IL-6/Gankyrin调节胆管癌Warburg效应促进其生长及转移的机制研究

项目名称： IL-6/Gankyrin调节胆管癌Warburg效应促进其生长及转移的机制研究

项目编号： No.81472322

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 郑桐森

作者单位： 哈尔滨医科大学

项目金额： 80万元

中文摘要： Warburg效应是肿瘤细胞能量代谢的重要特征，但其对胆管癌生长与转移的影响及机制尚不清楚。Gankyrin是一个在肿瘤发生发展中起重要作用的癌基因，我们前期研究发现Gankyrin/Rb/IL-6正反馈环路可促进胆管癌的生长与转移，但其能否影响胆管癌的糖酵解水平尚不明确。项目组预实验结果发现Gankyrin可以上调丙酮酸激酶M2（PKM2）并升高胆管癌糖酵解水平，但机制尚有待探讨。为此，我们提出IL-6/Gankyrin可以通过上调PKM2增强Warburg效应进而促进胆管癌生长及转移的假设，并将应用胆管癌细胞系与动物皮下、原位及转移模型为平台，采用免疫组化、PCR、慢病毒感染、葡萄糖吸收、乳酸水平及氧消耗检测等手段，从分子、细胞及动物水平多层面研究IL-6/Gankyrin/PKM2信号在胆管癌Warburg效应及生长与转移中的作用机制，率先从代谢角度为胆管癌的治疗提供新的思路与借鉴。

中文关键词： C10_胆囊；胆道肿瘤；Warburg效应；Gankyrin；丙酮酸激酶M2；肿瘤转移

英文摘要： The last decade has seen a huge growth in interest in tumor metabolism. Tumors show various metabolic anomalies but the oldest and best known, and possibly the most central to tumor proliferation, is that originally described by Otto Warburg in the 1920s. Now termed the 'Warburg effect', the unusually high rate of glycolysis and lactate production in tumors in the presence of oxygen led Warburg to speculate that aberrant metabolism could be the cause of many cancers. However, the influences of Warburg on cholangiocarcinoma (CCA) are still unknown. Gankyrin (also called p28 or PSMD10) is an oncoprotein commonly overexpressed in many kinds of cancers. Our previous study suggested that Gankyrin is crucial for CCA carcinogenesis and metastasis by activating IL-6/STAT3 signaling pathway through down-regulating Rb protein. However, whether IL-6/Gankyrin/Rb could affect warburg effect in CCA is still known. Our preliminary data suggested that Gankyrin could upregulate pyruvate kinase M2 (PKM2) and increase glycolysis in CCA cells. According to the above, the current project proposes the supposition that IL-6/Gankyrin could activate PKM2 to promote CCA carcinogenesis and metastasis. To verify this hypothesis, we will perform experiments using the methods of immunohistochemical, PCR, lentivirus, glucose uptake etc. to investigate the influences of Warburg effect on CCA and the role of IL-6/Gankyrin in the process. The project will provide new therapeutic targets and interventions for CCA from the perspective of Warburg effects and IL-6/Gankyrin/Rb/IL-6 signaling.

英文关键词： Biliary tract tumor;Warburg effect;Gankyrin;pyruvate kinase M2;tumor metastasis