大肠癌发病率逐年增高，与高脂饮食关系密切，后者可引起肠腔内次级胆汁酸尤其脱氧胆酸（DCA）水平显著升高。持续暴露DCA可诱导结肠上皮细胞产生凋亡抵抗从而促进癌变，但机制不明。我们发现DCA能显著增加小鼠肠道肿瘤数量并诱发癌变，还可活化EGFR产生凋亡抵抗并依赖ADAM-17的活性。文献报道ADAM-17能切割EGFR的相应配体从而活化EGFR，故我们推断"DCA通过活化ADAM-17/EGFR信号轴进而诱导凋亡抵抗促进癌变"。本项目首先采用靶向阻断和siRNA转染等方法观察阻断EGFR后细胞凋亡及凋亡蛋白变化，以明确EGFR活化在DCA诱导凋亡抵抗中的作用；进而运用ADAM-17基因转导的ADAM-17-/-细胞及其基因缺陷鼠模型，探讨DCA活化ADAM-17切割EGFR配体激活EGFR及其下游通路的机制。本项目旨在探索DCA如何诱导凋亡抵抗促进癌变的机制，为其相关肠癌的防治提供新靶点。

Nowadays the prevalence of colorectal cancers increases dramatically, and may closely correlate to diets high in fats, which result in elevated second bile acids, especially deoxycholic acid (DCA) in the intestine. Studies have found that long term exposure to DCA may result in apoptosis resistance of colonic epithelial cells and promote carcinogenesis; however, the mechanisms are not elucidated. Our previous study showed that DCA could increase the number and development of intestinal tumors in APCmin/+ mice. Moreover, DCA could transactivate epidermal growth factor receptor (EGFR),and result in apoptosis resistance, which required a disintegrin and metalloprotease-17 (ADAM-17) activity. It was reported that ADAM-17 can cleave some EGFR ligands and transactivate EGFR. Thus, we suppose that DCA can induce apoptosis resistance of colonic epithelial cells and promote carcinogenesis via ADAM-17/EGFR axis activation. Our proposal is firstly to evaluate the effects on the alteration of cell apoptosis and associated proteins after inhibiting EGFR activity using specific blockers and siRNA transfection assays, which will establish the role of EGFR transactivation in apoptosis resistance of colonic epithelial cells induced by DCA. The mechanisms that ADAM-17 activation by DCA may cleave EGFR ligands, and transactivate EGFR and its downstream signal pathways will be further investigated using ADAM-17-/- colonic epithelial cells transducted with wt ADAM-17 or vector only, and ADAM-17 deficient mice model. This project will elucidate the mechanisms how DCA induces apoptosis resistance and promotes carcinogenesis, and provide new potential targets for the treatment of bile acids-related colorectal cancers.