奥沙利铂耐药是中晚期结肠癌治疗失败的主要原因，寻找化疗耐药通路的关键蛋白并阐明其功能及分子机制，对晚期结肠癌的诊治具有重要意义。我们前期工作发现 347例结肠癌切片中丝精氨酸蛋白激酶SRPK1的高表达与奥沙利铂的耐药显著相关，上调SRPK1的表达可增加干性标志物CD44v3和抗凋亡蛋白Bcl-xL、Mcl-1L的异常可变剪接，增强结肠癌细胞的干细胞表型和EMT，激活Wnt和NF-κB信号通路。同时发现SRPK1与GSK3β的直接互作可以增强GSK3βS9的磷酸化，促进β-catenin入核。提示我们SRPK1-GSK3β通路与结肠癌细胞奥沙利铂的耐药密切相关。本项目将以结肠癌细胞耐药株和鼠肠原位PDX模型，深入探讨SRPK1对耐药基因的异常可变剪接及SRPK1对NF-κB和Wnt通路的激活，揭示奥沙利铂耐药的分子机制。本课题的实施可为结肠癌化疗耐药的诊治提供理论基础和新的药物治疗靶点。

Oxaliplatin (L-OHP) resistance is the main cause of treatment failure in the middle and late stage colorectal cancer patients. Identifying key proteins that participate in the chemotherapy resistance and elucidating the mechanism would be of great value for late stage colorectal cancer. Our previously study in 347 paraffin-embedded colorectal cancer tissue section by IHC showed that over expression of SRPK1 was associated with L-OHP resistance significantly. The up-regulation of SRPK1 could promote aberrant alternative splicing of cancer stem-cell like marker CD44v3 and expression level of anti-apoptosis protein Bcl-xL and Mcl-1L, enhance the CSCs-like phenotype and EMT, and activate Wnt and NF-κB signaling pathway. Furthermore, SRPK1 might interact with GSK3β directly and increased the phosphorylation of Ser9 of GSK3β, which in turn promoted translocation of β-catenin to the nucleus. The results above demonstrated that SRPK1-GSK3β signal pathway related to L-OHP resistance closely. In this project we aim to explore the effect of SRPK1 on aberrant alternative splicing of drug-resistant genes and activation of NF-κB/Wnt signal pathway and reveal the underlying mechanism of L-OHP resistance as well by using colorectal cell lines with L-OHP resistance trait and PDX (patient-derived xenograft model) mice model. The implementation of this project may provide a theoretical basis for the diagnosis and treatment of chemotherapeutic drug resistance in colorectal cancer and new targets for drug development.