RNA结合蛋白RBPMS通过调控KLF9/MMP9信号轴抑制卵巢癌侵袭转移的机制研究

Ovarian cancer is one of the gynecological malignancies with the highest mortality. Because of its latent onset and high recurrence rate，patients with ovarian cancer are usually found to be metastatic or recurrent. So revealing metastatic mechanism and exploring new therapeutic targets have become one of the key problems that are urgent to be resolved in ovarian cancer study. However, it is also very difficult. Through high throughput screening of genes differentially expressed in normal ovarian tissue and tumor tissues, we found that RNA binding protein RBPMS was a potential tumor suppressor gene in ovarian cancer, which can inhibit the proliferation, invasion and metastasis of ovarian cancer cells. Subsequently, we found that RBPMS may regulate malignant cell behaviors through KLF9/MMP9 signaling pathway, but the specific regulatory function and mechanism of this signaling pathway are still unclear at present. Therefore, we hypothesize that RBPMS is a suppressor gene of ovarian cancer, and we have done a lot of preliminary experiments. Based on our previous experiment results, we will further use in vivo and in vitro experiments to explore the underlying intrinsic regulatory mechanism of RBPMS/KLF9/MMP9 signaling pathway in ovarian cancer and its role in promoting metastasis and recurrence of ovarian cancer. Besides, we will clarify the correlation between these key molecules and clinicopathologic factors and prognosis of ovarian cancer in this study. Therefore, our study will be of great theoretical significance and potential clinical value for better understanding the metastatic and recurrent mechanisms of ovarian cancer, improving the risk assessment model of metastasis and recurrence for ovarian cancer, and identifying critical molecular targets for ovarian cancer treatment.

卵巢癌是致死率最高的妇科恶性肿瘤之一，其发病隐匿，发现时多为晚期，且复发率极高，故揭示其转移复发机制并探寻新的治疗靶点是研究的重点也是难点。本项目前期通过高通量筛选正常卵巢组织和卵巢癌组织中差异表达的基因，发现RNA结合蛋白RBPMS可能是潜在的卵巢癌抑癌基因，可以抑制卵巢癌细胞的增殖以及侵袭转移。并且研究发现RBPMS可能通过KLF9/MMP9信号通路来调控细胞恶性行为，但目前该信号通路的具体调控功能以及作用机理仍不明确。据此，本课题假设RBPMS是卵巢癌的抑癌基因，拟在前期工作基础上利用一系列的体内外实验来探讨RBPMS/KLF9/MMP9信号通路在卵巢癌中的内在调控网络及其促进肿瘤转移复发的作用机制，并明确其中关键分子与卵巢癌临床病理及预后的相关性，这对于更好地明确卵巢癌转移复发机制、完善卵巢癌转移复发风险评估模型和寻找卵巢癌治疗的新靶点具有重要的理论意义和潜在临床转化价值。

卵巢癌是致死率最高的妇科恶性肿瘤之一，其发病隐匿，发现时多为晚期，且复发率极高，故揭示其转移复发机制并探寻新的治疗靶点是研究的重点也是难点。本项目前期通过高通量筛选正常卵巢组织和卵巢癌组织中差异表达的基因，发现RNA结合蛋白RBPMS是潜在的卵巢癌抑癌基因，体外体内实验显示RBPMS可以抑制卵巢癌细胞的增殖以及侵袭转移。在机制研究中，我们发现其下游与本课题前期的假说不一致，RBPMS主要通过影响PHLDA1及FHL2影响AKT信号通路，进而促进卵巢癌的侵袭转移。在临床样本验证方面，课题组发现RBPMS是卵巢癌的独立预后因子。且AKT抑制剂联合铂类可以逆转卵巢癌铂耐药。该研究深入探讨了卵巢癌中的内在调控网络及其促进转移复发的作用机制，有利于寻找转移复发风险评估和治疗的分子靶点，对于探寻卵巢癌新的治疗方式具有重要的理论意义和潜在临床转化价值。