The Role of Glucose-6-Phosphatase in Hepatocellular Carcinoma

6-磷酸葡萄糖酶在肝细胞癌中的作用

• 批准号: 10153987
• 负责人: Sherwin Kelekar
• 金额: $ 3.65万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-03 至 2025-02-02
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10153987
• 关键词: Address; Agar; Anchorage-Independent Growth; Benign; Biological Assay; Biology; Cancer Etiology; Cancer Model; Carbon; Cell Line; Cell Proliferation; Cells; Cessation of life; Childhood; Cirrhosis; Clinical; Development; Diethylnitrosamine; Disease; Down-Regulation; Enzymes; Event; Evolution; Genes; Genetic; Germ-Line Mutation; Glucose; Glycogen; Glycogen Storage Disease; Glycogen Storage Disease Type I; Growth; Hepatocarcinogenesis; Hepatocyte; Human; Immunohistochemistry; In Vitro; Incidence; Injections; Isotopes; Knock-out; Knockout Mice; Lead; Lipids; Liver; Liver Glycogen; Liver neoplasms; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of liver; Measures; Metabolic; Metabolic Diseases; Metabolic Pathway; Metabolism; Modeling; Molecular; Mus; Mutation; Nature; Nucleotides; Oncogenes; Oncogenic; Pathogenesis; Pathway interactions; Patient-Focused Outcomes; Patients; Penetrance; Pentosephosphate Pathway; Pharmacology; Primary carcinoma of the liver cells; Recurrence; Role; S-Phase Fraction; Sampling; Somatic Mutation; Tail; Testing; The Cancer Genome Atlas; Therapeutic; Tissues; Tumor Burden; United States; blood glucose regulation; cell growth; cell transformation; glucose output; glucose-6-phosphatase; in vitro Model; in vivo; in vivo Model; insight; liver cell proliferation; liver injury; liver metabolism; mouse model; neoplastic cell; novel therapeutic intervention; overexpression; programs; stable isotope; therapeutic target; tool; tumor; tumor growth; tumor initiation; tumor progression; tumorigenesis

PROJECT SUMMARY Although hepatocellular carcinoma (HCC) is the most common form of liver cancer, there are few therapies that are effective in treating this malignant disease. With less than 10% of patients who have HCC surviving beyond 5 years, it is important to identify additional therapeutic vulnerabilities. Metabolic alterations are a key feature of HCC pathogenesis, and represent targets that may reveal liabilities in HCC. Glucose-6-Phosphatase (G6PC) is recurrently downregulated in HCC and the magnitude of this downregulation correlates with patient outcome. Sequencing studies of HCCs reveal that somatic mutations occur in a subset of these malignancies. Additional evidence for G6PC involvement in HCC comes from Glycogen Storage Disease Type 1a (GSD1a), where germline mutations in G6PC lead to benign and malignant forms of liver cancer without cirrhosis. The functional relevance of recurrent mutations in G6PC or loss of G6PC expression to HCC pathogenesis in unclear. I hypothesize that loss of G6PC stimulates anabolic metabolic pathways required for tumor cell growth and are sufficient to drive hepatocyte proliferation and tumor initiation. The Specific Aims of this proposal aim to (1) determine how loss of G6PC alters metabolism to support tumor growth, (2) test whether G6PC can increase proliferation, and (3) explore ways in which G6PC loss influences liver tumors initiation and progression in mouse HCC models. We will use G6PC deficient in vitro and in vivo models that faithfully recapitulate aspects of GSD1a biology in patients, and stable isotope tracing to dissect how loss of G6PC rewires metabolic pathways. Altogether, these Aims will elucidate how G6PC loss influences non-cirrhotic development of HCC, and will provide insight into Glycogen Storage Disease Type 1a. We hope to identify metabolic liabilities in HCC pathogenesis that may provide new therapeutic strategies for this deadly disease.

项目总结 尽管肝细胞癌是最常见的肝癌形式，但很少有治疗方法 对治疗这种恶性疾病很有效。不到10%的肝细胞癌患者存活超过 5年后，重要的是确定额外的治疗脆弱性。代谢改变是糖尿病的一个重要特征 肝细胞癌的发病机制，并代表了可能揭示肝细胞癌易感性的靶点。葡萄糖-6-磷酸酶(G6PC)是 在肝细胞癌中反复下调，这种下调的幅度与患者的预后相关。 对肝癌的测序研究表明，体细胞突变发生在这些恶性肿瘤的一部分中。其他内容 G6PC参与肝癌的证据来自1a型糖原储存疾病(GSD1a)，其中 G6PC的胚系突变导致良性和恶性形式的肝癌，而不是肝硬变。功能界别 G6PC反复突变或G6PC表达缺失与肝细胞癌发病机制的相关性尚不清楚。我 假设G6PC的缺失刺激了肿瘤细胞生长所需的合成代谢途径，并 足以推动肝细胞的增殖和肿瘤的发生。这项建议的具体目标是：(1) 确定G6PC丢失如何改变新陈代谢以支持肿瘤生长，(2)测试G6PC是否会增加 (3)探讨G6PC缺失对小鼠肝肿瘤发生发展的影响。 肝细胞癌模型。我们将使用G6PC缺陷的体外和体内模型，忠实地概括GSD1a的各个方面 患者的生物学和稳定同位素示踪，以剖析G6PC的丢失如何重新连接代谢途径。 总之，这些目标将阐明G6PC缺失如何影响肝细胞癌的非肝硬化性发展，并将 提供对1a型糖原储存疾病的洞察。我们希望确定肝细胞癌患者的代谢责任 可能为这种致命疾病提供新的治疗策略的致病机制。