The role of MicroRNAs in modulating ZEB2-driven EMT and metastasis

MicroRNAs (miRNAs) are small noncoding RNAs that fine-tune gene expression by promoting mRNA degradation or translational repression. In cancer, miRNAs serve as key regulators of tumor progression, acting either as oncogenes or tumor suppressors. A central aspect of their function is the regulation of epithelial-mesenchymal transition (EMT), a process that enables epithelial cells to acquire mesenchymal features, enhancing motility, invasion, and metastatic potential. ZEB2, a transcription factor and primary EMT driver, represses epithelial markers such as E-cadherin while promoting mesenchymal traits. Its overexpression is closely associated with cancer stem cell-like properties, recurrence, and drug resistance. Multiple miRNAs directly target ZEB2 to modulate EMT and metastatic behavior. Notably, the miR-200 family (miR-200a, miR-200b, miR-200c, miR-141, and miR-429) acts as a crucial suppressor of EMT by binding ZEB2 mRNA, thereby maintaining epithelial identity. Conversely, high ZEB2 expression represses miR-200 levels, establishing a feedback loop that dictates the balance between epithelial and mesenchymal states. Other miRNAs, including miR-205, miR-206, and miR-637, also suppress ZEB2 expression, with their downregulation correlating with enhanced invasion, metastasis, and poor patient outcomes. Dysregulation of these miRNA-ZEB2 interactions shifts the cellular phenotype toward mesenchymal dominance, facilitating cancer cell migration, dissemination, and colonization at distant sites. This study aims to explore the molecular and cellular mechanisms underlying the interactions between ZEB2 and miRNAs, with a particular focus on their role in regulating EMT, migration, and metastasis in cancer. This understanding may guide the development of novel therapeutic strategies targeting the miRNA-ZEB2 axis to prevent tumor progression and improve patient outcomes.