Dual Roles of Specific microRNA Clusters as Tumor Suppressors and Oncogenes in Epithelial Cancers: A Systematic Review

Abstract

Background: Epithelial cancers represent a major global cancer burden and frequently develop metastasis, recurrence, and treatment resistance despite advances in molecular therapy. MicroRNA clusters are increasingly recognized as coordinated post-transcriptional regulators of tumor biology, yet the same cluster may act as a tumor suppressor in one epithelial context and as an oncogene in another. This functional duality complicates biomarker interpretation and the development of miRNA-directed therapeutic strategies. Objective: This systematic review aimed to synthesize evidence on the context-dependent tumor-suppressive and oncogenic roles of selected microRNA clusters, including the miR-200 family, miR-17~92, miR-221/222, and miR-183/96/182, across epithelial cancers. Methods: A systematic review without meta-analysis was conducted in accordance with PRISMA 2020. PubMed/MEDLINE, Scopus, Web of Science Core Collection, and the Cochrane Library were searched for studies published from January 2019 to December 2024. Eligible studies were original experimental or translational investigations of predefined microRNA clusters in epithelial cancer models or patient specimens, reporting functional outcomes related to proliferation, apoptosis, epithelial-to-mesenchymal transition, invasion, metastasis, treatment response, or survival. Study selection, data extraction, and risk-of-bias assessment were performed independently by two reviewers. SYRCLE’s tool, the Newcastle-Ottawa Scale, and an adapted preclinical rigor checklist were used according to study design. Findings were synthesized narratively because of methodological and biological heterogeneity. Results: Of 1,847 records identified, 55 studies met the eligibility criteria. The miR-200 family and miR-17~92 cluster showed the strongest evidence of functional duality across epithelial cancer types. miR-221/222 was predominantly oncogenic but showed context-specific suppressive effects in prostate cancer, while miR-183/96/182 demonstrated divergent roles across gastrointestinal and pancreatic cancer contexts. Functional direction was influenced by tissue lineage, molecular subtype, driver mutation background, receptor signaling, treatment exposure, and microenvironmental conditions. Conclusion: Selected microRNA clusters cannot be classified as universally oncogenic or tumor-suppressive. Their biological and clinical interpretation requires a context-aware framework integrating epithelial origin, molecular subtype, pathway activity, and tumor microenvironment.