Tumor progression is effectively suppressed by miR-195 through direct targeting of YAP1

Wang Xiao-wei, Jin‐Chao Song, Ming-Ming Tang, Yi-Yu He, Zhigang Cai

Background Yes-associated protein 1 (YAP1) dysregulation is frequently observed in various human cancers. This study aimed to identify microRNAs (miRNAs) capable of suppressing YAP1 expression and to elucidate their functional roles in tumor progression. Methods We screened five candidate miRNAs using a luciferase reporter assay containing the YAP1 3’ untranslated region (3’ UTR). Functional validation was performed using gain- and loss-of-function experiments in HCT116 and A549 cell lines. The in vivo effects of miR-195 were evaluated using a xenograft model. Results Among the tested miRNAs, miR-195 demonstrated the most potent suppression of YAP1 3’ UTR activity. This interaction was direct and specific, as a mutation in the YAP1 3’ UTR seed sequence abolished miR-195-mediated repression. Consequently, miR-195 overexpression significantly reduced endogenous YAP1 protein levels and suppressed the expression of its downstream target, CTGF. Functionally, miR-195 overexpression inhibited cell viability and reduced colony formation by approximately 40% in HCT116 cells, while miR-195 knockdown promoted proliferation. Rescue experiments confirmed that the anti-proliferative effects of miR-195 were dependent on YAP1 suppression. In vivo , stable overexpression of miR-195 significantly attenuated tumor growth in xenograft models. Furthermore, analysis of clinical data revealed that downregulation of miR-195 is prevalent in multiple tumor types and correlates with poor patient survival. Conclusion Our findings establish miR-195 as a critical tumor suppressor that directly targets YAP1, highlighting its potential as a therapeutic target in cancer treatment.