囊性纤维化跨膜传导调节体(CFTR）调控Hedgehog信号通路介导结直肠癌发生的机制研究

The incidence and mortality of colorectal cancer have been increasing year by year in our country, and the molecular mechanism remains largely unknown. Preliminary study showed that CFTR might participate in the tumorigenesis of colorectal cancer. We further discovered that CFTR decreased significantly in colorectal cancer; mutation of CFTR activated proliferation and inhibited differentiation of intestinal epithelial cells; Hedgehog pathway which regulates the proliferation of intestinal epithelial cells was inhibited in the CFTR mutant mouse and CFTR knockdown cells. We thus hypothesize that CFTR may regulate the proliferation of intestinal epithelial cells by regulating Hedgehog pathway. To prove the hypothesis, we propose to: 1) investigate the relationship of CFTR and Hedgehog by Co-IP, immunostaining and bioinformatics; 2) investigate the regulation mechanism of Hedgehog pathway by CFTR in vivo CFTR knockout or mutant mouse models and in vitro intestinal epithelial cell model; 3) Prove the relationship of Hedgehog pathway and CFTR in clinical colorectal cancer samples. The results will improve the molecular mechanism of colorectal cancer regulated by CFTR, and it is expected to provide molecular target and theoretical basis for early diagnosis of colorectal cancer.

结直肠癌在我国发病率及死亡率逐年上升，其分子机制尚不明确。前期研究发现囊性纤维化跨膜传导调节体（CFTR）可能参与结直肠癌发生。我们进一步发现：CFTR在人结直肠癌组织中表达明显降低；CFTR突变引起小鼠胃肠道上皮细胞增殖活化及分化抑制；CFTR突变或敲减显著抑制调控肠上皮细胞增殖的Hedgehog通路的表达。课题推测CFTR可能通过调控Hedgehog通路而控制肠上皮细胞增殖。本研究拟：1）通过Co-IP、免疫荧光实验和生物信息学分析探讨CFTR和Hedgehog通路表达相关性；2）在CFTR突变小鼠和CFTR敲除肠上皮细胞模型中研究CFTR对Hedgehog的调控机制；3）在临床结直肠癌样本中了解CFTR表达与Hedgehog通路信号调控之间的关系。研究结果将完善CFTR调控结直肠癌发生的分子机制，并可望为结直肠癌早期诊断提供分子靶点和理论依据。

结直肠癌在我国发病率及死亡率逐年上升，其分子机制尚不明确。前期研究发现囊性纤维化跨膜传导调节体（CFTR）可能参与结直肠癌发生。我们发现：CFTR在人结直肠癌组织中表达明显降低；CFTR突变引起小鼠胃肠道上皮细胞增殖活化及分化抑制；CFTR突变或敲减显著抑制调控肠上皮细胞增殖的Hedgehog通路的表达。本研究通过下列实验证实了CFTR通过调控Hedgehog通路而控制肠上皮细胞增殖：1）通过Co-IP、免疫荧光实验和生物信息学分析证实CFTR和Hedgehog通路表达具有相关性；2）在CFTR突变小鼠和CFTR敲除肠上皮细胞模型中证实CFTR对Hedgehog的调控机制；3）在临床结直肠癌样本中证实CFTR表达与Hedgehog通路具有相关性。研究结果完善了CFTR调控结直肠癌发病的分子机制，并为结直肠癌早期诊断提供了一定的分子靶点和理论依据。