to cancer (2,3). These evolutionarily conserved molecules, derived from genomic DNA through RNA polymerase II-mediated transcription yet devoid of protein-coding capacity, exhibit remarkable evolutionary conservation and spatiotemporal specificity in their expression patterns (4). Their post-transcriptional gene regulation, which is mediated by suppressing protein translation or degrading messenger RNA (mRNA), significantly affects key cancer-related cellular processes, including metabolism, proliferation, differentiation, and apoptosis (4,5).

MiRNA dysregulation is implicated in diverse human diseases, including cancers, cardiovascular disorders, and neurological pathologies (6,7). In gastric cancer (GC), miRNAs critically regulate key cancer-related genes and signaling pathways, acting as either oncogenes or tumor suppressors (8). Gastric carcinogenesis is classically described by the Correa cascade: a stepwise progression from normal gastric mucosa to non-atrophic gastritis, atrophic gastritis, intestinal metaplasia (IM), dysplasia, and ultimately invasive GC (9). IM, a pivotal intermediate stage, involves the replacement of gastric epithelium with intestinal-type cells. While often an adaptive response to chronic inflammation, IM significantly increases the risk of cancer. At this stage, accumulated genetic aberrations and epigenetic modifications drive malignant transformation, making IM a critical window for intervention and biomarker discovery. Emerging evidence indicates that miRNA dysregulation drives the gastric carcinogenesis cascade, from chronic gastritis (CG) through IM to GC, and this dysregulation has profound implications for tumor biology and clinical outcomes (10).

This review systematically analyzes miRNA dysregulation patterns across the gastritis-metaplasia-carcinoma continuum (Figure 1), synthesizes recent advances in the understanding of miRNA mechanisms, and evaluates the potential of miRNAs as non-invasive biomarkers and therapeutic targets, ultimately proposing novel frameworks for precision diagnostics and RNA-based therapeutic development. We present this article in accordance with the Narrative Review reporting checklist (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-1-2642/rc).

Figure 1 miRNA regulatory network in gastritis, intestinal metaplasia, and gastric cancer. Let-7b inhibits gastritis progression by targeting the TLR4 3'-UTR, suppressing its post-transcriptional expression. As a key immune receptor, TLR4 activates NF-κB in response to inflammatory stimuli, driving pro-inflammatory cytokine release. Let-7b-mediated TLR4 downregulation thus inhibits inflammation. miR-21 promotes IM progression by targeting the 3'-UTR of SOX2. SOX2 facilitates gastric differentiation while suppressing intestinal lineage expression through its inhibitory protein complex with CDX2. MiR-21-mediated SOX2 suppression upregulates CDX2, driving intestinal reprogramming and accelerating IM progression. miR-362 drives GC progression by targeting the CYLD 3'-UTR to suppress its translation, thereby alleviating CYLD-mediated NF-κB suppression. This creates a pro-survival microenvironment that enhances tumor cell resistance to apoptosis. 3'-UTR, 3'untranslated region; IM, intestinal metaplasia; miRNA, microRNA.

Methods

This study employed a narrative review methodology to synthesize literature from the PubMed and Web of Science databases published up to March 2025 (Table 1). The researches were limited to articles published in English. The following combinations of keywords were used: “miRNA” AND “gastric cancer” OR “stomach cancer”; “miRNA” AND “gastritis”; “miRNA” AND “intestinal metaplasia”. Additional relevant articles were identified through manual screening of reference lists from key reviews and original studies.

Basic biological characteristics of miRNAs

Discovery and classification of miRNAs

MiRNAs were first discovered following a seminal breakthrough in 1993, when Ambros’s research team characterized lin-4, a 22-nucleotide non-coding RNA exhibiting multiple complementary sequences in the 3’untranslated region (3’-UTR) of lin-14 mRNA (11,12). This pioneering work established the foundational regulatory paradigm whereby lin-4 post-transcriptionally represses target gene expression through sequence-specific 3’-UTR interactions. The subsequent identification of let-7 miRNA led to an exponential growth in miRNA research. In 2024, these two scientists were awarded the Nobel Prize in Physiology or Medicine for their seminal contributions to miRNA research. This accolade underscores the critical scientific value and frontier status of miRNA research in contemporary life sciences. To date, over 2,500 human-specific miRNAs have been identified (13).

Based on their maturation stage, canonical miRNAs are classified into three distinct molecular forms (4): (I) primary microRNAs (pri-miRNAs) transcripts, which are long polyadenylated RNA polymerase II products (300–1,000 nt) containing stem-loop structures; (II) precursor microRNAs (pre-miRNAs), which are 70–90 nt hairpin intermediates generated by the nuclear Drosha-DGCR8 microprocessor complex-mediated cleavage; and (III) mature miRNAs, which are 20–24 nt functional duplexes produced through cytoplasmic Dicer endonuclease processing.

