miR-142-3p in cancer: intracellular tumor suppression and extracellular vesicle- mediated microenvironmental signaling

Abstract

miR-142-3p has emerged as an important regulator of cancer progression and treatment response, exhibiting predominantly tumor-suppressive functions. Intracellularly, miR-142-3p inhibits proliferation, promotes apoptosis, suppresses epithelial–mesenchymal transition (EMT), and enhances chemosensitivity through the downregulation of key pathways, including HMGB1, Wnt/β-catenin, and SIRT1-mediated autophagy. Notably, miR-142-3p is frequently enriched in extracellular vesicles (EVs), indicating selective export from tumor cells. This EV-mediated trafficking introduces functional complexity, as the loss of intracellular miR-142-3p may attenuate its tumor-suppressive effects, while its transfer to recipient cells within the tumor microenvironment (TME) may exert context-dependent roles. Within the TME, miR-142-3p has been associated with the regulation of cancer-associated fibroblast (CAF) activation, angiogenesis, and immune responses. Emerging evidence further suggests a potential role for EV-associated miR-142-3p in systemic processes such as cancer-associated cachexia through modulation of muscle-related pathways, although this remains poorly defined. This review summarizes the dual intracellular and extracellular functions of miR-142-3p in cancer and highlights its contribution to treatment sensitivity and TME interactions. We also discuss current challenges and future directions, including therapeutic strategies aimed at restoring intracellular miR-142-3p levels or modulating its EV-mediated transfer. A deeper understanding of its context-dependent roles will be critical for the development of targeted and clinically relevant therapeutic approaches.