KIAA1199的表达调控及其促进卵巢癌干细胞性和转移的机制研究

卵巢癌干细胞的扩增和远端转移是决定其恶性程度和转移的关键因素。课题组前期通过蛋白质组学检测发现KIAA1199在晚期转移性卵巢癌中显著增高，并发现其可通过调控透明质酸（HA）解聚促进ECM重塑和CD44通路，导致卵巢癌干细胞的扩增和侵袭。转录调控分析发现KIAA1199在卵巢癌中的高表达可能受TGF-β/Smads和IL-6/STAT3通路调控。基于此，课题组提出假说：KIAA1199受TGF-β/Smads和IL-6/STAT3通路转录活化，进而通过HA解聚促进卵巢癌ECM重塑和CD44通路，引起卵巢癌干细胞的扩增和转移，导致患者不良预后。本项目拟利用细胞、分子生物学等手段研究KIAA1199对卵巢癌干细胞扩增和侵袭的调控作用及机制。并利用动物实验及临床资料分析KIAA1199对卵巢癌的进程和转移的影响，并进一步探讨肿瘤恶性程度和预后情况，为卵巢癌治疗提供初步线索。

Ovarian cancer stem cell expansion and remote migration are determinant factors leading to ovarian cancer malignancy and metastasis. Using proteomic approaches, our preliminary data identified that KIAA1199 was abundantly expressed in late-stage metastatic ovarian cancer. In addition, we revealed that KIAA1199 might facilitate extracellular matrix (ECM) remodeling and CD44 pathway through modulating hyaluronan depolymerization, consequently resulting in ovarian cancer stem cell expansion and invasion. Transcriptional analysis revealed that the upregulation of KIAA1199 was potentially initiated by TGF-β/Smads and IL-6/STAT3 pathways. On the basis of these findings, our research group proposes the hypothesis that KIAA1199 is transcriptionally activated by TGF-β/Smads and IL-6/STAT3 pathways, and promotes ECM remodeling and CD44 pathway through the initiation of hyaluronan depolymerization, triggering resultant ovarian cancer stem cell expansion and metastasis as well as dismal prognosis of ovarian cancer patients. In this project, we plan to investigate the regulatory role of KIAA1199 in ovarian cancer stem cell expansion and invasion. Furthermore, we will analyze the impact of KIAA1199 on ovarian cancer progression and metastasis using metastatic xenograft tumor model and clinicopathological analysis. Moreover, we will further clarify the involvement of this molecular mechanism in ovarian cancer malignancy and prognosis and provide a novel rationale for the development of ovarian cancer treatment.