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）是美国高死亡率最快的癌症类型。肿瘤抑制剂p53通过调节细胞周期停滞，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，最近认为代谢变化（例如Warburg效应）是肿瘤发生的关键因素，也是肿瘤治疗的潜在靶标。我们确定了一种新型的p53靶基因，线粒体谷氨酰胺酶2（GLS2），这是一种编码参与线粒体呼吸的酶的基因，该酶为P53和代谢提供了直接联系。令人惊讶的是，我们来自有限数量的样品的数据表明，与相邻的正常或肝硬化肝组织相比，我们分析的几乎所有HCC标本中都没有GLS2表达或显着降低（以上超过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。根据我们的结果，我们假设GLS2通过调节代谢在肿瘤抑制中起关键作用。在这项提出的研究中，我们计划：1）确定另外100个HCC样品中的GLS2表达，以确定GLS2作为HCC的常见和特定事件的损失，这可能是潜在的肿瘤生物标志物。 2）检验以下假设：GLS2癫痫发作会促进肿瘤发生，而GLS2表达的恢复会抑制裸鼠的肝肿瘤发生。 3）确定肿瘤抑制中GLS2的机制。特别是，我们将确定GLS2在能量代谢，应力反应和抗氧化剂调节中的作用。 4）确定HCC中GLS2表达丧失的基础机制。为了响应RFA（PA-08-243）的标题为“肝细胞癌的病因，预防和治疗”，这项拟议的研究将大大提高我们对肝肿瘤发生的机制的理解，并扩展我们对p53机制在肿瘤抑制中的理解，尤其是在肿瘤中的作用在TUMORICENTOR中的作用和变化的作用。我们的期望是，这项研究将具有直接的潜力，可以将GLS2作为一种新型的肿瘤生物标志物和肿瘤疗法的治疗靶标，尤其是对于HCC。 公共卫生相关性：在这项拟议的研究中，我们将研究GLS2基因在肿瘤抑制中的作用和机制。这项研究将极大地增加我们对肿瘤发生的分子机制的理解，尤其是代谢变化在肿瘤启动和进展中的作用。这项研究将有直接的潜力提供GLS2作为肿瘤诊断的新型肿瘤生物标志物和肿瘤疗法的治疗靶标，尤其是用于肝癌。