NLK参与调控NRF2信号通路及其介导的大肠癌肿瘤细胞耐药性的研究

项目名称： NLK参与调控NRF2信号通路及其介导的大肠癌肿瘤细胞耐药性的研究

项目编号： No.31501148

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 生物科学

项目作者： 杜润蕾

作者单位： 武汉大学

项目金额： 20万元

中文摘要： 大肠癌是严重威胁人类的生命健康的主要肿瘤。手术切除、化疗和放疗是结直肠癌治疗的主要手段，但肿瘤细胞对化疗药物的耐药性是化疗的最大阻碍，肿瘤细胞产生耐药性的机制是急需解决的科学问题。抗氧化应激Nrf2-ARE信号可能与多种肿瘤药物耐药性机制相关，但具体机制及其调控目前还非常欠缺。NLK是一种进化上非常保守的丝氨酸/苏氨酸激酶，能够调控许多转录因子活性，我们前期结果显示NLK敲除的肠癌细胞系对紫杉醇等抗肿瘤药物更敏感，并有可能是通过调控NRF2实现的。因此，本项目旨在前期工作基础上，进一步证明NLK是否是通过调控NRF2的表达参与调控肿瘤细胞的耐药性及其分子机制，揭示NLK在肿瘤细胞耐药性中的分子机制，为认识肿瘤发生发展过程和肿瘤耐药性的机制提供有益的线索，最终为化疗药物耐药性逆转提供理论依据。

中文关键词： 肿瘤细胞耐药性；大肠癌；氧化应激；NLK；NRF2信号通路

英文摘要： Colorectal cancer is the third most common cancer and the third leading cause of cancer death in men and women. Surgical resection, chemotherapy and radiotherapy are the primary means to colorectal cancer treatment, but the chemoresistance of tumor cells to chemotherapy drugs is the biggest obstacle of chemotherapy, thus the mechanism needs to be resolved urgently. Resistance to Nrf2-ARE oxidative stress signal pathway may be associated with a variety of tumor chemoresistance mechanisms, but the exact mechanisms of its regulation remain lacking. Nemo-like kinase (NLK) is an evolutionarily conserved Serine/threonine protein kinase, which can regulate the activity of many transcription factors. Our preliminary results show that the NLK knockout cancer cell lines are more sensitive to antineoplastic drugs such as taxol, and possibly we can achieve the goal to eliminate the chemoresistance by regulating NRF2.Therefore, this project, based on the early stage of our work, aims to further confirm whether NLK regulates the chemoresistance of tumor cells by regulating the expression of NRF2, reveal the NLK molecular mechanisms of chemoresistance in tumor cells, and provide useful clues for the understanding of cancer development and tumor chemoresistance mechanisms, thus seeking out the theoretical basis for the chemoresistance reversal.

英文关键词： Chemoresistance;Colorectal Cancer;Oxidative Stress;NLK;NRF2 signal pathway