靶向糖感知信号通路：TRPV5-Aldolase-AMPK调控前列腺癌细胞增殖与转移的机制与临床意义

糖代谢信号通路在肿瘤的发生与进展中起重要作用，在肿瘤细胞，如何感知葡萄糖水平的下降？低糖感知信号通路对癌细胞的分解与合成代谢、对细胞增殖、转移产生什么影响？——目前认识不多。我们最近通过全基因组测序，筛选发现阳离子通道蛋白TRPV5在前列腺癌组织的表达明显上调，并已开展前期实验初步证实了这一发现。醛缩酶（Aldolase）是正常细胞感受低糖信号的感受器。本项目拟在已有前列腺癌糖代谢研究基础上，探索前列腺癌细胞内TRPV5结合醛缩酶、感知低糖信号，与v-ATPase结合促进AXIN-LKB1-Ragulator复合物形成，激活溶酶体AMPK活性，导致促进分解代谢、增加ATP的产出，维持癌细胞活跃增殖的旺盛能量需求的分子机制。并开展动物体内实验，与临床前列腺癌患者前列腺标本染色分析，探讨上述蛋白的预后价值与临床意义，从糖感知的角度，为前列腺癌的诊治提供新的生物标记物及分子治疗靶点。

Glucose metabolic signaling plays an important role in the carcinogenesis and progression of many kinds of tumors. In cancer cells, how the decreased glucose is sensed? What is the impact of the decreased glucose sensing signaling exerted on the catabolism, anabolism, proliferation and metastasis of prostate cancer cells? --Little is kown about the upper questions. . Recently, we have identified the expression of Transient Receptor Potential V Channel 5 (TRPV5) was up-regulated in the tissues of prostate cancer by whole gene sequencing. This finding was also confirmed by our initial experiments. . Aldolase was found to plays an important role in the regulating of glucose sensing. Based on our previous studies of prostate cancer glucose metabolic signal transduction pathways, this study aims to explore the mechanism of how TRPV5, combined with Aldolase, to sense and to transduce the change of the decreased glucose in tumor cells. . It will be furtherly investigated how TRPV5-Aldolase interact with v-ATPase to affect the combination of v-ATPase, Ragulator, and AXIN-LKB1, which finally leads to the activating of lysosome AMPK activity. The mechanism of how the activated AMPK promotes catabolism, increasing ATP production, keeping active cellular energy demand of active proliferation will be elucidated. . In vivo studies in nude mice will also be performed to demonstrate the effects. Pathological staining will be performed in the tissue samples of prostate cancer patients. The clinical prognosis significance of the expression TRPV5-related signaling proteins will be analyzed and evaluated. . Base on the academic perspective of glucose sensing，this study will provide novel biomarkers and therapy molecular targets for the diagnosis and for the treatment of prostate cancer patients.