MiR-196a促进宫颈癌细胞侵袭转移的分子机制

MicroRNAs have been shown to be closely related to cervical carcinogenesis and development. Previously, we identified several microRNAs from cervical cancer samples. We found for the first time that miR-196a promotes cervical cancer proliferation through targeting FOXO1 and p27 (Brit J Can, IF:5.082). Furthermore, our preliminary data demonstrated that ectopic expression of miR-196a induces EMT in cervical cancer cell lines. Moreover, bioinformatic analysis and biological experiments revealed that miR-196a may regulate MITF and CYLD by directly targeting their 3' untranslated region (3'-UTR), which in turn activates of Hedgehog and NFκB signaling pathway, respectively. Additionally, we observed that the oncogene C-Fos could activate the expression of miR-196a. However, the exact mechanisms involving the process remains unkown. Therefore, in the present project, we aim to employ chromatin immunoprecipitation (ChIP), co-immunoprecipitation (Co-IP) and luciferase reporter assays in both in vivo and in vitro systems, and use clinical samples to further investigate the mechanism by which miR-196a promotes the invasion and metastasis of cervical cancer, which may provide new biomarkers and targets for the diagnosis and .treatment of cervical cancer.

研究证实microRNA与宫颈癌的发生和发展密切相关。前期我们从宫颈癌临床标本中筛选出一系列microRNA，首次发现miR-196a可通过下调FOXO1和p27促进宫颈癌细胞的增殖（Brit J Can, IF:5.082）；进一步研究发现miR-196a能诱导宫颈癌发生上皮-间质转化（EMT）；通过软件分析，发现C-Fos可上调miR-196a；而miR-196a可能通过下调MITF和CYLD激活Hedgehog与NFκB信号通路，促进宫颈癌细胞侵袭转移。但其具体的分子机制尚不清楚。本项目将以过表达或抑制miR-196a的细胞为模型，通过免疫印迹、染色体免疫共沉淀及荧光素酶报告基因分析等方法，探讨miR-196a抑制Hedgehog和NFκB信号通路的具体分子机制；通过体内体外系统，并结合临床样品，验证miR-196a促进宫颈癌细胞侵袭转移的功能，为诊治宫颈癌提供新的分子靶标。

研究基于我们首次发现了miR-196a可通过下调FOXO1和p27促进宫颈癌细胞的增殖。进一步研究发现miR-196a可能促进宫颈癌细胞侵袭转移，但其分子机制不详。本项目旨在研究miR-196a促进宫颈癌细胞侵袭转移的分子机制，其主要成果包括：验证了miR-196a具有促进宫颈癌细胞侵袭及迁移的能力，通过机制研究表明，miR-196a 可能通过抑制抑癌基因 MITF 及CYLD的表达，分别激活了 Hedgehog 及NFκB 信号通路，进而促进宫颈癌细胞侵袭转移。我们的研究可以为宫颈癌的诊治及预后评估提供新的分子标靶，并可能为抗宫颈癌药物的研发提供有力的实验依据。