Biosynthesis and mechanism of action of miRNAs

The biogenesis of miRNAs begins with the RNA polymerase II–mediated transcription of pri-miRNA transcripts (14). These pri-miRNA transcripts are subsequently processed by the RNase (Ribonuclease Enzyme) III enzyme Drosha (a component of the multi-protein microprocessor complex) into pre-miRNAs (14). The newly synthesized pre-miRNAs are then exported to the cytoplasm via RNA-binding nuclear export receptors (e.g., Exportin-5) (14). In the cytoplasm, the pre-miRNAs undergo further cleavage by Dicer, another RNase III enzyme, to generate mature miRNA duplexes. During this process, double-stranded RNA-binding proteins facilitate precise strand separation (14). The guide strand is selectively incorporated into the RNA-induced silencing complex (RISC) and plays a regulatory function (14,15). The RISC-loaded miRNA guides the sequence-specific silencing of target mRNAs through complementary base pairing. Notably, individual miRNAs can regulate multiple mRNAs, and single mRNAs may be coordinately controlled by multiple miRNAs (Figure 2).

Figure 2 miRNA biosynthesis pathway and regulatory mechanism. The biogenesis of miRNAs begins with RNA polymerase II transcribing pri-miRNA transcripts. The pri-miRNA transcripts are cleaved by the Drosha complex into pre-miRNAs, which are then exported to the cytoplasm via Exportin-5. There, Dicer processes the pre-miRNAs into mature miRNA duplexes. With the assistance of double-stranded RNA-binding proteins, the duplexes separate, and the mature strand is incorporated into the RISC while the complementary strand degrades. Ultimately, the RISC-loaded miRNA silences or degrades target messenger RNAs through complementary binding. miRNAs, microRNAs; pre-miRNAs, precursor microRNAs; pri-miRNA, primary microRNA; RISC, RNA-induced silencing complex.

MiRNA dysregulation in CG

CG: consensus definitions and pathological characteristics

CG is defined as a persistent inflammatory state of the gastric mucosa induced by diverse etiological factors, and is one of the most prevalent endoscopic diagnoses worldwide. While Helicobacter pylori (H. pylori) infection represents the primary pathogenic factor, other contributing factors include chronic non-steroidal anti-inflammatory drug use, excessive alcohol intake, and bile reflux (16). Histopathologically, CG is classified into chronic non-atrophic gastritis, chronic atrophic gastritis (CAG), and rare subtypes. Notably, CAG frequently progresses to IM and dysplasia, which are recognized precancerous lesions that mark a critical transition from inflammation to malignancy (17). Sustained mucosal inflammation in CG drives a multistep carcinogenic cascade, making it a lifelong inflammatory disorder with a significantly elevated risk of cancer.

MiRNA dysregulation and molecular mechanisms in CG development

In recent years, the role of miRNAs in inflammatory processes has attracted significant research attention. As key regulators in various inflammatory disorders, miRNAs exert regulatory control over target genes in immune cells, thereby modulating inflammatory responses (18,19).

Several pro-inflammatory and pro-pathogenic miRNAs are upregulated in H. pylori-infected or CG tissues, which in turn enhance inflammatory pathways such as NF-κB, promoting immune cell infiltration, and affecting cell proliferation and apoptosis (20). For example, miR-155 is significantly upregulated in the gastric mucosa and serum of infected patients, and has been shown to regulate the immune responses of T cells and macrophages (21,22). Its upregulation is associated with the maintenance of chronic inflammation (21,22). Similarly, miR-21 is frequently upregulated in infected or inflamed gastric tissues, and participates in abnormal epithelial cell growth and survival by targeting various inflammation-related regulatory factors (23).

Conversely, several miRNAs exhibit anti-inflammatory or negative feedback regulatory functions that suppress excessive inflammatory responses and promote tissue homeostasis. For example, in intestinal and upper gastrointestinal inflammation models, miR-223 has been reported to regulate NF-κB signaling pathways and inflammatory cytokine expression, thereby exerting immunomodulatory/anti-inflammatory effects (24-26). Variations in miR-223 expression are directly correlated with the intensity of macrophage inflammatory responses, suggesting its protective potential in gastric mucosal inflammation regulation (24-26). Conversely, certain miRNAs with purported protective/anti-cancer functions, such as miR-148a, are frequently downregulated in H. pylori-associated gastritis tissues. This downregulation alleviates the suppression of target genes like ROCK1, subsequently promoting epithelial cell migration, fibrosis, or pro-inflammatory phenotypes, indicating that miR-148a deficiency may drive inflammation toward pathological modification or precancerous progression (27,28).

MiRNA dysregulation in IM

IM: consensus definitions and pathological characteristics

IM refers to the pathological transformation of normal gastric mucosal epithelium into intestinal-type epithelium characterized by squamous or goblet cell differentiation, acquiring phenotypical and functional features reminiscent of intestinal epithelial cells (29). Functioning as a paradoxical adaptive response to chronic mucosal insults (e.g., bile reflux or H. pylori-associated inflammation), IM represents a precancerous state of gastric adenocarcinoma (GAC) and serves as a critical transitional stage in the gastric carcinogenesis cascade (30).

