Citron调控Wnt/β-catenin通路促进结肠癌恶变进程的作用及分子机制研究

课题组前期研究首次发现结肠癌组织中Citron基因表达上调，而基因敲减后显著抑制肿瘤细胞增殖伴细胞凋亡增加；异常表达的Citron与Rac1结合后彼此激活；特异性刺激Wnt信号能部分逆转Citron基因敲减对结肠癌细胞的生长抑制及凋亡促进作用。据此分析结肠癌组织中异常表达的Citron与Rac1形成酶联激活正反馈环路，通过调控Wnt/β-catenin通路促进细胞增殖并抑制细胞凋亡，高效地易化结肠癌恶性进展。本研究拟进一步结合临床样本及信息，明确Citron与临床诊疗和预后的关联性及其与Wnt通路的相关性；正负向干预Citron基因表达，通过体内外功能实验证实并发掘促进结肠癌发展的作用；应用Wnt通路激活剂、抑制剂结合免疫共沉淀、GST pull-down技术明确Citron/Rac1调控Wnt信号的分子机制，旨在探讨Citron作为结肠癌发展的新作用分子,为临床诊疗提供新靶点。

The research team addressed that Citron was up-regulated in colon carcinoma tissues for the first time. Down-regulation of Citron inhibited cancer cell proliferation significantly accompanied with increased cell apoptosis. Citron functionally interacted with Rac1 to enzyme activate each other. Stimulating Wnt Signal specificly reversed the phonetype changes of the growth inhibition and apoptosis promotion of colon cancer cells induced by Citron knock down. Therefere,we propose that abnormal expressed Citron is capable of functionally interacting with Rac1 to form the positive feedback loop of cascade enzyme activation. Via activation of the Wnt / β-catenin pathway to promote cell proliferation and inhibit cell apoptosis, the loop facilitates cancer malignant transformation dramatically. Therefore, the applicants mean to further the archiving of clinical samples and information to make clear the relationship between the clinical significance and Citron expression as well as it's correlation with wnt pathway. Through positive and negative intervention in Citron expression conbined with functional experiments in vivo and in vitro, we aim to confirm and explore the role of Citron in promoting the development of colon cancer.Carrying out Wnt pathway activators and inhibitors binding with co-immunoprecipitation, GST pull-down analysis to confirm the molecular mechanisms of regulating Wnt signaling by Citron/Rac1. The research team intend to provide the experimental basis for further investigating the role of Citron in progress of colon cancer as well as a new target for diagnosis and treatment.