MiR-892b下调促进乳腺癌细胞增殖的分子机制

Previously, we demonstrated that pescadillo was markedly upregulated in breast cancer, and that overexpression of pescadillo plays an important role in the development and progression of breast cancer (Cancer Science, 2009, 100 (12): 2255-2260). However, the mechanism by which pescadillo is regulated in breast cancer is poorly characterized. Using a microRNA chip, we identified that miR-892b was significantly downregulated in breast cancer tissues compared to normal breast tissues, and miR-892b expression inversely correlated with the clinical stage of breast cancer. Furthermore, our preliminary data demonstrated that ectopic expression of miR-892 inhibited the proliferation of breast cancer cells by inducing G1/S arrest. Moreover, bioinformatic analysis and biological experiments revealed that miR-892b regulates pescadillo by directly targeting its 3` untranslated region (3`-UTR) and inactivates of NFκB pathway signalling. Additionally, we observed that the oncogene c-myc could repress the expression of miR-892b. Taken together, these results indicate that miR-892 plays important role in the prevention of breast cancer tumorigenesis. 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-892b inhibits the proliferation of breast cancer cells, which may provide new biomarkers and targets for the diagnosis and treatment of breast cancer.

前期我们已证明pescadillo蛋白在乳腺癌中的表达显著上升，并且通过激活PI3K/AKT信号通路而在乳腺癌的发展中具有重要作用（已发表）。进一步采用microRNA芯片技术，我们发现miR-892b在乳腺癌组织中表达降低，其表达水平与乳腺癌恶性程度负相关。预实验结果显示癌基因c-Myc可下调miR-892b；而高表达miR-892b可明显导致乳腺癌细胞G1/S停滞并抑制细胞的增殖；同时我们还发现高表达miR-892b可下调pescadillo蛋白和抑制NFκB信号通路，但分子机制尚待阐明。本项目将以高表达或抑制miR-892b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-892b抑制NFκB和PI3K/AKT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-892b抑制乳腺癌细胞增殖的功能，为诊治乳腺癌提供新的分子靶标。

乳腺癌是女性最常见的恶性肿瘤之一，其发病率高达1680000人，死亡人数约1522,000，是一种严重影响妇女身心健康甚至危及生命的恶性肿瘤. 尽管乳腺癌治疗方法的进步已使乳腺癌患者存活率有所提高，但高复发率和死亡率仍使乳腺癌的治疗面临着巨大的挑战。前期大量研究均已证实miRNA 在乳腺癌的发生发展中具有重大的作用。我们研究发现：miR-892b在乳腺癌中显著下降， 并与患者预后相关。 进一步研究显示miR-892b可抑制乳腺癌的恶性发展由于下调 TRAF2, TAK1, and TAB3而抑制NF-kB信号通路 (Cancer Research, 共同第一). 同时我们研究发现在乳腺癌中下调的miR-495可通过抑制Bmi-1原癌基因而抑制肿瘤的恶性增殖。 因此我们的研究为乳腺癌的恶性发展提供了新的分子机制。