IM is classified into two subtypes with distinct malignant potential (31):

• Complete intestinal metaplasia (CIM; type I), which features well-differentiated intestinal elements with coexisting goblet cells, absorptive enterocytes, and Paneth cells (32,33); and
• Incomplete intestinal metaplasia (IIM; types II/III), which is characterized by disorganized glandular structures containing goblet cells and hybrid columnar-intermediate cells, but lacking definitive intestinal differentiation (32,33). Notably, the risk of GC progression is substantially higher for IIM than CIM (34).

The molecular mechanisms governing the transition from normal gastric mucosa to IM remain poorly delineated. Elucidating these transitional mechanisms—particularly the sequential histopathological and epigenetic alterations—is critical for unravelling the pathogenesis of IM, identifying clinically actionable biomarkers, and developing interventions to reverse metaplastic progression, thereby mitigating the incidence of GC.

The expression profile of miRNAs in IM

Accumulating evidence has demonstrated the pivotal regulatory roles of miRNAs in IM pathogenesis (Table 2). These non-coding RNAs drive critical molecular processes underlying IM progression through the targeted modulation of transcription factors, signal pathway components, and epigenetic regulators, thereby driving IM and the malignant evolution of gastric mucosa (37). Distinct miRNA expression profiles characterized by dynamic spatiotemporal regulation patterns have been identified across IM progression stages. This section systematically examines the miRNAs that mechanistically contribute to IM initiation, maintenance, and malignant transition.

Emerging evidence highlights the dysregulation of miRNA expression patterns in the pathogenesis of IM. Studies have demonstrated that miR-146a, miR-155, miR-584, and miR-1290 are significantly upregulated in H. pylori-induced IM (37,43). Additionally, research on the miR-17-92 cluster found that the expression of all seven members (miR-17-5p, miR-17-3p, miR-20a, miR-18a, miR-92a, miR-19a, and miR-19b) was increased in IM tissues, with the expression levels surpassing even those observed in GC samples (44). A systematic investigation further revealed that miR-168 overexpression is positively correlated with IM severity (36).

In patients with bile reflux-associated IM, miR-92a-1-5p shows specific elevation, and thus can serve as a distinct molecular feature (38). Additionally, oncogenic miRNA clusters, including miR-17/92, miR-106b-93-25, and individual miRNAs, such as miR-21, miR-194, and miR-196, have been consistently found to be overexpressed in IM mucosa compared to non-metaplastic tissues (45).

In contrast to these upregulated miRNAs, certain miRNAs have been shown to be downregulated during IM progression. For example, the reduced expression of miR-490-3p and miR-30a has been mechanistically linked to the development of IM (46-48). Notably, miR-370—a tumor-suppressive miRNA that functions by directly targeting FoxM1 to inhibit its activity—has shown a progressive decline in expression across the disease continuum from superficial gastritis → atrophic gastritis → IM → GC (49).

The regulatory mechanisms of miRNAs in IM

The involvement of miRNAs in regulating the cell cycle has emerged as a critical mechanism in the occurrence and maintenance of IM. As a premalignant lesion closely associated with GC, IM is characterized by the early stage dysregulation of cell-cycle control (50). MiRNAs exert their regulatory effects through the precise modulation of cell-cycle checkpoints and proliferation-related signaling cascades, positioning them as pivotal mediators in IM progression (37).

Caudal-type homeobox transcription factor 1 (CDX1) has been shown to be aberrantly overexpressed in gastric mucosa during the development of IM, where it drives both the initiation and maintenance of metaplastic transformation (51,52). Notably, Li et al. revealed a paradoxical expression pattern: CDX1 exhibits tumor-suppressive properties in GC by arresting the cell cycle at the G0/G1 phase through its forced overexpression, while its endogenous expression is markedly downregulated in GC specimens compared with IM tissues (53). Mechanistically, this tumor-associated CDX1 suppression is mediated by miR-296-5p, which directly targets two conserved binding sites in the 3’-UTR of CDX1 mRNA (53). This regulatory cascade subsequently activates ERK1/2 signaling pathway, triggering the following dual oncogenic effects: (I) the transcriptional activation of cyclin D1 to accelerate G1-S phase transition; and (II) the modulation of the Bcl2/Bax ratio to enhance tumor cell survival (54-56). Taken together, these findings delineate a miR-296-5p/CDX1/ERK axis that drives malignant transformation from IM to tumor through the synergistic promotion of cell-cycle progression and anti-apoptotic signaling.

IM is a critical precursor lesion in gastric carcinogenesis, characterized by the phenotypic transition of gastric epithelial cells toward an intestinal lineage (57,58). This transformation is marked by the emergence of mucin-containing goblet cells, Paneth cells, and absorptive cells, resulting in the replacement of normal gastric mucosa and associated glands with intestinal-type epithelium (57,58). Accumulating evidence suggests that miRNAs, as key post-transcriptional regulators, play an essential role in governing epithelial cell differentiation and maintaining cellular plasticity. They exert their effects on IM initiation and progression primarily by modulating differentiation-related transcription factors and signaling cascades.

