斯钙素2通过活化AMPK/STAT3信号诱导卵巢癌顺铂抵抗的机制研究

卵巢癌发病率低但因对顺铂等化疗抵抗而死亡率极高，因此探明顺铂抵抗的系统机制是提高卵巢癌生存的关键。研究表明DNA修复和自噬可能主导卵巢癌对顺铂化疗抵抗。本课题前期数据提示斯钙素2（STC2）可能通过促进DNA修复与自噬诱导卵巢癌细胞对顺铂抵抗。我们发现STC2在卵巢癌细胞系和组织中高表达，过表达STC2活化AMPK-ATM信号、促进DNA修复，上调STAT3S727磷酸化和细胞核内定位、增强自噬，最终诱导卵巢癌细胞对顺铂抵抗，因而可能是STC2诱导顺铂抵抗的关键机制和主要科学假说，但需要大量研究来验证。本项目拟从分子、细胞、动物、组学和临床组织水平分别研究AMPK活化ATM促进DNA修复和STAT3磷酸化诱导自噬的途径及其临床意义，全面阐释STC2信号诱导卵巢癌顺铂抵抗的机制。本项目的完成有望发现全新的卵巢癌顺铂抵抗相关靶向分子，为精准治疗卵巢癌和提高卵巢癌患者生存提供充分的理论和实践依据

Ovarian cancer occurs with low frequency, but with high mortality due to resistance to cisplatin chemotherapy. Therefore, understanding of the systematic cisplatin resistant mechanism is the key to improve ovarian cancer survival. Studies have shown that DNA repair and autophagy may mainly mediate ovarian cancer resistance to cisplatin. The preliminary data of this project indicate that Stanniocalcin 2 （STC2） may induce ovarian cancer chemoresistance to cisplatin through facilitating DNA repair and autophagy. We found that STC2 was highly expressed in both ovarian cancer cell lines and tissues. Overexpression of STC2 activates the AMPK-ATM signaling to strengthen DNA repair, and upregulates the phosphorylation of STAT3 at Ser727 and its nuclear localization to promote autophagy, which eventually induces ovarian cancer resistance to cisplatin treatment, which may be the key mechanism of STC2-induced cisplatin resistance and the major scientific hypothesis of this project. This project, at the levels of molecules, cells, animals, omics and human clinical specimens, is aimed to investigate the signaling of DNA repair induced by AMPK-activated ATM and autophagy induced by phosphorylation of STAT3, as well as the related clinical significance, to systematically elucidate the STC2 signaling-induced resistance of ovarian cancer to cisplatin. The fulfillment of this project may uncover some novel molecular targets associated with ovarian cancer cisplatin resistance, which may provide both theoretical and practical evidence for precise treatment of ovarian cancer and for effective improvement of ovarian cancer patient survivals