原纤维蛋白FBN1调控卵巢癌转移侵袭机理研究

Advanced ovarian cancer is liable to metastasis and recurrence, which results in high 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. We previously identified that Fibrillin-1 promotes epithelial-mesenchymal transition (EMT) of ovarian cancer and ovarian cancer metastasis. Subsequently, it was found that transcription factors SLUG induced the high expression of FBN1, and FBN1 interacted with integrin beta 4 (ITGB4) which may activate relevant signaling pathways to regulate EMT process of ovarian cancer cells, however, the correlation of these two aspects and the specific mechanism remain unclear. Therefore, based on previous works, this study will use in vivo and in vitro experiments, such as dual luciferase report gene, chromatin precipitation, gene/tissue chips and small animal in vivo imaging and immunohistochemical staining, to explore the underlying intrinsic molecular mechanisms of SLUG/FBN1/ITGB4/EMT 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 target for the prognosis and therapy, which may have important theoretical significance and potential value.

晚期卵巢癌易转移复发而导致疗效不佳和高死亡率，故揭示其转移机制并探寻治疗新的靶点是有效治疗的关键。本项目前期研究发现原纤维蛋白1(FBN1)可促进卵巢癌上皮间质转化(EMT)，增强卵巢癌细胞转移侵袭能力。随后研究发现转录因子SLUG在转录水平上可诱导FBN1高表达，同时FBN1又可与整合素蛋白β4直接相互作用，可能激活下游相关信号通路来调节卵巢癌EMT过程，但这两方面之间的联系以及具体作用机制仍不清楚。因此，本项目拟在前期工作的基础上利用双荧光素报告基因、染色质免疫沉淀、基因/组织芯片、小动物活体成像以及免疫组化等体内外实验来研究SLUG/FBN1/ITGB4/EMT信号通路的内在调控网络和促进卵巢癌转移的作用机制，这对于明确卵巢癌转移机理和寻找可用于转移风险评估和治疗的分子靶点具有较重要的理论意义和潜在应用价值。

晚期卵巢癌易转移复发而导致疗效不佳和高死亡率，故揭示其转移机制并探寻治疗新的靶点是有效治疗的关键。本项目研究发现原纤维蛋白1(FBN1)可促进卵巢癌上皮间质转化(EMT)，增强卵巢癌细胞转移侵袭能力。随后研究发现转录因子SLUG在转录水平上可诱导FBN1高表达；双荧光素报告基因、染色质免疫沉淀以及定点突变等实验证明SLUG在FBN1启动子序列上具有结合位点。同时，DNA二代测序结果显示FBN1可通过ITGB4/FAK/STAT1信号通路调节β-catenin转录表达，进而下游相关信号通路来调节卵巢癌EMT过程，影响卵巢癌细胞转移。组织芯片以及卵巢癌病人预后资料分析表明，SLUG、FBN1、ITGB4等蛋白在卵巢癌病人组织中高表达，并与病人预后情况呈负相关,并与病人转移风险呈正相关性。因此，本项目通过上述体内外实验阐明了SLUG/FBN1/ITGB4/EMT信号通路的内在调控网络和促进卵巢癌转移的作用机制，对于明确卵巢癌转移机理和寻找可用于转移风险评估和治疗的分子靶点具有较重要的理论意义和潜在应用价值。