CDX2 is an intestinal-specific transcription factor that acts as a triggering factor for gastroIM, capable of inducing and maintaining intestinal differentiation in the gastric environment (59). The effect of CDX2 is mediated by promoting the expression of intestinal markers, such as Krüppel-like factor 4 (KLF4), VILLIN (VIL1), MUCIN 2 (MUC2), and sucrase-isomaltase (S-I) (60). A study has shown that miR-92a-1-5p is involved in this transdifferentiation process (38).

Bile acids activate FXR receptors to upregulate miR-92a-1-5p in gastric cells. This miRNA directly suppresses FOXD1 expression by binding to its 3’-UTR. FOXD1 has been found to be dysregulated in various solid tumors, including GC, and to inhibit NF-κB activation, particularly of the RELA (p65) subunit (61). Reduced FOXD1 disrupts the FOXD1/FOXJ1 axis, leading to the dysregulation of IκBβ and the subsequent activation of NF-κB signaling (38). Phosphorylated NF-κB (p-p65) translocates to the nucleus and binds to the CDX2 promoter, inducing the transcription of this master intestinal transcription factor (38). CDX2 then drives the expression of intestinal markers (e.g., KLF4, MUC2, and VIL1), promoting the transdifferentiation of gastric epithelial cells into an intestinal phenotype (IM) (38).

The IM progression landscape is further shaped by the coordinated dysregulation of miR-30 family members and miR-194 (35). These miRNAs regulate IM through the dual transcriptional control of the:

• miR-30/HNF4γ pathway: miR-30 downregulation elevates hepatocyte nuclear factor 4γ (HNF4γ), activating intestinal markers VIL1 and TFF3 (35); and
• miR-194/NR2F2 pathway: miR-194 upregulation suppresses nuclear receptor subfamily 2 group F member 2 (NR2F2), amplifying HNF4γ-mediated VIL1 activation (35,62).

This synergistic miRNA network establishes an intestinal gene expression signature through epigenetic crosstalk, where NR2F2 depletion potentiates HNF4γ-driven activation of the intestinal markers VIL1 and TFF3, accelerating gastric-to-intestinal phenotypic conversion.

Cells expressing the H. pylori virulence factor CagA exhibit significant upregulation of miR-584 and miR-1290, indicative of pathogen-driven epigenetic reprogramming (37). The CagA-Erk1/2 cascade upregulates miR-1290, which targets NF-κB repressing factor to activate NF-κB-mediated miR-584 transcription (37). This dual miRNA amplification loop sustains Erk1/2 activation via Protein Phosphatase 2A inhibition while simultaneously suppressing forkhead box A1 (Foxa1)—a guardian of epithelial homeostasis (37). Foxa1 downregulation triggers epithelial-mesenchymal transition (EMT), a hallmark of premalignant progression that facilitates the advancement of IM (63-66). Thus, CagA suppresses Foxa1 expression via the upregulation of miR-584 and miR-1290, thereby driving EMT and potentiating IM progression.

MiRNA dysregulation in GC

Expression profile of miRNAs in GC (Table 3)

As key post-transcriptional regulators of cancer-associated genes, miRNAs exert oncogenic or tumor-suppressive functions by binding to complementary sequences in the 3’-UTRs of target mRNAs (80,81). The aberrant expression of miRNAs plays a critical role in the initiation and progression of GC. Comprehensive profiling of oncogenic and tumor-suppressive miRNA expression patterns in GC tissues could provide novel therapeutic avenues and pave the way for innovative treatment strategies (82,83).

In recent years, numerous studies have confirmed that various miRNAs exhibit significant differential expression in GC and contribute to tumor initiation and progression by modulating key signaling pathways. Among the upregulated miRNAs, miR-21, a well-characterized oncogenic miRNA, promotes GC cell proliferation, invasion, and metastasis, and enhances chemoresistance by suppressing tumor suppressor genes such as PTEN and PDCD4, thereby activating the PI3K/AKT pathway (84). miR-221-3p is markedly overexpressed in clinical GC tissue samples and facilitates cell proliferation and invasion, while its inhibition induces ferroptosis through the activation of the ATF3-GPX4/HRD1 axis (85). MiR-1290, which is enriched in GC-derived exosomes, targets GRHL2 and activates the ZEB1/PD-L1 axis, thereby mediating immune evasion (86). In addition, miR-32-5p, miR-708-3p, and the mirtronic miRNA miR-4646-5p have also been shown to be highly expressed in GC, promoting malignant tumor progression by regulating the cell cycle and metastasis-associated factors (87-89).

Conversely, a series of miRNAs are downregulated in GC and exert tumor-suppressive effects. The reduced expression of miR-204-5p is closely associated with lymph node metastasis and a poor prognosis: circSLAMF6 binds to miR-204-5p and regulates the miR-204-5p/MYH9 axis in GC, leading to its downregulation and thereby promoting tumor cell migration and invasion (90). miR-34a enhances chemosensitivity by targeting the Netrin-1/MEK-ERK pathway, and is significantly downregulated in clinical tumor specimens and cisplatin-resistant cells (91). miR-148a-3p inhibits GC cell invasion and migration, and is associated with 5-year disease-free survival (92,93). A study has shown that in GC, miR-148a-3p is competitively bound by lncRNA H19, leading to its reduced expression, which relieves the suppression of SOX-12, and promotes cell migration and invasion (94). In addition, miR-145-5p, miR-375, and miR-29c are also significantly downregulated in GC tissues and plasma, and functional studies have confirmed their roles in inhibiting cell proliferation and angiogenesis (95,96).

