Abstract
SMURF2 is a member of the HECT family of E3 ubiquitin ligases that have important roles as a negative regulator of transforming growth factor-β (TGF-β) signaling through ubiquitin-mediated degradation of TGF-β receptor I. However, the regulatory mechanism of SMURF2 is largely unknown. In this study, we identified that micro(mi)R-195 and miR-497 putatively target SMURF2 using several target prediction databases. Both miR-195 and miR-497 bind to the 3'-UTR of the SMURF2 mRNA and inhibit SMURF2 expression. Furthermore, miR-195 and miR-497 regulate SMURF2-dependent TβRI ubiquitination and cause the activation of the TGF-β signaling pathway in lung cancer cells. Upregulation of miR-195 and miR-497 significantly reduced cell viability and colony formation through the activation of TGF-β signaling. Interestingly, miR-195 and miR-497 also reduced the invasion ability of lung cancer cells when cells were treated with TGF-β1. Subsequent in vivo studies in xenograft nude mice model revealed that miR-195 and miR-497 repress tumor growth. These findings demonstrate that miR-195 and miR-497 act as a tumor suppressor by suppressing ubiquitination-mediated degradation of TGF-β receptors through SMURF2, and suggest that miR-195 and miR-497 are potential therapeutic targets for lung cancer.