Investigation of HIF-dependent and -independent tumor suppressor functions of VHL

VHL 的 HIF 依赖性和非依赖性肿瘤抑制功能的研究

• 批准号: 8297583
• 负责人: Haifeng Yang
• 金额: $ 32.58万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8297583
• 关键词: Accounting; Affect; Agonist; Apoptosis; Cell Proliferation; Cells; Clear Cell; Clinic; Clinical; Complex; Conventional (Clear Cell) Renal Cell Carcinoma; Development; Disease; EGF gene; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Genes; Genetic Transcription; Goals; Histone H3; Hypoxia Inducible Factor; Hypoxia-Inducible Factor Pathway; Investigation; Knowledge; Lead; Light; Lysine; Maintenance; Malignant Epithelial Cell; Malignant Neoplasms; Mediating; Mutate; Oncogenes; Oncogenic; Pathogenesis; Pharmaceutical Preparations; Phosphoric Monoester Hydrolases; Play; Proteins; Radio; Receptor Protein-Tyrosine Kinases; Receptor Signaling; Renal Cell Carcinoma; Renal carcinoma; Research; Resistance; Role; Signal Pathway; Signal Transduction; Source; Testing; Therapeutic; Therapeutic Intervention; Translations; Tumor Suppressor Genes; Tumor Suppressor Proteins; VHL gene; VHL protein; Work; Xenograft Model; antiangiogenesis therapy; inhibitor/antagonist; insight; loss of function; mutant; novel strategies; protein degradation; receptor expression; response; tumor; tumor growth; ubiquitin-protein ligase

DESCRIPTION (provided by applicant): Kidney cancer is a deadly disease despite the emergence of new treatments. Inactivation of the VHL tumor suppressor gene plays a causal role in the pathogenesis of clear cell renal carcinomas (ccRCC), a pathological subtype that accounts for the majority of kidney cancer. However, the tumor suppressing mechanism(s) of pVHL remains incompletely understood. Loss of functions of pVHL leads to constitutive activation of HIF, which was critical for tumor formation. In clinic, anti-angiogenesis drugs that partially block the activated HIF pathway have shown positive but transient clinical activity against ccRCC. Although HIF activation is critical for formation and maintenance of kidney cancer, it alone is not enough to cause ccRCC. It was recently discovered that pVHL negatively regulates the activity of EGFR, a receptor tyrosine kinase that is oncogenic when abnormally activated in many cancers. This proposal will investigate how pVHL antagonizes EGFR through multiple mechanisms: a) promoting c-Cbl-independent poly-ubiquitylation and degradation of activated EGFR; b) affecting EGFR signaling transcriptionally by suppressing JARID1C to maintain the overall H3K4Me3 level (H3K4Me3 is critical for active gene transcription); and c) maintaining the sensitivity of EGFR to its inhibitors in VHL+/+ ccRCC cells through an EGFR phosphatase. The proposed studies will uncover and elucidate new tumor-suppressing functions of pVHL. It will also shed light on the tumor-suppressive function of JARID1C, a cancer gene recently identified in ccRCC, and reveal its effect on EGFR signaling. Finally, this study will also provide insights as to why VHL-defective ccRCC tumors are resistant to EGFR inhibitors (EGFRi). Such knowledge can lead to ways to transform EGFRi into effective therapeutics against these tumors.) PUBLIC HEALTH RELEVANCE: Kidney cancer is a deadly disease that requires effective management. Inactivation of the VHL tumor suppressor gene plays a causal role in the pathogenesis of the majority of kidney cancer but its tumor suppressing mechanism(s) remains incompletely understood. The proposed study of HIF-dependent and HIF-independent tumor suppressor functions of pVHL will provide detailed mechanistic understanding of how pVHL works and the knowledge might provide new ways of therapeutic intervention for kidney cancer.

描述（由申请人提供）：尽管出现了新疗法，但肾癌还是一种致命的疾病。 VHL肿瘤抑制基因的失活在透明细胞肾癌（CCRCC）的发病机理中起因果作用，这是一种病理亚型，占大多数肾脏癌。然而，PVHL的肿瘤抑制机制仍未完全理解。 PVHL功能的丧失导致HIF的组成性激活，这对于肿瘤形成至关重要。在诊所中，部分阻断活化的HIF途径的抗血管生成药物对CCRCC表现出阳性但短暂的临床活性。尽管HIF激活对于肾癌的形成和维持至关重要，但仅它不足以引起CCRCC。最近发现，PVHL负责调节EGFR的活性，EGFR是一种受体酪氨酸激酶，在许多癌症中异常激活时具有致癌性。该提案将通过多种机制研究PVHL如何拮抗EGFR：a）促进非依赖性的多渗透和激活的EGFR的降解； b）通过抑制JARID1C维持总体H3K4ME3水平（H3K4ME3对于活性基因转录至关重要），通过抑制JARID1C来影响EGFR信号传导； c）通过EGFR磷酸酶维持EGFR对VHL+/+ CCRCC细胞中其抑制剂的敏感性。拟议的研究将发现并阐明PVHL的新肿瘤抑制功能。它还将阐明JARID1C的肿瘤抑制功能，JARID1C是最近在CCRCC中鉴定出的癌症基因，并揭示了其对EGFR信号传导的影响。最后，这项研究还将提供有关为什么VHL缺陷CCRCC肿瘤对EGFR抑制剂（EGFRI）具有抗性的见解。这种知识可以导致将EGFRI转化为针对这些肿瘤的有效治疗剂的方法。） 公共卫生相关性：肾癌是一种需要有效管理的致命疾病。 VHL肿瘤抑制基因的失活在大多数肾癌的发病机理中起因果作用，但其肿瘤抑制机制（S）仍未完全了解。对PVHL的HIF依赖性和非依赖性肿瘤抑制功能的拟议研究将对PVHL的工作方式提供详细的机械理解，并且知识可能为肾脏癌提供新的治疗干预方式。