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

代谢中新型 p53 靶基因谷氨酰胺酶 2 在肝癌中的作用

• 批准号: 8699974
• 负责人: Zhaohui Feng
• 金额: $ 22.26万
• 依托单位: RBHS -CANCER INSTITUTE OF NEW JERSEY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-01 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8699974
• 关键词: Accounting; Apoptosis; Biological Assay; Biological Markers; Cell Cycle Arrest; Cells; Cirrhosis; Code; Data; Detection; Development; Diagnosis; Early Diagnosis; Energy Metabolism; Enzymes; Epigenetic Process; Etiology; Event; Gene Mutation; Gene Targeting; Genes; Glutaminase; Glycolysis; Human; Hypermethylation; Lead; Link; Liver; Loss of Heterozygosity; Malignant - descriptor; Malignant Epithelial Cell; Malignant neoplasm of liver; Metabolic; Metabolism; Mitochondria; Modeling; Molecular; Mutation; Nude Mice; Play; Prevention; Primary carcinoma of the liver cells; Protein p53; Proteins; RNA; Radiation; Regulation; Residual state; Respiration; Role; Sampling; Series; Specimen; TP53 gene; Testing; Tetanus Helper Peptide; Therapeutic; Tissues; Transfection; Tumor Suppression; United States; Warburg Effect; Xenograft procedure; base; biological adaptation to stress; cancer prevention; cancer therapy; cancer type; cell growth regulation; chemotherapeutic agent; effective therapy; expression vector; in vivo; knock-down; mRNA Expression; mortality; mouse model; mutant; neoplastic cell; new therapeutic target; novel; novel therapeutics; prevent; promoter; public health relevance; response; restoration; senescence; small hairpin RNA; therapeutic target; tumor; tumor initiation; tumor progression; tumorigenesis; vector

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.

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通过调节细胞周期阻滞、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。最近的研究表明p53在肿瘤抑制中具有新的功能，即p53调节能量代谢。作为肿瘤细胞的标志，代谢变化（如瓦尔堡效应）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，线粒体转氨酶2（GLS 2），一个编码参与线粒体呼吸的酶的基因，它为p53和代谢提供了直接的联系。引人注目的是，我们从有限数量的样本中获得的数据显示，与邻近的正常或肝硬化组织相比，在我们分析的几乎所有HCC标本中，GLS 2表达都不存在或显著降低（超过20倍）。我们的初步数据进一步表明，GLS 2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GLS 2可能通过其代谢调节在肿瘤抑制中发挥关键作用。在这项拟议的研究中，我们计划：1）确定另外100份HCC标本中的GLS 2表达，以确定GLS 2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)在裸鼠中检验GLS 2表达缺失促进肿瘤发生而GLS 2表达恢复抑制肝脏肿瘤发生的假设。3)确定GLS 2在肿瘤抑制中的机制。特别是，我们将确定GLS 2在调节能量代谢，应激反应和抗氧化方面的作用。4)确定HCC中GLS 2表达缺失的潜在机制。作为对标题为“肝细胞癌的病因、预防和治疗”的RFA（PA-08-243）的回应，这项拟议研究将大大增加我们对肝脏肿瘤发生机制的理解，并扩大我们对p53在肿瘤抑制中的机制的理解，特别是代谢变化在肿瘤发生中的作用以及逆转代谢变化在肿瘤治疗中的作用。我们预期，这项研究将有直接的潜力，提供GLS 2作为一种新的肿瘤生物标志物和治疗靶点的肿瘤治疗，特别是肝癌。 公共卫生相关性：在这项拟议的研究中，我们将研究GLS 2基因在肿瘤抑制中的作用和机制。这项研究将大大增加我们对肿瘤发生的分子机制的理解，特别是代谢变化在肿瘤发生和发展中的作用。本研究将为肿瘤诊断提供新的肿瘤生物标志物，为肿瘤治疗提供新的治疗靶点，尤其是肝癌的治疗。