TGF-β1通路相关miRNA调节癌基因trib2在肺腺癌发病中的作用

TRIB2, acting as one oncogene, is over-expressed in lung adenocarcinoma tissues. Inhibition of TRIB2 expression can lead to apoptosis of lung adenocarcinoma cells. miRNAs play important roles in the procession of gene expression, cell migration and invasion. It becomes a hot research topic to study the TGF-β1-pathway-related miRNAs. In recent study, we established the nude mice model xenografted with A549 cells and found that antisense RNA could inhibit lung adenocarcinoma cell proliferation in vivo by suppressing the expression of oncogenic miRNA. Based on the previous study of miRNAs, our results showed that miR-206 could inhibit expression of Smad3 and trib2 in lung adenocarcinoma cells, and Smad3 is one of the important factors in TGF-β1 pathway, which indicated that miR-206 might attend TGF-β1 pathway. In this research, we will further study whether both TRIB2 and miR-206 attend TGF-β1 pathway, and whether TRIB2 expression is regulated by Smad3. We will also investigate the roles of trib2 expression regulated by TGF-β1-pathway-related-miRNAs in pathogeny of lung adenocarcinoma. This project will provide new gene targets for therapy of lung adenocarcinoma and drug design.

TRIB2具有癌基因样作用，在肺腺癌组织中表达明显增高。抑制TRIB2表达能诱发肺腺癌细胞凋亡。miRNAs参与了肺癌基因表达、细胞转移和浸润等过程；有关TGF-β1通路miRNA的研究已成为肺腺癌研究的热点之一。 近期研究中，我们建立了移植肺腺癌细胞的小鼠模型，发现反义核酸能有效抑制癌基因miRNA表达，进而抑制肺腺癌细胞在小鼠体内增殖。本项目在课题组研究miRNAs的基础上，发现miR-206能抑制肺腺癌细胞Smad3及癌基因trib2表达，而Smad3是TGF-β1通路的重要因子，提示miR-206可能参与了TGF-β1通路及肺腺癌的发病过程。以此为出发点，我们将深入研究TRIB2及miR-206等是否参与了TGF-β1通路、TRIB2表达是否受Smad3因子的调节，探讨TGF-β1通路相关miRNA调节癌基因trib2在肺腺癌发病中的作用，为肺腺癌临床治疗及药物设计提供新靶点。

TRIB2 具有癌基因样作用，在肺腺癌组织中表达明显增高。抑制TRIB2 表达能诱发肺腺癌细胞凋亡。我们发现TRIB2上游microRNAs (miR-511及miR-1297)具有抑癌基因作用，可抑制TRIB2的表达，诱发肺腺癌细胞凋亡，但TRIB2参与肺腺癌的信号通路及发病机制还有待深入研究。miRNAs 参与了肺癌基因表达、细胞转移和浸润等过程；TGF-β1 通路相关miRNA 参与了肺腺癌的致病过程，已成为肺腺癌研究的热点之一。本项目，我们探讨了TGF-β1通路相关miRNA调节癌基因trib2在肺腺癌发病中的作用。. （1）微RNA和TGF-β1通路Smad3参与了多种疾病的病理生理过程。研究中我们筛选了能特异性调节Smad3表达的miRNAs，研究了这些miRNAs在肺腺癌细胞凋亡、增殖及迁移中的作用。发现miR-206和miR-140能有效抑制Smad3和p-Smad3的表达，二者参与了TGF-β1 通路，它们之间的调节存在负反馈关系。. （2）Smad3能通过结合TRIB2基因启动子“CAGACA”盒，调节TRIB2的表达，miR-140/206可调节上述过程。. （3）miR-206 和miR-140能有效抑制肺腺癌细胞在体内和体外增殖，其机理与靶向调节 Smad3/P-Samd3 表达，进而影响癌基因TRIB2的表达有关。肺癌组织的结果也进一步支持miR-206 和miR-140 发挥抑癌基因样miRNAs的作用，高表达TRIB2与患者的生存曲线呈负相关。. 总之，本项目发现miR-206 和miR-140具有抑癌基因的作用，能抑制肺腺癌细胞的增殖，诱导肺腺癌细胞发生凋亡，其具体机理与靶向调节 Smad3的表达，进而通过调节TRIB2启动子，影响癌基因TRIB2的表达水平有关。miR-206 和miR-140还能通过抑制肺腺癌细胞的EMT现象，抑制肿瘤细胞的迁移。本项目的完成为肺腺癌临床治疗及药物设计提供新靶点。