阐明结肠癌发生发展的分子机制，对结肠癌的防治具有重要意义。申请人前期分析多种数据库和生物信息学网站发现，CLCA4在结肠癌中表达显著下调，并与患者预后成正相关。免疫组化揭示CLCA4在20例结肠正常组织中有18例高表达，而在110例结肠癌组织中仅12例高表达；干扰CLCA4表达促进结肠癌细胞增殖、干性维持及耐药。以上结果初步表明，CLCA4可能与结肠癌发生发展密切相关。据此，本项目拟开展如下研究：1）CLCA4对结肠癌细胞增殖、干性维持及耐药的调控作用；2）高通量测序和蛋白质组学方法筛选CLCA4调控结肠癌细胞生物学行为的信号通路及下游互作蛋白，并对互作蛋白功能进行验证；3）证实转录因子AP-1直接调控CLCA4表达及其功能验证；4）明确DNA甲基化与结肠癌中CLCA4表达下调的相关性；5）临床标本中分析CLCA4及其上下游调控基因的表达及临床病理意义。本项目将为结肠癌防治提供新的思路。

It is necessary to explore molecule and mechanism of colon cancer initiation and progression for the prevention and treatment of colon cancer. We analyzed various databases and bioinformatics sites and found that CLCA4 expression was significantly reduced in colon cancer and was positively related to the prognosis of patients. The immunohistochemical results revealed that CLCA4 was high expressed in 18 of the 20 cases of normal colon tissues, but only 12 of 110 cases of colon cancer tissues. The knockdown of CLCA4 expression was found to promote the proliferation, stemness maintenance and drug resistance of colon cancer cells. The above results initially indicate that CLCA4 may be closely correlated with the initiation and progression of colon cancer. Therefore, we plan to: 1) clarify the effects of CLCA4 on the proliferation, stemness maintenance and drug resistance of colon cancer cells ; 2) use high-throughput sequencing and proteomics methods to screen the signal pathways and direct interactive proteins that regulate the biological behavior of colon cancer cells, and further verify the function of interactive proteins; 3) confirm that transcription factor AP-1 directly regulates CLCA4 expression and its functional verification; 4) clarify the relationship between DNA methylation and the down-regulation of CLCA4 expression in colon cancer; 5) analyze CLCA4, its upstream and downstream regulatory gene expression and clinicopathological significance in clinical specimens. This project will provide new ideas for the prevention and treatment of colon cancer.