Overall, the extensive molecular landscape and functional networks of miRNAs in GC not only provide potential biomarkers for diagnosis and prognostic evaluation but also lay the foundation for precision therapeutic strategies targeting miRNAs.

Regulatory mechanisms of miRNAs in GC cell proliferation and apoptosis

miRNAs can modulate key target genes, thereby influencing tumor cell proliferation, apoptosis, and invasion, and ultimately exerting a bidirectional role in the initiation and progression of GC (97). Certain miRNAs exhibit tumor-suppressive properties by promoting apoptosis and inhibiting cell-cycle progression; conversely, some miRNAs exert oncogenic effects by suppressing apoptosis or enhancing proliferative signaling (98). Elucidating the functions and underlying mechanisms of these miRNAs not only extends our understanding of the molecular basis of GC development but also provides important insights for identifying novel diagnostic biomarkers and therapeutic targets.

In GC cells, miR-320a-3p exerts tumor-suppressive effects through multiple synergistic mechanisms. First, as a dominant regulatory axis, miR-320a-3p binds to the 3’UTR of PD-L1, thereby suppressing PD-L1 expression, which not only mitigates immune evasion but also attenuates PD-L1-mediated intrinsic pro-survival signaling (99). Second, miR-320a-3p upregulates the expression of pro-apoptotic genes, including CASP3 and TP53, in GC cells, thereby promoting apoptosis (99). Third, miR-320a-3p downregulates CDK16, leading to the inhibition of the cell cycle and proliferation, and potentially further reducing PD-L1 expression, thereby enhancing antitumor activity (100).

MiR-146a-5p inhibits GC progression by targeting the cell-cycle regulator CDC14A. Mechanistically, miR-146a-5p binds to the CDC14A’s 3’-UTR, reducing its expression and causing spindle defects, chromosomal missegregation, and abnormal cytoplasmic separation (75,101,102). A comparative analysis revealed the significant downregulation of miR-146a-5p expression concomitant with elevated CDC14A levels in gastric cancer specimens relative to adjacent normal tissues, indicating their synergistic involvement in driving gastric carcinogenesis (75).

miR-125a-5p is generally downregulated in GC, and its restoration not only suppresses tumor cell proliferation but also induces apoptosis (103). A study has also revealed that in GC, DNA methyltransferase 1 (DNMT1) induces the methylation of miR-125a-5p, leading to its transcriptional silencing and consequently promoting high expression of SERPINH1, which facilitates GC cell proliferation and EMT, thereby accelerating GC initiation and progression (104). SERPINE1, a member of the serine protease inhibitor family, is a key regulator of the plasminogen/plasmin system (105). Previous research has demonstrated that SERPINE1 possesses pro-angiogenic, growth-promoting, migration-stimulating, and anti-apoptotic properties, all of which act in a targeted manner to support tumor cell growth and survival (105).

A comparative analysis of GC specimens and normal gastric epithelium specimens revealed the significant downregulation of phosphatase and tensin homolog (PTEN) at both the transcriptional and translational levels, revealing an inverse correlation with miR-575 expression (71). PTEN exerts its tumor-suppressive function by dephosphorylating phosphatidylinositol (3,4,5)-trisphosphate (PIP3), the lipid second messenger generated by PI3K, thereby antagonizing the activation of the oncogenic PI3K/AKT/mTOR signaling cascade (106). Mechanistic examination via luciferase reporter assays established PTEN as a direct molecular target of miR-575, with functional assays confirming that this epigenetic regulatory axis mediates the tumor-promoting effects of miR-575 through the coordinated modulation of cellular proliferation and apoptotic pathways in gastric carcinogenesis (71). This miR-575/PTEN regulatory circuit represents a critical pathogenic mechanism underlying GC progression.

MiR-21, an oncogenic miRNA, contributes to the development of various cancers (e.g., acute myeloid leukemia and lung cancer) by targeting tumor suppressor genes (107,108). A study has found that miR-21 is significantly upregulated in H. pylori-infected GC tissues and directly binds to the 3’-UTR of ASPP2 mRNA, resulting in reduced ASPP2 expression and consequently weakening its pro-apoptotic function (109). ASPP2 plays a crucial role in regulating cell growth and apoptosis, and has been identified as a tumor suppressor (110). Experimental evidence indicates that miR-21 reduces ASPP2 protein levels, thereby indirectly impairing the stability and transcriptional activity of CHOP (CCAAT/enhancer-binding protein homologous protein). This attenuation diminishes the ability of CHOP to activate downstream pro-apoptotic target genes such as NOXA and BAK, while relieving its inhibitory effect on the anti-apoptotic protein BCL-2. Consequently, cells exhibit increased resistance to both intrinsic and extrinsic apoptotic stimuli (109,111,112). Collectively, the H. pylori-induced upregulation of miR-21 targets ASPP2 and suppresses the CHOP-driven pro-apoptotic transcriptional program, establishing a molecular axis that promotes GC cell survival and tolerance to cell death signals.

