泛素连接酶SPOP调控MDM2-P53信号通路在结直肠癌细胞增殖与转移中的作用及分子机制研究

The abnormality of MDM2-P53 signaling pathway plays an important role in the occurrence and development of cancer. Our preliminary data showed the Cullin 3-based ubiquitin ligase SPOP (speckle-type POZ protein) specifically interacts with MDM2 and promotes ubiquitination and degradation of MDM2, which can activate the expression of P53 and prevent cancer. However, SPOP is down-regulated and the MATH domain of SPOP is mutated in human colorectal cancer. Furthermore, SPOP down-regulation and mutants are deficient in binding and promoting the degradation of MDM2, leading to the abnormal accumulation of MDM2, suppression of P53 expression and at last result in malignant tumor. In the present study, we plan to carry out an investigation on the correlation between the expression level of SPOP (including SPOP mutants and SPOP expression level) /MDM2/P53 pathway and tumorgenesis, metastasis, prognosis and sensitivity to chemotherapy or radiotherapy. And we will have a deep investigation on the biology fuction of SPOP/MDM2/P53 pathway in the proliferation and metastasis of colorectal cancer cells. Moreover, we will focus on the the detailed molecular mechanisms how SPOP regulates MDM2-P53 pathway. These data will improve theoretical foundations of MDM2-P53 pathway regulation and accelerate related drug discovery.

MDM2-P53通路的异常活化在肿瘤的发生、发展中发挥着重要作用。前期工作中，我们发现：泛素连接酶SPOP能与MDM2结合，并使其发生泛素化降解，从而激活P53，防止肿瘤发生。但在结直肠癌中，泛素连接酶SPOP的表达会下调或其底物结合区MATH会发生突变，异常的SPOP不能介导MDM2泛素化降解，故MDM2异常蓄积，P53表达受到抑制，肿瘤发生。本课题拟在前期研究基础之上，深入探讨SPOP的突变情况及SPOP/MDM2/P53通路在结直肠癌细胞增殖、侵袭与转移中的作用，并进一步通过免疫共沉淀、pull-down、定点突变等技术阐明SPOP调控MDM2-P53通路的分子机制。本课题研究结果将丰富MDM2-P53通路调控的相关理论，为靶向该通路抗癌药物的研发提供新的切入点。

MDM2-p53通路的异常活化在肿瘤的发生、发展中发挥着重要作用。在本课题中，我们发现：泛素连接酶SPOP能与MDM2结合，并使其发生泛素化降解，从而激活p53，防止肿瘤发生。但在结直肠癌中，泛素连接酶SPOP的表达会下调，MDM2异常蓄积，p53表达受到抑制，肿瘤发生。此外，本课题的研究结果阐明SPOP在结直肠癌的发生、转移、化疗药物耐药及临床预后中的作用，并通过免疫共沉淀、泛素化等实验研究SPOP调控MDM2-P53通路的分子机制。本课题研究结果将丰富MDM2-p53通路调控的相关理论，为靶向该通路抗癌药物的研发提供新的切入点。