Recent Advances of miRNAs in the Development and Clinical Application of Gastric Cancer
Gastric cancer (GC) remains a leading cause of cancer-related morbidity and mortality worldwide, particularly in Asia, Latin America, and parts of Europe. Despite advancements in diagnostic and therapeutic approaches, the underlying mechanisms driving GC progression and resistance to treatment remain poorly understood. MicroRNAs (miRNAs), small non-coding RNAs approximately 22 nucleotides in length, have emerged as critical regulators of tumorigenesis, influencing key cellular processes such as proliferation, apoptosis, metastasis, drug resistance, and stemness. This review synthesizes recent discoveries regarding the roles of miRNAs in GC pathogenesis and their potential applications in diagnosis, prognosis, and therapy.
miRNAs in Gastric Cancer Pathogenesis
Proliferation and Apoptosis
miRNAs exert dual roles as oncogenes or tumor suppressors by modulating proliferation and apoptosis. For example, miR-21 is frequently overexpressed in GC tissues and cell lines, promoting cell proliferation by targeting RECK, a suppressor of matrix metalloproteinases. Conversely, miR-29c acts as a tumor suppressor by inhibiting integrin β1, which is critical for cell adhesion and survival. The let-7 family, silenced by H. pylori CagA, suppresses proliferation by targeting HMGA2 and Ras, while miR-503 similarly downregulates HMGA2 to impair cell growth. The NF-κB pathway, a central regulator of inflammation and oncogenesis, is modulated by miRNAs like miR-508-3p, which targets NF-κB1 and RELA, and miR-411, which suppresses SETD6.
Apoptosis is regulated by miRNAs through interactions with apoptotic genes and signaling pathways. miR-24 inhibits apoptosis by targeting BCL2L11, a pro-apoptotic protein. In contrast, miR-17-5p and miR-20a promote apoptosis and cell cycle arrest by downregulating SOCS6. miR-30a enhances cisplatin sensitivity by suppressing integrin α2, while miR-1254 inhibits Smurf1 to activate the PI3K/AKT pathway, thereby reducing chemoresistance.
Invasion and Metastasis
miRNAs are pivotal in regulating GC invasion and metastasis. miR-194 promotes metastasis by suppressing SUFU, a negative regulator of Wnt signaling, whereas miR-29c-3p drives invasiveness via KIAA1199, which activates FGFR4/EGFR pathways. The miR-17-92 cluster, including miR-19a/b, enhances metastasis by forming feedback loops with c-Myc and Max. miR-27a promotes metastasis through the AKT/GSK3β pathway by targeting PHLPP2, while miR-939 inhibits metastasis by suppressing SLC34A2 and its downstream Raf/MEK/ERK signaling.
Angiogenesis, essential for tumor growth and dissemination, is influenced by miRNAs such as miR-21, which upregulates VEGF via RECK inhibition. Exosomal miRNAs, including miR-155 and miR-23a, promote angiogenesis by targeting c-Myb and PTEN, respectively. Interactions between miRNAs and non-coding RNAs further modulate metastasis; for example, lncRNA TRPM2-AS sequesters miR-574 to enhance tumor aggressiveness.
Drug Resistance
Chemoresistance in GC is intricately linked to miRNA dysregulation. miR-29 family members reverse cisplatin resistance by inhibiting catenin-δ and RhoA. miR-148a-3p sensitizes cells to cisplatin by blocking protective autophagy, while miR-143-3p targets Brd2 to restore chemosensitivity. Multi-drug resistance is modulated by miR-508-5p, which downregulates ABCB1 and ZNRD1. Exosomal miRNAs, such as miR-374a-5p and miR-214, are critical in transferring resistance traits; nanoparticle-mediated delivery of anti-miR-214 or miR-200c synergizes with chemotherapy to overcome resistance.
Cancer Stem Cells (CSCs)
CSCs contribute to tumor recurrence and therapy resistance. miR-34a suppresses CSC stemness by targeting CD44 and Bmi-1, while miR-200c nanoparticles inhibit EMT and CSC properties. miR-501-5p enhances stemness via Wnt/β-catenin activation, and IL-1-induced miR-135b promotes invasiveness by repressing RECK and FOXN3. The miR-17-92 cluster, including miR-92a and miR-19a/b, sustains CSC self-renewal by modulating Wnt signaling.
Precancerous Inflammatory Lesions
Chronic inflammation driven by H. pylori infection is a key risk factor for GC. miR-7 and miR-223-3p are upregulated by H. pylori to promote carcinogenesis via NF-κB and ARID1A targeting. miR-22 suppresses NLRP3 inflammasome activity, while miR-3178 inhibits inflammation by targeting TRAF3.
Clinical Applications of miRNAs in GC
Diagnostic Biomarkers
miRNA expression profiles distinguish GC subtypes and stages. Tissue-specific miRNAs, such as miR-138 and miR-196a, differentiate gastric MALT lymphomas, while miR-145 and miR-133a are overexpressed in diffuse-type GC. Circulating miRNAs in serum, plasma, or gastric juice offer non-invasive diagnostic potential. For instance, a three-miRNA panel (miR-652, miR-629, miR-627) achieves 86.7% sensitivity and 85.5% specificity in plasma. Gastric juice miR-21 and miR-106a distinguish GC from benign conditions with AUC values up to 0.969.
Prognostic Predictors
miRNA signatures correlate with clinical outcomes. A seven-miRNA panel (miR-30a-5p, miR-21, miR-126, let-7a, etc.) predicts overall survival (HR = 3.046) and relapse-free survival (HR = 3.337). Low serum miR-203 and high miR-25 independently predict metastasis and poor prognosis. Plasma miR-1229-3p is an independent predictor of recurrence (HR = 3.710).
Therapeutic Potential
miRNA-based therapies are under exploration. MRX34, a miR-34 mimic, showed promise in clinical trials but was halted due to immune toxicity. Nanoparticle delivery of miR-200c or anti-miR-214 enhances chemosensitivity and targets CSCs. Exosome-mediated transfer of anti-miRNAs, such as anti-miR-374a-5p, reverses drug resistance by restoring NDRG1 expression.
Challenges and Future Directions
Despite progress, challenges remain in translating miRNA research into clinical practice. Heterogeneity in miRNA expression across studies, limited validation in large cohorts, and safety concerns regarding miRNA-based therapies necessitate further investigation. The integration of miRNA signatures with clinical parameters and the development of targeted delivery systems hold promise for personalized GC management.
doi.org/10.1097/CM9.0000000000000921
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