极光激酶A通过斯钙素2促进卵巢癌化疗抵抗的机理研究

Ovarian cancer is the most fatal among gynecological tumors. Chemo-resistance acquired during treatment leads to a poor prognosis. Aurora A is over-expressed in ovarian cancer and confers chemo-resistance. Recently we found that Aurora A up-regulated STC2. Studies demonstrated that Aurora A phosphorylated IKKα/β to activate NF-κB and promoted nuclear translocation of NF-κB p65 subunit. Nuclear p65 could interact with STC2 promoter to induce STC2 transcription. Moreover, we found that STC2 promoted chemo-resistance in ovarian cancer, and the underlying mechanism may be related to inhibition of cytosolic Ca2+. These results suggested the importance role of Aurora A/NF-κB/STC2 / Ca2+signaling in chemo-resistance. The study aims to investigate the mechanism of Aurora A/NF-κB/STC2/ Ca2+ signaling and their effect on chemo-resistance in ovarian cancer, which may not only reveal a new mechanism for chemo-resistance but also provide a reference for clinical treatment of ovarian cancer.

卵巢癌在妇科肿瘤中死亡率最高，治疗过程中容易产生化疗耐药。极光激酶Aurora A在卵巢癌中高表达，并与细胞化疗耐药密切相关。最近我们发现卵巢癌中Aurora A可诱导斯钙素2（STC2）的表达。研究发现Aurora A通过磷酸化IKKα/β，诱导 NF-κB p65入核。而p65可能与STC2 启动子上的结合位点相互作用促进STC2的转录。我们也发现STC2可促进卵巢癌细胞的化疗耐药，随后的机制研究表明STC2降低胞内Ca2+浓度促进细胞存活，提示Aurora A/NF-κB/STC2/ Ca2+信号通路在调控卵巢癌化疗耐药中的重要作用。本项目中我们将从分子，细胞，组织三个层面系统地研究Aurora A/NF-κB/STC2/ Ca2+信号的调控机制并探讨其对卵巢癌化疗的影响，为卵巢癌耐药机制的研究提供新思路，为临床治疗提供参考。

卵巢癌是妇科肿瘤中致死率最高的恶性肿瘤，化疗耐药是导致卵巢癌治疗失败的重要原因之一。极光激酶Aurora A可促进卵巢癌化疗耐药，但具体机制仍需探究。斯钙素STC2是一种分泌性糖蛋白，近年来发现STC2可作为多种肿瘤的预后指标，但其在卵巢癌中的作用尚不明确。我们的研究发现Aurora A可通过NF-κB，调控STC2的启动子活性，进而促进STC2的表达；STC2可与L型电压门控钙离子通道相互结合，降低细胞内钙离子浓度，激活STAT3, ERK和AMPK，从而促进细胞对化疗药物的抵抗；同时我们发现转录因子CREBBP在卵巢癌发生发展及耐药中也发挥重要作用，而CREBBP也可调控STC2的表达，提示STC2在卵巢癌中的重要作用。我们的研究为揭示Aurora A调控化疗耐药提供了新思路，为卵巢癌诊疗提供新的潜在靶标。