KIAA1199调控Nanog参与肝癌干细胞自我更新的分子机制研究

Hepatocellular carcinoma (HCC) is one of the most common malignant cancers in China. The CSCs model suggests that tumor progression, metastasis and recurrence after therapy can be driven by a rare subgroup of tumoral cells that have the capacity to self-renewal, while the bulk of the tumor does not have this capacity. Therefore, the unveiling of this self-renewal process leading to stem cell expansion may be a key event in treatment of HCC. Previous results in our laboratory have confirmed that cancer cells with high expression of Nanog have the characteristics of cancer stem cells. Microarray analysis of gene expression indicated that expression of KIAA1199 is significantly up-regulated in NanogPos CSCs. Furthermore, knock-down of KIAA1199 by RNAi can reduce the expression of Nanog and weaken the self-renewal capacity maintained by Nanog in cancer stem cells. KIAA1199 functions as a regulator in Wnt signaling pathway involved in the self-renewal process of cancer stem cells.Based on our proceeding work, we proposed the hypothesis that KIAA1199 play an indispensable role in self-renewal in HCC. This research will explore the mechanism through which KIAA1199 regulate Nanog by analyzing the correlation between KIAA1199 and poor prognosis of patients with HCC, altering dynamically the expression of KIAA1199. Ultimately, our aim is uncovering the possible mechanism driving self-renewal, providing experimental supports for finding the recipe specifically targeting to liver cancer stem cells.

肝癌是我国常见的恶性肿瘤，肝癌干细胞的存在及干性维持被认为是肝癌复发和转移的根源，因此破译其"干性"维持的分子机制是肝癌治疗取得突破的关键。我们前期研究发现，Nanog高表达的肝癌细胞具有肿瘤干细胞特性。基因表达谱芯片结果显示KIAA1199在Nanog阳性细胞中显著上调，且抑制该基因表达可削弱Nanog维持的干性。Wnt通路参与肿瘤干细胞的自我更新，而KIAA1199是Wnt通路的关键调控因子，因此我们推测KIAA1199可能在肝癌干细胞自我更新中发挥重要作用。因此，本研究拟分析KIAA1199的表达与临床病理的相关性；通过动态调控KIAA1199的表达，研究该基因在肝癌干细胞自我更新中的作用；探究KIAA1199如何调控Nanog表达并参与干性维持的分子机制。该研究将阐明KIAA1199在调控肝癌干细胞自我更新中的作用及分子机制，为探索特异性靶向肝癌干细胞的治疗策略提供依据。

本研究在课题组前期已建立的以Nanog为标记的肝癌干细胞模型基础上，发现KIAA1199的表达水平与Nanog呈正相关，并阐明了KIAA1199在Nanog阳性的肝癌干细胞自我更新调控中发挥重要作用。KIAA1199在肝癌干细胞中显著高表达，通过影响Nanog启动子的活性和激活Wnt信号通路，调控核心干性转录因子Nanog的表达，维持了肝癌干细胞的自我更新。此外，我们的研究结果还发现KIAA1199可参与泛素介导的蛋白质降解过程，为进一步探索KIAA1199调控肝癌干细胞自我更新的新的分子机制提供思路。本项目的研究成果将为寻找特异性靶向肝癌干细胞的治疗新靶点提供依据，具有重要的意义。