GC cells secrete exosomes enriched with miR-541-5p, delivering this miRNA to macrophages in the tumor microenvironment (113). In macrophages, miR-541-5p directly targets and downregulates the expression of dual-specificity phosphatase DUSP3, thereby relieving its negative regulation of the JAK2/STAT3 signaling pathway (113). The JAK2/STAT3 pathway not only plays a key role in regulating cell proliferation and differentiation but is also closely associated with the polarization of M2-type macrophages (114,115). DUSP3, as a dephosphorylation enzyme, catalyzes the dephosphorylation of substrate proteins (116). The loss of DUSP3 function results in the sustained phosphorylation of JAK2 and STAT3, driving macrophages toward a M2 phenotype (characterized by upregulated M2 marker expression and immunosuppressive properties), thereby establishing an immunoregulatory network in the local tumor microenvironment that promotes tumor growth and immune evasion (113).

Regulatory mechanisms of miRNAs in GC cell invasion and metastasis

MiRNAs play pivotal roles in regulating the invasion and metastasis of GC cells. This section systematically examines GC-associated miRNAs that modulate cellular invasion/metastasis pathways, with a particular emphasis on their molecular mechanisms.

Multiple studies have demonstrated that miR-223-3p is highly expressed in GC, and its expression level is significantly positively correlated with lymph node metastasis and invasion depth (117-119). Sorbin and SH3 domain-containing protein 1 (SORBS1) plays a crucial role in miR-223-3p mediated GC progression (120). As an adaptor protein, SORBS1 can interact with cytoskeletal regulatory factors, thereby contributing to the regulation of cytoskeletal dynamics, cell spreading, and motility (121). Further, Jin et al. reported that cancer-associated fibroblast-derived extracellular vesicles can deliver miR-223-3p to GC cells, promoting cell migration and invasion by targeting SORBS1 (120). Thus, the miR-223-3p/SORBS1 axis plays a pivotal role in GC malignant progression by enhancing cellular invasion and metastasis.

MiR-204-5p is significantly downregulated in GC tissues, and its low expression is closely associated with lymph node metastasis and an advanced tumor stage (122). Pan et al. confirmed through bioinformatic analyses and luciferase reporter assays that RAB22A is a direct target of miR-204-5p, and that the overexpression of miR-204-5p markedly reduces RAB22A protein levels (122). RAB22A, a member of the small GTPase (guanosine triphosphatase) RAB family (RAB GTPase family), is a key regulator of intracellular membrane trafficking and is overexpressed in various cancers, including breast cancer (123), melanoma (124), lung adenocarcinoma (125), and thyroid cancer (126), where it promotes tumor growth and metastasis via the activation of oncogenic signaling pathways. A study has revealed that miR-204-5p suppresses the PI3K/AKT signaling pathway in GC cells by targeting RAB22A (122). The PI3K/AKT pathway, a well-established oncogenic signaling cascade, is frequently activated in GC, contributing to tumor progression and chemoresistance (127,128). In summary, miR-204-5p exerts a tumor-suppressive effect in GC by modulating the RAB22A/PI3K/AKT axis.

Recent research identified miR-29c as a tumor suppressor in GC, with its inhibitory effects being partially mediated via the regulation of its downstream target gene integrin β1 (ITGB1) (79). The loss of miR-29c expression represents an early molecular event in GC pathogenesis. ITGB1, a transmembrane adhesion receptor composed of α and β subunits, plays crucial roles in multiple biological processes, including cell adhesion, tissue repair, immune responses, and tumor metastasis—all of which are essential for GC initiation and progression (79,129). Clinically significant findings demonstrate that ITGB1 upregulation promotes GC cell invasion and is strongly associated with poor patient prognosis and increased recurrence rates (130-132).

Potential of miRNAs as biomarkers in GC

MiRNAs as promising biomarkers in early GC detection

MiRNAs have emerged as clinically valuable biomarkers due to their frequent dysregulation in solid tumors, including GC (133,134). The distinct expression patterns of circulating miRNAs in biofluids (blood, urine, and gastric juice) demonstrate remarkable stability and accessibility, making them ideal candidates for early GC detection. This section examines recent advancements in miRNA-based diagnostic strategies.

