DDR1通过调控HMGB1介导自噬在胃癌化疗抵抗中的作用及机制研究

胃癌是我国第二常见的恶性肿瘤，预后差，其治疗的主要困难在于肿瘤细胞的化疗敏感性低。近年来，大量文献报道，肿瘤细胞的化疗抵抗与细胞内自噬水平增强密切相关，但具体的分子机制却仍未明确。课题组前期已证明酪氨酸激酶受体DDR1促进胃癌细胞的化疗耐药，近期体外实验结果显示其还促进胃癌细胞LC3和HMGB1表达，上调自噬水平。我们推测DDR1在胃癌细胞中可能通过促进HMGB1出核释放进而调控Bcl2-Beclin1复合体，增强细胞自噬水平，最终促进胃癌细胞存活并导致其化疗抵抗。本项目拟采用激光共聚焦、透射电镜、Western-blot、免疫荧光、免疫共沉淀、慢病毒载体等方法，结合体内外模型及临床标本，旨在阐明DDR1促进胃癌细胞自噬，并通过其诱导化疗抵抗的分子机制。通过以上研究不仅可以增加我们对DDR1蛋白生物学功能的认识，也为解析自噬在胃癌细胞化疗耐药中的作用机制及研发新靶点提供理论基础。

Gastric cancer is the second most prevalent cancer in China. The prognosis of gastric cancer is poor mainly due to chemoresistance. Recent research showed that autophagy induction may contribute to the resistance of tumor cells to chemotherapy. However, the precise molecular mechanism remains unclear. Our previous studies showed that DDR1, a newly discovered receptor tyrosine kinase (RTK), promoted resistance to chemotherapy in gastric cancer. Our further experiments showed that DDR1 regulate the expression of LC3 and HMGB1 and activate autophagy in vitro. Thus we proposed a possible mechanism connecting DDR1 to the autophagy machinery relies on the translocation and expression of HMGB1, which would then facilitate the dissociation of BCL2-Beclin1 complex finally leading to drug resistance. Thus this study will validate the effect of DDR1 on autophagy which result in drug resistance through the confocal laser scanning microscope, electron microscopy, Western-blot, immunofluorescence, co-immunoprecipitation and lentiviral vector in vitro and in vivo. Our study aimed to reveal the biological function of DDR1 and the mechanisms of autophagy in chemoresistance, which may lay the basis for supporting that DDR1 serve as a treatment target in gastric cancer.