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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

基本信息

批准号：
10560507
负责人：
Sherwin Kelekar
金额：
$ 4.74万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
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/10560507
关键词：
Address Agar Anchorage-Independent Growth Benign Biological Assay Biology Cancer Etiology 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 Growth Hepatocarcinogenesis Hepatocyte Human Immunohistochemistry In Vitro Incidence Injections Isotopes Knockout Mice Lead Lipids Liver Liver Glycogen Liver neoplasms Malignant - descriptor Malignant Neoplasms Malignant neoplasm of liver Measures Metabolic Metabolic Diseases Metabolic Pathway Metabolism Molecular Mus Mutation Nature Nucleotides Oncogenes Oncogenic Pathogenesis Pathway interactions Patient-Focused Outcomes Patients Penetrance Pentosephosphate Pathway Primary carcinoma of the liver cells Proliferating Recurrence Role 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 indexing insight liver cancer model liver cell proliferation liver injury liver metabolism mouse model neoplastic cell novel therapeutic intervention overexpression pharmacologic programs stable isotope therapeutic target tool tumor tumor growth tumor initiation tumor progression tumorigenesis

项目摘要

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