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

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.

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。

上皮性卵巢癌转移严重影响患者预后，近年来，在上皮性卵巢癌检测到KIAA1199的表达有异常，但它与卵巢癌发生发展有关的机制尚不明确。课题组研究证实了KIAA1199通过调控IL-6/STAT3通路对卵巢癌细胞生物学行为有影响，并通过免疫组化证实了卵巢恶性上皮性肿瘤中该蛋白表达均有升高，同时根据回顾性分析发现KIAA1199低表达的卵巢癌患者5年生存率明显高于高表达的患者。在使用IL-6刺激卵巢癌细胞株后，KIAA1199、STAT3和p-STAT3表达水平显著增加，而使用IL-6/STAT3通路抑制剂后KIAA1199、p-STAT3、STAT3表达水平显著降低。课题组还发现在裸鼠模型中敲除KIAA1199的稳转细胞株肿瘤的生长明显减慢，说明KIAA1199确实促进卵巢恶性肿瘤的生长。这些结果表明KIAA1199可加速卵巢癌的恶化，且机制与IL6/STAT3通路的调控有关，从而可将其作为卵巢癌不良预后因素和潜在治疗靶点。