A growing number of studies have investigated circulating microRNAs as non-invasive biomarkers for GC, with both single-miRNA indicators and multi-miRNA panels showing promising diagnostic value. The following key diagnostic candidates have been identified:

• miR-222
  • Clinical correlation: the high expression of miR-222 in plasma is associated with advanced tumor stage and poorer nutritional status in patients with GC (135).
  • Diagnostic superiority: a receiver operating characteristic curve analysis showed that plasma miR-222 expression levels demonstrate good diagnostic performance for GC, exhibiting both high sensitivity and specificity (135).
• Multi-miRNA panels
  • Early gastric cancer (EGC) Index: researchers have developed an EGC Index using serum levels of four miRNAs (miR-4257, miR-6785-5p, miR-187-5p, and miR-5739), which has demonstrated high specificity and sensitivity for early GC screening (136). The EGC group exhibited elevated miR-4257/miR-187-5p and reduced miR-6785-5p levels compared to the non-cancer control group. Validated through large-scale cohort analysis, the diagnostic precision of this optimized three-miRNA panel (comprising miR-4257, miR-6785-5p, and miR-187-5p) was shown to outperform existing biomarkers in early stage GC detection.
  • Destinex diagnostic panel: a diagnostic panel named Destinex has been developed, comprising five overlapping cell-free and exosomal miRNAs (miR-21-3p, miR-21-5p, miR-215-5p, miR-27a-3p, and miR-95-3p). In validation cohorts, Destinex demonstrated remarkable diagnostic performance, achieving an area under the curve of 94.8% (137). Notably, Destinex exhibited higher sensitivity in distinguishing early stage GC patients from disease-free controls, with detection rates of 94.7% for pT1 (pathologic tumor stage 1) compared to 86.0% for pT2–T4 (pathologic tumor stage 2–4) tumors (137).

Cumulative evidence demonstrates the efficacy of miRNAs as early predictive biomarkers for GC. Compared with conventional serum biomarkers (e.g., CEA, CA19-9, and CA72-4), which show limited sensitivity for early-stage GC, circulating miRNA panels consistently demonstrate superior diagnostic performance. Notably, several panels achieve sensitivities exceeding 85–90% in early GC, underscoring their potential clinical advantage in early detection (138,139). Although the specific miRNA composition of diagnostic panels differs among studies, many identified miRNAs converge on common biological pathways related to epithelial–mesenchymal transition, cell cycle regulation, and inflammatory signaling, indicating functional consistency despite marker-level heterogeneity. These miRNAs have superior specificity and sensitivity. Their clinical implementation holds significant potential to enhance early detection rates, enabling timely interventions that improve 5-year survival outcomes.

MiRNAs as predictive biomarkers in GC therapy efficacy

Due to their abundance in blood and their ability to reflect tumor biological behavior, circulating miRNAs and exosomal miRNAs have increasingly become a key focus for investigating treatment responses, including chemotherapy, targeted therapy, and immunotherapy responses.

Recent evidence has highlighted the critical role of exosome-mediated intercellular communication in modulating chemotherapeutic responses in GC. Notably, miR-21, which is abundantly enriched in exosomes derived from M2-polarized tumor-associated macrophages, has been shown to be efficiently internalized by GC cells, where it confers marked resistance to cisplatin treatment (140). Mechanistic studies have shown that miR-21 exerts its oncogenic effects primarily through the inhibition of the tumor suppressor PTEN, leading to the activation of the PI3K/AKT signaling cascade and subsequent upregulation of the anti-apoptotic protein Bcl-2 (140,141). This signaling axis effectively attenuates apoptosis and promotes cell survival under chemotherapeutic stress, thereby contributing to the development of cisplatin resistance. Collectively, these findings underscore the functional significance of tumor-associated macrophage (TAM)-derived exosomal miR-21 in shaping the chemoresistant phenotype of GC and suggest that targeting the miR-21/PTEN/PI3K/AKT axis may represent a promising therapeutic strategy for overcoming drug resistance.

MiRNA modulation, which significantly enhances chemotherapeutic efficacy in GC, has emerged as a promising adjuvant therapeutic strategy. miRNA profiling enables precision medicine approaches through personalized treatment regimens that optimize therapeutic outcomes while minimizing adverse effects. Particularly noteworthy is the synergistic potential of miRNA-chemotherapeutic combinations, which effectively counteract multidrug resistance mechanisms in GC cells, demonstrating substantial clinical translation prospects.

Research advances in miRNAs as prognostic biomarkers for GC

Despite advancements in diagnostic technologies and perioperative management, which have improved early detection rates and reduced mortality in GC, patients with advanced-stage GC continue to exhibit frequent disease recurrence and extremely poor survival outcomes following extended radical resection (142). The identification of reliable biomarkers to predict survival and recurrence in GC patients remains critically important. This section reviews recent progress in evaluating miRNAs as biomarkers for prognostic assessment in GC.

Recent study has identified four memory B cell-related miRNAs that are significantly associated with the prognosis of GC (i.e., hsa-mir-221, hsa-mir-100, hsa-mir-145, and hsa-mir-125b-2), based on which a prognostic risk model was constructed (143). Hsa-mir-221 expression was found to be low in the high-risk group, while hsa-mir-100, hsa-mir-145, while hsa-mir-125b-2 expression was found to be high in this group (143). It is well established that persistent genomic instability (GI)-associated mutations promote tumorigenesis, progression, and treatment resistance, and accumulating evidence indicates that miRNAs are closely involved in maintaining genomic stability in GC cells (144-146). Building on this, a GI-related 12-miRNA model was developed to predict GC prognosis, revealing that miR-100-5p and miR-145-3p promote GC cell proliferation, invasion, and migration, and this model was found to have high clinical value for prognostic assessment (147). Yu et al. found that STAT3-regulated miR-200 family-associated genes hold superior predictive value for overall survival in GC patients (148). Additionally, Chen et al. developed a prognostic model incorporating six miRNAs (miR-549, miR-100, miR-653, miR-374a, miR-668, and miR-509-3p), which effectively stratified patients into high- and low-risk groups and predicted 3- and 5-year survival rates (149).

