质子感知受体TDAG8在酸性环境中调控肿瘤代谢关键环节的分子机理

The reprogrammed energy metabolism in tumor cell leads to large amount of glucose breakdown into lactic acid because of increased glycolysis. The tumor cells need to strengthen glucose intake to adopt energy supply for the high proliferation, metastasis and the extracellular excretion of lactic acid to prevent the apoptosis from acidosis through increased expression of glucose transporter and lactic acid transporter. It induced by HIF during this process. The lactic acid excreted from the cell contributes to make an acidic micro-environment outside of the tumor cell. Our previous studies found that acidic condition induced the expression of proton-sensing receptor TDAG8 and TDAG8 further induced the expression of lactic acid transporter and CD147 to improve cancer survival and transfer activity. We also found that TDAG8 up- regulated HIF and glucose transporter. So，it is considered that TDAG8 receptor is involved in tumor cells to adapt to the low oxygen and acidic environment through induction of the most key protein - HIF expression. In this study, we plan to clarify the signaling mechanism of TDAG8 induced HIF expression and its regulatory role in the Key processes of tumor Metabolism in Acidic micro-environment. TDAG8 transgenic hepatocellular （carcinoma）cells and lung cancer cells were used as models in the study. Our research would provide a novel therapeutic target for cancer treatment which focusing on tumor acidic environment（acidic barrier），the unsolved problem in drug resistance and lymphocyte apoptosis.

肿瘤细胞能量代谢重编程导致糖酵解增强而使大量葡萄糖分解成乳酸。在此过程中，通过上调低氧诱导因子（HIF）来诱导葡萄糖转运体和乳酸转运体的表达，强化葡萄糖摄入以适应其高增殖与转移活性所需能量供给和乳酸的胞外排出而防止酸性引起的细胞凋亡。排出胞外的乳酸是造就肿瘤酸性微环境的主要成分。在前一课题中我们发现，酸性可诱导脂质-质子双配体受体TDAG8的表达，而TDAG8通过诱导乳酸转运体和CD147来提高肿瘤生存率和转移活性。继而又发现TDAG8可上调HIF和葡萄糖转运体。我们认为TDAG8参与肿瘤细胞适应低氧酸性环境的最关键蛋白-HIF的表达。所以，在本课题中，以TDAG8转基因肝癌和肺癌细胞作模型，重点研究TDAG8在酸性（质子）条件下诱导HIF的信号机制和肿瘤代谢关键环节中的调控作用及其代谢机理。为肿瘤治疗中尚未突破的酸性“屏障”（药物抵抗与淋巴细胞凋亡）的攻克研究中指出新的靶位点。

肿瘤细胞能量代谢重新编程导致糖酵解增强而使大量葡萄糖分解成乳酸。在此过程中，通过上调低氧诱导因子（HIF）来诱导葡萄糖转运体和乳酸转运体的表达，强化葡萄糖摄入以适应其高增殖与转移活性所需能量供给和乳酸的胞外排出而防止酸性引起的细胞凋亡。被排出的乳酸在胞外造就肿瘤酸性微环境。在前一课题中发现酸性可诱导质子感知体受体TDAG8表达，而TDAG8通过诱导乳酸转运体来提高肿瘤生存率和转移活性。继而又发现TDAG8可上调HIF和葡萄糖转运体。认为TDAG8参与肿瘤细胞适应低氧酸性环境的最关键蛋白-HIF的表达。在本课题中，以TDAG8转基因肝癌和肺癌细胞作模型，研究TDAG8在酸性条件下诱导HIF的信号机制和肿瘤代谢关键环节中的调控作用及其代谢机理。为肿瘤治疗中尚未突破的酸性“屏障”（药物抵抗与淋巴细胞凋亡）的攻克研究中指出新靶位点。研究中发现1）在肿瘤的酸性环境中TDAG8表达量上升，在癌细胞组织中普遍高表达；TDAG8可提高肿瘤细胞在酸性条件下存活、抗凋亡和迁移能力，并在体内显著提高肿瘤生长和转移活性。2）TDAG8通过上调低氧诱导因子（HIF-1）促进肿瘤代谢重编程，从而提高肿瘤细胞适应酸性低氧环境中得以生存与转移所必须的GLUT1、MCT1、MCT4，VEGF和PDGF等关键分子表达，并强化这些分子的作用，体现在糖酵解、糖异生、氧化磷酸化作用、葡萄糖摄入、乳酸的排出及肿瘤组织血管生成的显著提高。3）TDAG8通过cAMP-途径激活NF-κB信号通路上调HIF-1表达；并首次发现TDAG8还通过非依赖HIF-1介导诱导MCT1、MCT4的表达。4）MAPK（ERK1/2，P38，JNK）、Ras、TNF、PI3K-Akt、Hippo等信号通路参与介导TDAG8的促进肿瘤细胞生存与转移过程。5）在肾癌案例大数据分析结果也显示，TDAG8在肾癌组织中显著表达，并与肾癌患者生存率成负相关，与临床肿瘤TNM分期系统显著相关，是肾癌的一个预后不良因素和生物标记物。总之，酸性微环境在肿瘤周围形成一个“屏障”，使肿瘤细胞TDAG8表达增加，TDAG8感知酸性，并与HIF-1系统形成肿瘤细胞适应低氧酸性环境中得以生存与转移的关键调控中心。