盆腔浆液性癌中核因子Nrf2的作用及机制研究

Pelvic serous carcinomas (PSC) have mainly three sources including serous carcinoma of the ovary, peritoneum, and the fallopian tube. PSC is one of reproductive system tumors with the highest mortality rate, which threatens women's health. Recently, the pathogenesis and chemoresistance studies have been the keys for improving understanding as well as developing diagnostic and therapeutic strategy in pelvic serous carcinoma. Studies show that nuclear factor Nrf2 is involved in the occurrence and development of many human tumors and has close relationship with tumor chemoresistance. The cross talk between Nrf2-ARE and p53 pathways affects the proliferation and apoptosis of cancer cells. In this study, we plan to test the expression of Nrf2 and related genes,as well as the incidence of gene mutation, methylation and LOH in pelvic serous carcinoma using different molecular biology methods. The expected results will provide new molecular biology basis for the pathogenesis of pelvic serous carcinoma. Our study will also elucidate the mechanism of cross talk between Nrf2-ARE and p53 pathways. With the most important clinical value, we will estimate the efffect of brusatol as a chemotherapy sensitizer in the treatment of pelvic serous carcinoma, which will provide preclinical laboratory evidence for the exploitation of new gene-targeted agents in this area.

盆腔浆液性癌包括卵巢、腹膜、输卵管来源的浆液性癌。盆腔浆液性癌是女性生殖系统死亡率最高的恶性肿瘤，严重威胁女性健康。目前盆腔浆液性癌发病机理及化疗耐药相关研究成为提高对疾病认识及发展临床诊断治疗策略的关键之一。研究表明核因子Nrf2参与了多种人体肿瘤的发生发展过程，且与肿瘤耐药的形成关系密切。 Nrf2-ARE通路与p53通路的串话影响了肿瘤的进程与细胞凋亡。本研究拟通过多种分子生物学手段，检测盆腔浆液性癌中Nrf2及其相关基因的表达水平和基因突变、甲基化、LOH发生率，为不同级别盆腔浆液性癌的发病机制提供新的理论依据，并阐明盆腔浆液性癌中Nrf2-ARE通路与p53信号通路间的串话机制。同时通过体内外实验评估鸦胆子苦醇作为化疗增敏剂在盆腔浆液性癌治疗中的作用，为新的盆腔浆液性癌靶向药物的开发提供临床前实验室证据。