The microRNA (miR) cluster miR-143/145 represents a well-characterized tumor-suppressive regulatory system with a multifaceted role in prostate cancer. Both miRs are consistently downregulated during disease progression, and their loss is associated with enhanced proliferation, invasion, epithelial–mesenchymal transition, and metastatic competence. Mechanistically, the cluster modulates Rat Sarcoma Viral Oncogene Homolog (RAS)-Mitogen Activated Protein Kinase (MAPK) signaling via Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) and Extracellular Signal-Regulated Kinase 5 (ERK5), Tumor Protein p53 (p53)-dependent growth control through MYC Proto-Oncogene, Basic Helix-Loop-Helix Transcription Factor (c-MYC) repression, apoptosis via B-Cell Lymphoma 2 Interacting Protein 3 (BNIP3), and cytoskeleton-associated motility factors including Fascin Actin-Bundling Protein 1 (FSCN1), Human Enhancer of Filamentation 1/ Neural Precursor Cell Expressed, Developmentally Down-Regulated Protein 9 (HEF1/NEDD9), Golgi Membrane Protein 1 (GOLM1), and Fibronectin Type III Domain Containing 3B (FNDC3B). Downregulation is mainly driven by p53 dysfunction, promoter methylation, and RAS-dependent transcriptional repression. A defining feature is pronounced cell-type specificity, with tumor-suppressive effects in epithelial cells and context-dependent pro-angiogenic functions in stromal compartments, with direct translational relevance. Clinically, miR-143/145 contribute to multimarker diagnostic signatures, while reduced miR-145 correlates with adverse pathology and biochemical recurrence. Preclinical replacement strategies reduce tumor growth and enhance docetaxel sensitivity, yet context-dependent effects necessitate cell type-specific delivery. Overall, the cluster represents a central regulator with diagnostic, prognostic, and therapeutic potential requiring prospective validation.
Stope et al. (Sat,) studied this question.