维甲酸相关孤核受体RORα通过调控肿瘤血管生成和糖酵解作用来调节卵巢癌细胞转移的机制研究

Ovarian cancer is liable to metastasis and recurrence, which results in bad therapeutic effect and higher mortality, so revealing of metastasis mechanism and exploring of new therapeutic targets have become one of the key problems urgently to be solved in ovarian cancer treatment. Through high throughput screening of genes differentially expressed in normal ovarian tissue, tumor tissues, and metastases, we found that retinoid acid receptor-related orphan receptor α (RORα) was a potential tumor suppressor gene in ovarian cancer, which not only inhibited ovarian cancer cell metastasis, but also reduced cell glycolysis and angiogenesis. Further study indicated that RORα might exert its effect on cell metastasis by regulating cell glycolysis and angiogenesis through ECM1/VEGFR2 signaling pathway, but the underlying mechanism remains unclear. Therefore, based on previous works, this study will use in vivo and in vitro experiments, such as dual luciferase report gene, gene/tissue chips and small animal in vivo imaging and immunohistochemical staining, to explore the underlying intrinsic molecular mechanisms of RORα/ECM1/VEGFR2 signaling pathway and the role in metastasis of ovarian cancer. Our study may further explore the molecular mechanism of metastasis of ovarian cancer and identify critical molecular targets for the prognosis and therapy, which may have the important theoretical significance and the potential value.

转移复发是导致卵巢癌治疗效果不佳和死亡率较高的重要原因，故揭示其转移复发机制并探寻新的治疗靶点是其有效治疗的关键。本项目前期通过高通量筛选卵巢正常组织、肿瘤组织以及转移灶中差异表达的基因，发现维甲酸相关孤核受体RORα是卵巢癌潜在的抑癌基因，既可以抑制卵巢癌细胞侵袭转移，又可以降低细胞糖酵解水平和阻止肿瘤血管生成。随后研究发现RORα可能通过ECM1/VEGFR2信号通路来调控细胞糖酵解和肿瘤血管生成过程，进而影响细胞侵袭转移，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，本项目拟在前期工作基础上利用分子克隆、双荧光素报告基因、基因/组织芯片、小动物活体成像等体内外实验来研究RORα/ECM1/VEGFR2信号通路的内在调控网络及其促进卵巢癌转移复发的作用机制，这对于明确卵巢癌转移复发机制和寻找可用于转移复发风险评估和治疗的分子靶点具有重要的理论意义和潜在临床转化价值。

卵巢癌易发生转移和复发，治疗效果差，死亡率高。破解卵巢癌转移机制，发现新的治疗靶点，是提高卵巢癌治疗亟待解决的关键问题。在此，我们确定了维甲酸受体相关孤儿受体α (RORα)是一种与生存相关的肿瘤抑制因子。过表达RORα可抑制卵巢癌细胞的增殖、糖酵解、血管生成和转移。此外，我们发现RORα富集在细胞外基质蛋白1 (ECM1)启动子中，并转录抑制ECM1 mRNA的表达。ECM1与内皮生长因子受体2 (VEGFR2)结合并稳定，从而调节卵巢癌转移。我们的研究表明，RORα可通过RORα/ECM1/VEGFR2信号通路促进卵巢癌糖酵解、血管生成和转移。我们的发现为RORα如何调控转移提供了新的见解，并表明RORα可作为逆转卵巢癌转移的潜在治疗靶点。