A growing body of evidence supports the utility of miRNAs as prognostic biomarkers in GC. Future research should focus on integrating miRNA profiles with traditional clinicopathological characteristics, such as tumor grade and stage, to establish more accurate prognostic models, thereby enhancing clinical decision-making and personalized therapeutic strategies.

Role of miRNAs in disease progression

GC, a malignancy with high global incidence and mortality, arises through a multifactorial, multistep process typically progressing from CG to IM, and ultimately to invasive carcinoma (150). miRNAs, a class of non-coding RNAs, regulate critical biological processes, including cell differentiation, proliferation, apoptosis, and tissue remodeling, by binding to complementary sequences in target mRNAs (151). Understanding dynamic miRNA alterations during disease progression is essential for advancing early diagnosis and targeted therapies.

Bi et al. found that miR-3613-5p is overexpressed in the early stages of the disease continuum, including in the gastric mucosa of human cancer cell lines and mouse CAG models (152). This consistent upregulation across stages (CAG → IM → GC) positions miR-3613-5p as a key molecular driver in the precancerous stage. Researchers have also observed that the overexpression of miR-3613-5p in CAG mice exacerbates gastric mucosal pathological changes, including atrophy, hyperplasia, inflammatory cell infiltration, and IM, while increasing serum levels of the pro-inflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) (152). Critically, silencing miR-3613-5p alleviates these pathological changes, reduces inflammation, and underscores its functional necessity in disease progression.

The role of miR-3613-5p in the continuum of lesions is associated with its direct targeting of the aquaporin 4 (AQP4) gene: miR-3613-5p binds to the 3’UTR of AQP4 mRNA, leading to its degradation or translational repression (152). The loss of AQP4 may amplify local IL-6 concentrations in CAG by promoting the activation of inflammatory cells such as macrophages and neutrophils (153). IL-6 activates the JAK/STAT signaling pathway, enhancing the proliferation and anti-apoptotic capacity of cancer cells (154). The miR-3613-5p-mediated inhibition of AQP4 disrupts cellular homeostasis and contributes to the formation of a pro-tumorigenic inflammatory microenvironment, facilitating the transition from CAG-induced mucosal damage to the uncontrolled cell proliferation and migration characteristics of GC.

In summary, miR-3613-5p exemplifies a miRNA dynamically upregulated across the CG (specifically CAG)-IM-GC continuum. Its overexpression drives disease progression. Rather than acting as a static oncogenic factor, miR-3613-5p exhibits functional plasticity during disease progression. In precancerous stages (CAG and IM), its sustained upregulation promotes mucosal inflammation and epithelial injury through AQP4 suppression and IL-6-JAK/STAT activation, whereas in established GC, this inflammatory axis may be repurposed to support tumor proliferation, survival, and microenvironmental remodeling. In addition, miR-3613-5p likely operates within a broader co-regulatory network of inflammation-responsive miRNAs and cytokine-driven pathways.

Conclusions

MiRNAs play pivotal roles in CG, IM, and GC by regulating gene expression and modulating biological processes such as cell proliferation, apoptosis, and differentiation, thereby driving disease initiation and progression. Advances in high-throughput sequencing technologies have accelerated the identification of miRNAs associated with gastrointestinal pathologies. Emerging studies highlight miRNA expression profiles as promising biomarkers for distinguishing between CG, IM, and GC. Further, in vitro and in vivo experimental models have enabled the mechanistic validation of miRNA-disease relationships, deepening our understanding of their biological underpinnings.

The clinical applications of miRNAs include:

• Diagnosis: circulating miRNAs detected via liquid biopsy (e.g., blood-based assays) offer non-invasive tools for early disease detection;
• Therapy: miRNA replacement or inhibition strategies (e.g., antagomiRs or miRNA mimics) show potential for restoring dysregulated miRNA expression; and
• Prognosis: specific miRNA signatures are correlated with survival rates and recurrence risks, and thus can aid in patient stratification.

Despite progress, critical gaps persist. While certain miRNAs have been established as key regulators in CG, IM, and GC, their precise molecular mechanisms remain incompletely characterized. Future research should integrate multi-omics approaches (e.g., transcriptomics and epigenomics) and machine learning to unravel miRNA interaction networks and their disease-specific roles. Such efforts will accelerate the translation of miRNA discoveries into clinical applications, including precision diagnostics and targeted therapies.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-1-2642/rc

Peer Review File: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-1-2642/prf

Funding: This work was supported by the National Natural Science Foundation of China (No. 82203854); Key Research and Development Program of Shandong Province (No. 2021CXGC011104); and Special Foundation for Taishan Scholars Program of Shandong Province (Nos. ts20190978 and tsqn202408363).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-1-2642/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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(English Language Editor: L. Huleatt)