Zhang Yan-Xia, Yan Yun-Fei, Liu Yue-Mei, Li You-Jie, Zhang Han-Han, Pang Min, Hu Jin-Xia, Zhao Wei, Xie Ning, Zhou Ling, Wang Ping-Yu, Xie Shu-Yang
Key Laboratory of Tumor Molecular Biology in Binzhou Medical University, Department of Biochemistry and Molecular Biology, Binzhou Medical University, YanTai, ShanDong, P.R.China.
Department of Chest Surgery, YanTaiShan Hospital, YanTai, ShanDong, P.R.China.
Cell Death Dis. 2016 Dec 22;7(12):e2528. doi: 10.1038/cddis.2016.432.
MicroRNAs (miRNAs) and Smad3, as key transcription factors in transforming growth factor-β1 (TGF-β1) signaling, help regulate various physiological and pathological processes. We investigated the roles of Smad3-regulated miRNAs with respect to lung adenocarcinoma cell apoptosis, proliferation, and metastasis. We observed that Smad3 and phospho-SMAD3 (p-Smad3) were decreased in miR-206- (or miR-140)-treated cells and there might be a feedback loop between miR-206 (or miR-140) and TGF-β1 expression. Smad3-related miRNAs affected tribbles homolog 2 (TRIB2) expression by regulating trib2 promoter activity through the CAGACA box. MiR-206 and miR-140 inhibited lung adenocarcinoma cell proliferation in vitro and in vivo by suppressing p-Smad3/Smad3 and TRIB2. Moreover, lung adenocarcinoma data supported a suppressive role for miR-206/miR-140 and an oncogenic role for TRIB2-patients with higher TRIB2 levels had poorer survival. In summary, miR-206 and miR-140, as tumor suppressors, induced lung adenocarcinoma cell death and inhibited cell proliferation by modifying oncogenic TRIB2 promoter activity through p-Smad3. MiR-206 and miR-140 also suppressed lung adenocarcinoma cell metastasis in vitro and in vivo by regulating EMT-related factors.
微小RNA（miRNA）和Smad3作为转化生长因子-β1（TGF-β1）信号通路中的关键转录因子，有助于调节各种生理和病理过程。我们研究了Smad3调控的miRNA在肺腺癌细胞凋亡、增殖和转移方面的作用。我们观察到，在经miR-206-（或miR-140）处理的细胞中，Smad3和磷酸化Smad3（p-Smad3）水平降低，并且miR-206（或miR-140）与TGF-β1表达之间可能存在反馈回路。与Smad3相关的miRNA通过CAGACA框调节trib2启动子活性，从而影响TRIB2（tribbles同源物2）的表达。MiR-206和miR-140通过抑制p-Smad3/Smad3和TRIB2，在体外和体内抑制肺腺癌细胞增殖。此外，肺腺癌数据支持miR-206/miR-140具有抑制作用，而TRIB2具有致癌作用——TRIB2水平较高的患者生存率较低。总之，miR-206和miR-140作为肿瘤抑制因子，通过p-Smad3改变致癌性TRIB2启动子活性，诱导肺腺癌细胞死亡并抑制细胞增殖。MiR-206和miR-140还通过调节上皮-间质转化（EMT）相关因子，在体外和体内抑制肺腺癌细胞转移。
