Cullin-RINGE3泛素连接酶在非小细胞肺癌多西他赛耐药中的作用及分子机制

At present, Lung cancer is one of the most frequently diagnosed types of malignant tumor and a leading cause of mortality worldwide. Systemic chemotherapy is still an important treatment option for advanced lung cancer. However, drug resistance acquired by lung cancer cells usually leads to treatment failure. Our previous study showed that Cullin 7（CUL7）plays a critical role in the development and progression of non-small cell lung cancer (NSCLC). Furthermore, we found that the expression of CUL7 was significantly increased in the docetaxel-resistant NSCLC cells. To understand the underlying molecular mechanisms of docetaxel resistance in NSCLC and to identify molecular targets for therapy, this project aims to investigate the function of CUL7 and the inhibitor(MLN4924) in the docetaxel-resistant NSCLC cells. To determine whether CUL7 involved in docetaxel resistance of NSCLC by regulating epithelial - mesenchymal transition（EMT）or 3M complex（FBXW8-CUL7-OBSL1-CCDC8）-CUL9-survivin pathway. Our results will not only help to elucidate the underlying molecular mechanisms of docetaxel resistance in lung cancer, but also provide theoretical evidences for clinical personalized medicine, reversal of drug resistance or molecular targeted therapy in lung cancer.

肺癌是目前病死率最高的常见恶性肿瘤。以化疗为主的综合治疗仍是晚期肺癌的主要治疗手段。肺癌细胞对化疗药物产生耐药，常常导致化疗失败。前期研究结果发现Cullin7（CUL7）与非小细胞肺癌(non-small cell lung cancer, NSCLC)发生、发展密切相关。而且，CUL7在多西他赛耐药的NSCLC细胞表达显著增高。为研究NSCLC多西他赛耐药机制和分子靶向治疗，本项目拟深入研究CUL7和抑制剂MLN4924在NSCLC多西他赛耐药中的作用及分子作用机制。研究确定CUL7是否通过上皮-间质转化（EMT）或3M复合体（FBXW8-CUL7-OBSL1- CCDC8）-CUL9-survivin通路等机制介导参与NSCLC细胞多西他赛耐药形成。研究结果将有助于阐明肺癌多西他赛耐药的分子机制，为肺癌的临床个体化用药或逆转耐药性的产生，以及肺癌的分子靶向治疗等提供关键的理论依据。

近年，我国肺癌的发病率和病死率呈快速上升趋势。肺癌细胞对化疗药物产生耐药是导致化疗失败的主要原因。多西他赛在临床上广泛用于乳腺癌、非小细胞肺癌（NSCLC）、卵巢癌等的治疗。本研究项目发现泛素连接酶Cul7在非小细胞肺癌（NSCLC）多西他赛耐药细胞中高表达，并且在NSCLC亲本细胞中能被多西他赛和依托泊苷诱导表达增加。NSCLC多西他赛耐药细胞中Cul7和Survivin表达上调，凋亡减少。敲低或过表达Cul7能够引起Survivin的下调或上调，细胞对多西他赛和依托泊苷的敏感性增加或降低。Cul7和Survivin在NSCLC肿瘤组织中高表达，瞬时敲低Survivin可以逆转Cul7高表达引起的耐药。项目执行期间共发表论文6篇，其中SCI论文1篇，培养硕士研究生3人。研究结果将有助于阐明肺癌耐药相关分子机制，将有助于筛选出可用于临床指导多西他赛个体化用药的分子靶标，为临床肿瘤多西他赛耐药的干预策略研究提供新的思路。