The role of glutaminase 2, a novel p53 target gene in metabolism, in liver cancer

描述（由申请人提供）：肝细胞癌（HCC）是美国增长最快的癌症类型，死亡率高。肿瘤抑制因子p53通过调控细胞周期阻滞、细胞凋亡和衰老，在包括HCC在内的肿瘤预防中起着至关重要的作用。近年来的研究表明，p53在肿瘤抑制中具有新的功能，即调节能量代谢。作为肿瘤细胞的标志，代谢变化（如Warburg效应）最近被认为是肿瘤发生的关键因素，也是肿瘤治疗的潜在靶点。我们发现了一个新的p53靶基因，线粒体谷氨酰胺酶2 (GLS2)，这个基因编码一种参与线粒体呼吸的酶，它为p53和代谢提供了直接的联系。引人注目的是，我们来自有限样本的数据显示，与邻近的正常或肝硬化肝组织相比，我们分析的几乎所有HCC标本中GLS2表达缺失或显著降低（超过20倍）。我们的初步数据进一步表明GLS2可能抑制肿瘤发生并调节能量代谢。基于我们的研究结果，我们假设GLS2可能通过调节代谢在肿瘤抑制中发挥关键作用。在本研究中，我们计划：1)确定GLS2在另外100个HCC标本中的表达，以确定GLS2的缺失是HCC的常见和特异性事件，可能是潜在的肿瘤生物标志物。2)验证GLS2表达缺失促进裸鼠肝脏肿瘤发生，而恢复GLS2表达抑制裸鼠肝脏肿瘤发生的假说。3)明确GLS2在肿瘤抑制中的作用机制。特别是，我们将确定GLS2在调节能量代谢、应激反应和抗氧化中的作用。4)确定GLS2在HCC中表达缺失的机制。针对RFA （PA-08-243）题为“病因学、预防和治疗肝细胞癌”，本研究将大大增加我们对肝脏肿瘤发生机制的认识，扩大我们对p53抑制肿瘤的机制的认识，特别是代谢变化在肿瘤发生中的作用和逆转代谢变化在肿瘤治疗中的作用。我们预计，本研究将有直接潜力为肿瘤治疗，特别是肝癌治疗提供GLS2作为新的肿瘤生物标志物和治疗靶点。

DESCRIPTION (provided by applicant): Hepatocellular carcinoma (HCC) is the most rapidly increasing type of cancer with high mortality in the United States. Tumor suppressor p53 plays a crucial role in tumor prevention, including HCC, through its regulation of cell cycle arrest, apoptosis and senescence. Recent studies suggested a novel function for p53 in tumor suppression, i.e. p53 regulates energy metabolism. As a hallmark of tumor cells, metabolic changes (e.g. Warburg effect) were recently suggested to be a key contributor to tumorigenesis and a potential target for tumor therapy. We identified a novel p53 target gene, the mitochondrial glutaminase 2 (GLS2), a gene encoding an enzyme involved in mitochondrial respiration, which provides a direct link for p53 and metabolism. Strikingly, our data from a limited number of samples show that GLS2 expression is absent or significantly decreased (by over 20-fold) in almost all of the HCC specimens we analyzed as compared with the adjacent normal or cirrhotic liver tissues. Our preliminary data further suggest that GLS2 may suppress tumorigenesis and regulates energy metabolism. Based on our results, we hypothesize that GLS2 may play a critical role in tumor suppression through its regulation of metabolism. In this proposed study we plan to: 1) determine the GLS2 expression in additional 100 HCC specimens to establish the loss of GLS2 as a common and specific event for HCC which could be a potential tumor biomarker. 2) Test the hypothesis that loss of GLS2 epxression promotes tumorigenesis while restoration of GLS2 expression inhibits liver tumorigenesis in nude mice. 3) Identify mechanisms for GLS2 in tumor suppression. In particular, we will determine GLS2's role in regulation of energy metabolism, stress responses and antioxidantion. 4) Identify mechanisms underlying the loss of the GLS2 expression in HCC. In response to RFA (PA-08-243) entitled "Etiology, Prevention, and Treatment of Hepatocellular Carcinoma", this proposed study will greatly increase our understanding of the mechanisms for liver tumorigenesis and expand our understanding of mechanisms of p53 in tumor suppression, especially the role of metabolic changes in tumorigenesis and the role of reversing metabolic changes in tumor therapy. It is our anticipation that this study will have direct potential to provide GLS2 as a novel tumor biomarker and therapeutic target for tumor therapy, especially for HCC. PUBLIC HEALTH RELEVANCE: In this proposed study we will study the role and mechanisms of GLS2 gene in tumor suppression. This study will greatly increase our understanding of the molecular mechanisms for tumorigenesis, especially the role of metabolic changes in tumor initiation and progression. This study will have direct potential to provide GLS2 as a novel tumor biomarker for tumor diagnosis and therapeutic target for tumor therapy, especially for liver cancer.