化疗耐药是临床肿瘤治疗的难题之一。我们前期发现：蛋白激酶DCLK1在结直肠癌5-Fu耐药细胞中的表达明显高于亲代细胞，并证实其具有促进结直肠癌5-Fu耐药的生物学功能，但作用机制尚不明确。我们进一步发现：DCLK1与Myc相互作用，抑制Myc蛋白的降解，使其蛋白表达水平上调。原癌基因Myc是一个极不稳定蛋白，其降解由泛素蛋白酶体系统调控。免疫沉淀实验发现：Myc与DCLK1结合增多，则Myc与E3泛素连接酶FBW7结合减少。因此，我们推测：DCLK1可能与FBW7竞争结合Myc，抑制FBW7介导的泛素化蛋白酶体降解，正向调控Myc蛋白稳定性和生物学功能，从而促进结直肠癌5-Fu耐药。本研究拟通过体内外实验，阐明DCLK1正向调控Myc蛋白稳定性的机制及其生物学意义，并研究DCLK1与Myc在结直肠癌中表达的相关性及其临床意义，以期为结直肠癌5-Fu化疗耐药的临床防治提供新的理论依据和靶点。

Chemoresistance is a major cause of treatment failure in clinical oncology. Identifying the involved biomarkers and clarifying the regulatory mechanisms are of great importance to overcome chemoresistance. In our previous research, we discovered that protein kinase DCLK1 showed higher expression in 5-Fu-resistant colorectal cancer cells compared to the parental tumor cells. Further research indicated that up-regulation of DCLK1 promoted chemoresistance of colorectal cancer cells to 5-Fu in vitro and in vivo. However, the mechanism by which DCLK1 promoted chemoresistance of colorectal cancer to 5-Fu had not been elucidated. Notably, we identified the interaction between DCLK1 and Myc by co-immunoprecipitation and mass spectrometry. Meanwhile, we found that DCLK1 inhibited the degradation of Myc. Many researches demonstrated that proto-oncogene Myc was deregulated in human cancer, and the stability of Myc was tightly controlled by the ubiquitin-proteasome system. Moreover, in our research, decreased FBW7 protein level in the Myc immunoprecipitates was observed when cells were cotransfected with increased amounts of DCLK1. Therefore, we deduce that DCLK1 competes with FBW7 for Myc binding, suppresses the activity of FBW7-mediated ubiquitin-proteasome system, and consequently inhibits the degradation of Myc, up-regulates the stability and biological function of Myc, and ultimately promotes chemoresistance of colorectal cancer to 5-Fu. In the current research, we will perform in vitro and in vivo experiments, to reveal the mechanism by which DCLK1 regulate the stability of Myc and the subsequent biological effects, and to clarify the correlation between DCLK1 and Myc in colorectal cancer and the potential clinical significance. This project will provide a new theoretical foundation and a new therapeutic target for the clinical prevention and treatment of 5-Fu chemoresistance in colorectal cancer.