Role of the RB tumor suppressor in liver tumorigenesis

RB抑癌基因在肝脏肿瘤发生中的作用

• 批准号: 7614845
• 负责人: Erik Knudsen
• 金额: $ 32.08万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-12-07 至 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7614845
• 关键词: Address; Aflatoxin B; Cancer Etiology; Carcinogens; Cell Cycle; Cell Cycle Progression; Cell Cycle Regulation; Cell Proliferation; Cells; Cessation of life; Chronic; Class; Condition; Cytogenetics; DNA biosynthesis; Data; Development; Diagnosis; Disease; Disruption; Employee Strikes; Environment; Etiology; Event; Exposure to; Frequencies; Gene Expression; Genes; Genetic; Genome; Genome Stability; Genomic Instability; Health; Hepatic; Hepatitis Viruses; Hepatocarcinogenesis; Hepatocyte; Human; Hyperplasia; Incidence; Lesion; Liver; Liver neoplasms; Maintenance; Malignant neoplasm of liver; Mediating; Mitotic; Modeling; Mouse Strains; Mutation; Natural regeneration; Pathologic; Pathology; Pathway interactions; Play; Ploidies; Predisposition; Primary carcinoma of the liver cells; Process; Regulation; Relative (related person); Role; Stress; Tissues; Tumor Suppression; Tumor Suppressor Proteins; United States; Virus Diseases; gene interaction; in vivo; mouse model; novel; prevent; response; retinoblastoma tumor suppressor; tumor; tumorigenesis; tumorigenic

DESCRIPTION (provided by applicant): Hepatocellular carcinoma, the major manifestation of liver cancer is a major health concern. Currently, this disease is the 3rd leading cause of cancer deaths worldwide with over 500,000 deaths each year. The high incidence of hepatocellular carcinoma development is attributed to environmental insult or viral infections that can induce chronic liver damage and tumor development. One of the key genetic lesions found in liver cancer is inactivation of the retinoblastoma tumor suppressor (RB) pathway. This pathway is disrupted in most liver tumors; however, the role of RB loss in tumor etiology and progression remains largely undefined. Classically, RB is believed to inhibit cell cycle progression and serves as a critical deterrent to hyperplastic proliferation. To determine the mechanism(s) by which RB prevents tumor formation in the liver, we developed a mouse model of liver specific RB deletion. While RB loss causes transient alterations in cell cycle control, no hyperplasia was observed. Rather, RB-deficient hepatocytes undergo aberrant rounds of DNA replication leading to alterations in DNA ploidy suggesting a role for RB in the maintenance of genome integrity. The effects of RB loss are exacerbated by challenge with hepatocarcinogens, wherein the RB loss synergized with carcinogenic exposure to promote genome instability. These effects on genome stability are associated with a striking predisposition of RB-deficient livers to tumorigenesis. Combined, these data reveal novel mechanisms of RB function, and suggest that RB action in this tissue is distinct from its ability to prevent unchecked cellular proliferation. Rather, our data support the hypothesis that RB loss cooperates with hepatic carcinogens to induce genomic instability and promote liver tumorigenesis. We challenge this hypothesis and the role of RB in liver cancer by: determining the mechanisms through which RB loss compromises cell cycle control to alter genome stability in the liver (Aim 1); delineating the impact of RB loss on genome stability and hepatocarcinogenesis under specific pathologic conditions (Aim 2); and defining the action of temporal gene/environment and gene/gene interactions on liver tumorigenesis (Aim 3).Liver cancer is the 3rd leading cause of cancer deaths worldwide with in excess of 500,000 cases. A key event occurring in most liver cancers is loss of the retinoblastoma tumor suppressor pathway. In this proposal we will dissect how disruption of this pathway contributes to liver cancer that will support long-term efforts to intervene more-effectively in preventing and treating this disease.

描述（由申请人提供）：肝细胞癌，肝癌的主要体现是一个主要的健康问题。目前，这种疾病是全世界癌症死亡的第三主要原因，每年有超过500,000人死亡。肝细胞癌发育的高发病率归因于可以诱导慢性肝损伤和肿瘤发育的环境损伤或病毒感染。在肝癌中发现的关键遗传病变之一是衰老肿瘤抑制剂（RB）途径失活。在大多数肝肿瘤中，该途径被破坏。但是，RB损失在肿瘤病因和进展中的作用在很大程度上仍然不确定。从经典上讲，RB被认为会抑制细胞周期的进展，并成为增生增殖的关键威慑。为了确定RB阻止肝脏中肿瘤形成的机制，我们开发了一种肝脏特异性RB缺失的小鼠模型。虽然RB损失会导致细胞周期控制的短暂变化，但未观察到增生。相反，RB缺陷型肝细胞会经历异常的DNA复制，导致DNA倍动的改变，这表明RB在维持基因组完整性中的作用。肝癌质量挑战会加剧RB损失的影响，其中RB损失随致癌性暴露而协同以促进基因组不稳定性。这些对基因组稳定性的影响与RB缺陷肝脏对肿瘤发生的惊人倾向有关。这些数据结合在一起揭示了RB功能的新机制，并表明该组织中的RB作用与防止未检查的细胞增殖的能力不同。相反，我们的数据支持RB损失与肝癌合作以诱导基因组不稳定性并促进肝肿瘤发生的假设。我们通过以下方式挑战了这一假设和RB在肝癌中的作用：确定RB损失会损害细胞周期控制以改变肝脏中基因组稳定性的机制（AIM 1）；在特定的病理条件下描述了RB损失对基因组稳定性和肝癌发生的影响（AIM 2）；定义时间基因/环境以及基因/基因相互作用对肝肿瘤发生的作用（AIM 3）。LiverCancer是全球癌症死亡的第三主要原因，占500,000例。大多数肝癌发生的关键事件是丧失视网膜细胞瘤肿瘤抑制途径。在此提案中，我们将阐述该途径的破坏如何导致肝癌，这将支持长期努力，以更有效地预防和治疗这种疾病。