hCINAP在肿瘤细胞代谢和增殖中的调节作用及分子机制研究

Warburg效应是肿瘤细胞代谢的标志性特征，肿瘤细胞代谢的异常调控显著影响肿瘤细胞的增殖。但有关肿瘤细胞代谢调控的分子机制有待于深入研究。因此，鉴定肿瘤细胞代谢新的调控因子，揭示其对肿瘤细胞增殖的影响及分子机制具有重要意义。我们的前期研究发现，具有ATPase/AK活性的蛋白hCINAP在肿瘤组织中高表达，与癌症病人的预后密切相关，敲低hCINAP能够明显抑制裸鼠肿瘤的生长。并且，hCINAP与乳酸脱氢酶等相互作用并明显影响其酶的活性。该基因的全敲除导致小鼠胚胎死亡。在此基础上，本课题将利用hCINAP肝脏组织特异性敲除和hCINAP+/-小鼠观察hCINAP的缺失所引起的代谢表型和成瘤的变化。同时利用生化、分子、细胞和结构生物学等方法，鉴定更多受hCINAP调控的蛋白，深入地研究hCINAP在肿瘤细胞代谢、细胞增殖和肿瘤发生发展中的调控作用和分子机理，为寻找新的肿瘤治疗靶点提供有用信息

Warburg effect or aerobic glycosis is known as the most common metabolic phenotype of cancer cells. Even under sufficient oxygen condition, cancer cells prefer to use glycolysis instead of oxidative phosphorylation. A significant amount of evidence demonstrates that upregulated glycosis is correlated to activated oncogenes, and which stimulate the proliferation of cancer cells. Therefore, Warburg effect is considered as a hallmark of cancer. Despite the fact that increased glycolysis is correlated with upregulated biosynthetic metabolism, the detailed molecular mechanisms how increased glycosis is regulated are still not well understood. Therefore, identification of novel regulators involved in Warburg effect and study the molecular mechanism attract great attenuations for scientists and has important biological significance. Our previous study showed that ATPase/AK activity containing hCINAP is highly expressed in cancers, which promotes tumorigenesis and correlates with poor cancer patient survival. Both in vitro and in vivo experiments revealed that depletion of hCINAP significant inhibited tumorigenesis. And our preliminary work has shown that hCINAP may interact with some critical enzymes in aerobic glycolysis and is essential to the enzyme activities. Moreover, homozygous CINAP-/- mice show embryonic lethality. Based on our new findings, by using hCINAP liver-specific knockout mice together with various techniques of molecular biology, biochemistry, cell biology and structural biology, we aim to identify more partners of hCINAP, investigate the regulatory functions and underlying mechanisms of hCINAP in Warburg effect and tumor cell proliferation, and understand the correlation to tumorigenesis. These studies will contribute to the overall understanding of aerobic glycosis and tumorigenesis, and provide effective target for cancer therapy and theoretical basis for drug design.