NOK癌基因对肿瘤糖代谢的影响及作用机制研究

The abnormal growth of tumor cells may eventually damage mitochondrial energy metabolism and results in energy production through aerobic glycolysis. This type of phenomenon is often called Warburg effect. NOK is a member of receptor protein tyrosine kinase superfamily and possesses strong capacity to promote tumorigenesis and metastasis. However, it is currently unknown whether NOK is involved in Warburg effect and what is the mechanism controlling NOK mediated Warburg effect. The aims of this proposal is to study the alterations of metabolic profiling of NOK related tumors which we will mainly focus on the mechanistic study on NOK mediated aerobic glycolysis. We will use NOK transformed cell line, the animal model of NOK induced tumor and clinal samples of NOK related diseases to confirm the results of metabolic profiling. This study will reveal the relationship between NOK and c-Myc and HIF-1?, two important transcriptional factors controlling glycose metabolism, and also reveal the roles of some key enzymes such as pyruvate kinase M2 (PKM2), hexokinase 2 (HK2) and pyruvate dehydrogenase (PDH) in NOK mediated aerobic glycolysis. This proposed study will produce great values for the diagnosis and therapy on NOK related cancers.

肿瘤细胞增值异常，最终导致线粒体能量代谢途径破坏，表现为即使有氧存在条件下也主要以糖酵解方式获取能量，肿瘤细胞的这一现象被称作瓦伯格效应(Warburg effect)。NOK是受体蛋白酪氨酸激酶(RPTK)超家族成员, 具有很强的促肿瘤生成与转移能力，但目前对于NOK是否参与瓦伯格效应，以及NOK诱导瓦伯格效应的作用机制还不清楚。本项目旨在利用基因芯片及串联质谱等技术研究NOK相关的肿瘤代谢谱表达变化，着重研究NOK调控有氧糖酵解的作用机制。特别是利用NOK转化的细胞模型、NOK诱导的肿瘤动物模型及NOK相关临床样本验证代谢基因表达谱检测所得结果。注重在分子水平揭示NOK与糖酵解相关的转录因子如c-Myc及HIF1的关系，以及NOK对糖酵解关键酶类如M2型丙酮酸激酶(PKM2)、2型己糖激酶(HK2)和丙酮酸脱氢酶(PHD)活性的影响。本项目对NOK相关肿瘤疾病的诊断与治疗有重要意义

本研究的目的旨在系统检测NOK介导的肿瘤糖酵解的分子作用机制，为未来NOK相关肿瘤的治疗提供重要线索。首先采用基因芯片的方法完成了NOK代谢谱的变化检测。系统检测了NOK对有氧糖酵解通路的激活与影响；系统地检测了NOK对三羧酸循环及氧化磷酸化的影响；在转基因动物水平初步检测了NOK对有氧糖酵解的影响等。本研究结果说明：NOK癌基因显著促进细胞的有氧糖酵解过程，可产生典型的瓦博格效应。我们的研究显示，NOK蛋白在线粒体有定位及分布。虽然，NOK对线粒体三羧酸循环的影响有限，但NOK可显著抑制线粒体的氧化磷酸化。我们的研究还发现，NOK可促进丙酮酸脱氢酶复合物从线粒体到细胞核的转位与表达，从而在促进肿瘤细胞的转录与增殖方面发挥重要作用。