Role of the RB Tumor Suppression in Liver Tumorigenesis

RB 肿瘤抑制在肝脏肿瘤发生中的作用

• 批准号: 9663130
• 负责人: Erik Knudsen
• 金额: $ 44.08万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9663130
• 关键词: Address; Adhesions; Automobile Driving; Bypass; CDK4 gene; CDKN2A gene; Cancer Etiology; Carcinogens; Cell Cycle; Cessation of life; Clinical; Clinical Trials; Complex; Development; Diagnosis; Disease; Disease Progression; Etiology; Event; Exposure to; Failure; Financial compensation; Funding; Genes; Genetic; Genetic Models; Health; Hepatic; Hepatocarcinogenesis; Human; Hyperplasia; Incidence; Intervention; Lesion; Liver; Liver neoplasms; Malignant Neoplasms; Malignant neoplasm of liver; Mediating; Metabolic Diseases; Modeling; Molecular Analysis; Monitor; Mus; Mutagens; Normal tissue morphology; Oncogenes; Pathway interactions; Phosphorylation; Play; Primary carcinoma of the liver cells; Process; Protein Deregulation; Role; S Phase; Seeds; Specimen; Stem cells; Stress; Testing; Therapeutic; Therapeutic Intervention; Transcription Process; Transcriptional Activation; Transcriptional Regulation; Tumor Suppression; Tumor Suppressor Genes; Tumor Suppressor Proteins; Virus Diseases; Work; advanced disease; base; carcinogenicity; cdc Genes; genome integrity; genotoxicity; inhibitor/antagonist; insight; mouse model; novel; novel therapeutic intervention; outcome forecast; preclinical study; prevent; public health relevance; response; retinoblastoma tumor suppressor; targeted treatment; tumor; tumor initiation; tumor progression

 DESCRIPTION (provided by applicant): Hepatocellular Carcinoma is a major health concern. Currently, this disease is the 3rd leading cause of cancer deaths worldwide with over 500,000 new diagnoses each year. This high incidence of hepatocellular carcinoma development is attributed to environmental insults ranging from exposure to hepatocarcinogens, viral infections, to metabolic disorders. 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 via a number of discrete mechanisms including loss of RB gene or deregulation of protein phosphorylation (e.g., p16ink4a loss). Over the last funding cycle we extensively interrogated how RB loss contributes to tumor development. In mouse models, we found that in the absence of carcinogenic stress RB loss is insufficient for tumor development. This is due to extensive compensation of the RB-deficient state and led us to explore unique functions of RB that are not subject to compensatory processes. These analyses demonstrated a novel function of RB in maintaining transcriptional control and cell cycle exit in the presence of specific carcinogenic stresses. Consonantly, RB-deficiency was associated with significantly increased tumor development under such conditions. These combined findings provide the basis for fully understanding how RB-status impinges on transcriptional processes under stress conditions and the specific consequence related to genome integrity driving tumor development (Aim 1). Interestingly, in the course of these studies we found that RB loss is associated with rapid proliferation and progression to advanced tumor grade in mouse models. Molecular analysis of mouse and human HCC tumors revealed that RB plays a complex role on cell cycle and other processes (e.g., adhesion and EMT) that are relevant for disease progression and associate with poor prognosis. The poor survival of HCC is due, in part, to failure to effectively treat advanced disease. Given the key role of RB in tumor etiology/progression, we investigated the ability to activate the RB-pathway as a therapeutic strategy. The findings from these studies indicated that it is possible to therapeutically reinstate the RB-pathway using specific CDK4/6 inhibitors, which are being tested in clinical trials. These combined findings provide the basis fo determining how RB modulates disease progression and how to systematically target the RB-pathway therapeutically in the treatment of HCC (Aim 2).

 描述（由申请人提供）：肝细胞癌是一个主要的健康问题。目前，这种疾病是全球第三大癌症死亡原因，每年新诊断病例超过 500,000 例。肝细胞癌的高发病率归因于环境损害，包括接触肝癌物质、病毒感染和代谢紊乱。肝癌中发现的关键遗传病变之一是失活 视网膜母细胞瘤肿瘤抑制（RB）途径。在大多数肝脏肿瘤中，该途径通过许多离散机制被破坏，包括 RB 基因丢失或蛋白质磷酸化失调（例如 p16ink4a 丢失）。 在上一个资助周期中，我们广泛询问了 RB 损失如何促进肿瘤发展。在小鼠模型中，我们发现在没有致癌应激的情况下，RB 损失不足以促进肿瘤的发展。这是由于 RB 缺乏状态的广泛补偿，并促使我们探索不受补偿过程影响的 RB 独特功能。这些分析证明了 RB 在特定致癌应激存在下维持转录控制和细胞周期退出方面的新功能。相应地，RB 缺乏与这种条件下肿瘤发展显着增加有关。这些综合发现为充分理解 RB 状态在应激条件下如何影响转录过程以及与驱动肿瘤发展的基因组完整性相关的特定后果提供了基础（目标 1）。有趣的是，在这些研究过程中，我们发现 RB 损失与小鼠模型中的快速增殖和进展为晚期肿瘤级别相关。对小鼠和人类 HCC 肿瘤的分子分析表明，RB 在细胞周期和其他与疾病进展相关并与不良预后相关的过程（例如粘附和 EMT）中发挥着复杂的作用。 HCC 生存率低的部分原因是未能有效治疗晚期疾病。鉴于 RB 在肿瘤病因/进展中的关键作用，我们研究了激活 RB 通路作为治疗策略的能力。这些研究的结果表明，使用特定的 CDK4/6 抑制剂可以治疗性地恢复 RB 通路，这些抑制剂正在临床试验中进行测试。这些综合发现为确定 RB 如何调节疾病进展以及如何在 HCC 治疗中系统地靶向 RB 通路提供了基础（目标 2）。