泛素连接酶FBW7常泛素化肿瘤相关因子，如原癌基因AIB1和mTOR、NOTCH1等，导致底物降解。我们前期研究发现，胆管癌样品中FBW7高突变，且伴有 AIB1 高表达，同时AIB1还可促进胆管癌细胞增殖和抗药性。我们假设 FBW7 突变致其功能缺失，不能泛素化AIB1等，使之高表达，促进细胞的增殖和抗药性。本项目拟首先检测样品中FBW7的突变情况，通过荧光定量PCR、免疫组化等检测样品中FBW7、AIB1、mTOR、NOTCH1等的表达；然后运用过表达、基因沉默研究FBW7的表达变化对胆管癌细胞增殖和抗药性的影响；最后探讨FBW7对AIB1的作用，及其与mTOR和NOTCH1通路的关系，论证FBW7通过泛素化AIB1、mTOR或NOTCH1等影响胆管癌细胞增殖和抗药性，揭示FBW7在胆管癌增殖和抗药性中的作用和分子机制，丰富胆管癌细胞信号通路信息，为寻找更为安全有效的治疗靶点提供思路。

FBW7 plays important roles in the ubiquuitination of certain factors related with tumor, such as oncogene AIB1, and mTOR, NOTCH1 signaling et al., resulting the degradation of substrates through polyubiquitination. In our previous work, we found FBW7 mutated in cholangiocarcinoma (CC) samples and AIB1 was over-expressed in these samples. We also have confirmed that SRC-3/AIB1 could enhance human CC cell proliferation and chemoresistance. Our hypothesis is that the mutation of FBW7 in CC would lead to the functional deficiency of itself and high expression of AIB1, promoting the proliferation and drug resistance of CC. First, we would analyze the mutation situation of FBW7 and the expression level of FBW7, AIB1,mTOR,NOTCH1 in CC samples by immunohistochemistry， fluorescent quantitation PCR and western blot ; Then, we would undertake the technology of over-expression and gene silence to study the impact of FBW7 on CC cell in the respects of proliferation and drug resistence; Thirdly, we would explore the interaction between FBW7 and AIB1, mTor, NOTCH1 signaling. At last, we are going to confirm if FBW7 could regulate the level of AIB1, mTor or NOTCH1, leading proliferation and chemoresistance of CC, by which to explore the function and mechanism of FBW7 in the proliferation and chemoresistance of CC. Our study would enrich the signal pathway information of CC cell, providing some novel ideal on safe and effective therapeutic targets of CC.