BRCA1调节EGFR介导的自噬在卵巢癌顺铂耐药中的作用及机制研究

Chemoresistance is the main cause for the poor prognosis of ovarian cancer patients, but the underlying mechanisms are poorly understood. DNA repair plays an important role in determining chemosensitivity. Notably, BRCA1 is a key molecule for DNA damage repair. Our previous studies confirmed that BRCA1 may be a potential regulator of the epidermal growth factor receptor (EGFR) in ovarian cancer cells (BRCA1 binding sites exist in EGFR promoter). Accumulating evidence indicates that (i) there is a significant correlation between EGFR expression and chemosensitivity; (ii) there is a relationship between EGFR-mediated signaling pathways and autophagy induction; (iii) induction of autophagy in response to microenvironment, which contributes to drug resistance. Therefore, it can be speculated that there is a functional relationship among BRCA1-mediated EGFR expression, autophagy induction and cisplatin resistance in ovarian cancer cells. The present study was undertaken to investigate: (i) which is the key regulatory element for BRCA1 binding in the EGFR promoter; (ii) the relationship between EGFR expression and autophagy induction; (iii) the relationship between autophagy induction and cisplatin resistance; (iv) and to further prove that distinct roles of autophagy in EGFR-mediated cisplatin resistance. The study will provide novel insights into the BRCA1 regulates EGFR-mediated autophagy in cisplatin-resistant ovarian cancer.

化疗耐药是卵巢癌预后不良的主要原因，但机制尚未明了。DNA损伤修复是影响卵巢癌化疗敏感性的关键因素，已知BRCA1是DNA损伤修复的重要因子；我们前期研究证实BRCA1能够调节卵巢癌EGFR表达（预测EGFR启动子存在BRCA1结合位点）；综合分析新近研究发现：①卵巢癌EGFR活性与化疗敏感性显著相关；②EGFR介导的信号通路与自噬关系密切；③自噬作为肿瘤微环境的关键介导者，在肿瘤细胞耐药表型中扮演重要角色。由此我们尝试推测BRCA1介导的EGFR与卵巢癌细胞自噬及顺铂耐药间的分子联系?本研究拟深入探讨：①BRCA1结合EGFR启动子区域的关键位点及具体调节机制；②EGFR与自噬调节；③自噬与顺铂耐药；④并进一步明确，自噬在EGFR介导的卵巢癌顺铂耐药中的作用。该研究将从一个全新的角度诠释：BRCA1调节EGFR介导的自噬与顺铂耐药的分子机制，为卵巢癌病因学研究及治疗策略提供新思路。

化疗耐药是卵巢癌预后不良的主要原因，但机制尚未明了。已知BRCA1、SIRT1、EGFR显著参与卵巢癌化疗耐药，但交互作用和分子机制仍不清楚。我们的数据证实：相比顺铂敏感的卵巢癌组织，顺铂耐药的卵巢癌组织BRCA1, SIRT1和EGFR水平显著升高；BRCA1启动子甲基化介导的BRCA1失活事件显著提升了SIRT1的表达，降低了NAD依赖的SIRT1的活性，同时伴随EGFR水平的降低；用5和10μg/ml顺铂分别处理诱导了一个逐渐升高的BRCA1和SIRT1水平和逐渐降低的NAD水平和NAD介导的SIRT1活性，而EGFR水平先增高，后降低；过表达SIRT1，或者增强SIRT1活性协同加强了BRCA1介导的EGFR转录，相反敲除SIRT1和抑制SIRT1活性抑制了BRCA1介导的EGFR转录；裸鼠移植瘤模型，敲除BRCA1的移植瘤SIRT1水平降低，EGFR水平增高，卵巢癌顺铂敏感性增强。这些数据建议，BRCA1-SIRT1-EGFR axis是BRCA1调节卵巢癌顺铂敏感性的重要分子途径。