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.

中文翻译：

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MiR-195和miR-497通过抑制SMURF2诱导的TGF-β受体I泛素化来抑制肺癌的发生。

SMURF2是E3泛素连接酶的HECT家族的成员，其作为通过泛素介导的TGF-β受体I降解来转化生长因子-β（TGF-β）信号的负调节剂，具有重要作用。 SMURF2在很大程度上是未知的。在这项研究中，我们使用几个目标预测数据库确定了micro（mi）R-195和miR-497可能靶向SMURF2。miR-195和miR-497均与SMURF2 mRNA的3'-UTR结合并抑制SMURF2表达。此外，miR-195和miR-497调节SMURF2依赖性TβRI泛素化并引起肺癌细胞中TGF-β信号通路的激活。miR-195和miR-497的上调通过激活TGF-β信号传导显着降低了细胞活力和集落形成。有趣的是 当用TGF-β1处理细胞时，miR-195和miR-497也降低了肺癌细胞的侵袭能力。随后在异种移植裸鼠模型中进行的体内研究表明，miR-195和miR-497抑制肿瘤的生长。这些发现表明，miR-195和miR-497通过抑制通过SMURF2的泛素介导的TGF-β受体的降解而充当肿瘤抑制剂，并且表明miR-195和miR-497是肺癌的潜在治疗靶标。