Context dependent roles of MicroRNA-377 in cancer from epigenetic silencing to therapeutic reactivation

MicroRNA-377 (miR-377) is a predominantly tumor-suppressive microRNA with context-dependent functions in cancer. Located within the imprinted DLK1-DIO3 region on chromosome 14q32, miR-377 regulates proliferation, apoptosis, invasion, metastasis, and treatment response, and its dysregulation contributes to cancer development, progression, and therapy resistance. This review examines the molecular basis of miR-377 silencing, including DNMT1-mediated DNA hypermethylation, EZH2-driven repressive histone modifications, and competing endogenous RNA (ceRNA) mediated post-transcriptional repression. miR-377 exerts convergent effects across multiple oncogenic pathways, including PI3K/AKT, Wnt/β-catenin, TGF-β, NF-κB, and MAPK signaling. Although predominantly tumor-suppressive, context-dependent oncogenic roles have also been reported, particularly in lung, hepatocellular, colorectal, and gastric cancer, underscoring the need for cancer- and isoform-specific interpretation. Circulating miR-377 shows potential as a non-invasive biomarker, though clinical validation remains limited. Preclinical strategies to restore miR-377 function include miRNA mimics, nanoparticle-based delivery, epigenetic reactivation, and CRISPR-based approaches; however, substantial translational barriers remain, and miR-377 restoration warrants further investigation in appropriately defined molecular and clinical settings.