Role of Id1 in adiposity, energy balance and obesity associated liver tumorigenes

Id1 在肥胖、能量平衡和肥胖相关肝脏肿瘤发生中的作用

• 批准号: 8350925
• 负责人: Satyanarayana Ande
• 金额: $ 14.63万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8350925
• 关键词: Ablation; Adipose tissue; Adult; Adverse effects; Age; BAY 54-9085; BHLH Protein; Blood Circulation; Brown Fat; Cancer Cell Growth; Cancer Etiology; Cell Line; Cell Proliferation; Cell physiology; Cessation of life; Chronic Hepatitis B; DNA Binding; Diet; Drug Targeting; Energy Metabolism; Epidemiologic Studies; FDA approved; Fatty acid glycerol esters; Gene Targeting; Genes; Genetic; Goals; Helix-Turn-Helix Motifs; Hepatitis B; Hepatitis C; Hepatocyte; Human; In Vitro; Infection; Inflammatory; Interleukin-6; Knockout Mice; Liver; Liver diseases; Liver neoplasms; Malignant Neoplasms; Malignant neoplasm of liver; Malignant neoplasm of lung; Mediating; Metabolic Diseases; Metabolism; Modeling; Molecular Target; Mus; Obesity; Obesity associated cancer; Oncogenes; Overweight; Pathway interactions; Primary carcinoma of the liver cells; Proteins; Regulation; Research; Research Personnel; Risk Factors; Role; Sampling; TNF gene; Thermogenesis; Transgenic Mice; Transgenic Model; Unresectable; Work; base; cancer cell; cancer initiation; cancer risk; cytokine; differentiation protein 1 inhibitor; energy balance; inhibitor/antagonist; liver inflammation; malignant stomach neoplasm; mouse model; novel; overexpression; prevent; public health relevance; transcription factor; tumor growth; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): Hepatocellular carcinoma (HCC) is one of the leading causes of cancer deaths worldwide. Recent epidemiological studies revealed that obesity results in a substantial increase in cancer risk including HCC. Accordingly, it was described that obesity promotes liver inflammation and tumorigenesis in mice by enhancing circulating levels of inflammatory cytokines such as IL-6 and TNF¿. Therefore, in obesity associated cancers an ideal molecular target is the one whose inhibition should a) suppress cancer cell proliferation, and b) reduce body adiposity and circulating inflammatory cytokines. Id1 (inhibitor of DNA binding 1) is a helix-loop-helix (HLH) transcription factor that functions as a negative regulator f basic helix-loop-helix (bHLH) transcription factors. Id1 promotes cell proliferation and inhibits cellular differentiation. It was shown that Id1 is overexpressed in many human cancers including HCC, however, the specific role of Id1 in HCC initiation and progression is not known. Recently, I discovered that Id1 is highly expressed in adipose tissues, especially in brown adipose tissue (BAT), and Id1-deficiency in mice resulted in enhanced thermogenesis due to induced expression of PGC1¿ and UCP1, critical regulators of thermogenesis. These studies together suggest that Id1 functions as a critical regulator in two different cellular processes; cell proliferation and cellular metabolism. Taken together, I hypothesize that deletion of Id1 suppresses obesity associated HCC by two mechanisms: 1. Id1 is required for cancer cell proliferation, and deletion of Id1 suppresses liver tumor growth. 2. Deletion of Id1 enhances thermogenesis, reduces body adiposity and circulating inflammatory cytokines, therefore, prevents liver inflammation that contributes to liver tumor growth. The objective of this proposal is to investigate the specific role of Id1 in obesity associated liver tumorigenesis. In pursuit of this two specific aims are proposed. Aim 1: I will investigate the consequence of loss of Id1 in the regulation of PGC1¿ and UCP1 in BAT mediated thermogenesis. For this purpose, I generated Id1fl/fl conditional knockout mice and adipose tissue specific deletion of Id1 will be achieved by crossing with aP2Cre mice which will allow me to investigate the impact of loss of Id1 in the regulation of thermogenic pathway and body adiposity. Aim 2: The second aim will investigate the effect of loss and overexpression of Id1 in liver tumorigenesis, and identify potential cooperating partners of Id1 that are involved in HCC progression. For this purpose I will use Id1fl/flAlbCre mice, and generate a new transgenic model (Alb- Id1Tg) to evaluate the consequence of liver specific loss and overexpression of Id1 on HCC initiation and progression. In addition, by combined deletion of Id1 in adipose tissue and liver, and by utilizing high fat die (HFD) model of obesity, I will investigate if lack of Id1 prevents obesity associated HCC.

描述（由申请人提供）：肝细胞癌（HCC）是全球癌症死亡的主要原因之一。最近的流行病学研究表明，肥胖导致癌症风险大幅增加，包括HCC。因此，据描述，肥胖通过提高炎性细胞因子如IL-6和TNF-α的循环水平来促进小鼠的肝脏炎症和肿瘤发生。因此，在肥胖相关的癌症中，理想的分子靶标是其抑制应该a）抑制癌细胞增殖，和B）减少身体肥胖和循环炎性细胞因子的分子靶标。Id 1（inhibitor of DNA binding 1）是一种螺旋-环-螺旋（helix-loop-helix，HLH）转录因子，对碱性螺旋-环-螺旋（basic helix-loop-helix，bHLH）转录因子起负调节作用。Id 1促进细胞增殖并抑制细胞分化。研究表明，Id 1在包括HCC在内的许多人类癌症中过表达，然而，Id 1在HCC发生和进展中的具体作用尚不清楚。最近，我发现Id 1在脂肪组织中高度表达，特别是在棕色脂肪组织（BAT）中，并且由于PGC 1和UCP 1（产热的关键调节因子）的诱导表达，小鼠中Id 1缺乏导致产热增强。这些研究共同表明，Id 1在两个不同的细胞过程中起着关键的调节作用;细胞增殖和细胞代谢。综上所述，我假设Id 1的缺失通过两种机制抑制肥胖相关的HCC：1。Id 1是癌细胞增殖所必需的，Id 1的缺失抑制了肝肿瘤的生长。2. Id 1的缺失增强产热，减少身体肥胖和循环炎性细胞因子，因此，防止肝脏炎症，有助于肝脏肿瘤生长。本研究的目的是探讨Id 1在肥胖相关肝肿瘤发生中的具体作用。为了追求 提出了这两个具体目标。目的1：我将研究在BAT介导的产热过程中，Id 1缺失对PGC 1 <$和UCP 1调节的后果。为此，我产生了Id 1fl/fl条件性敲除小鼠，并通过与aP 2Cre小鼠杂交实现Id 1的脂肪组织特异性缺失，这将使我能够研究Id 1缺失对产热途径和身体肥胖的调节的影响。目标二：第二个目标是研究Id 1的缺失和过表达在肝肿瘤发生中的作用，并确定参与HCC进展的Id 1的潜在合作伙伴。为此，我将使用Id 1fl/flAlbCre小鼠，并产生一个新的转基因模型（Alb-Id 1 Tg），以评估肝特异性丢失和过度表达Id 1对HCC发生和进展的后果。此外，通过在脂肪组织和肝脏中联合缺失Id 1，并通过利用肥胖的高脂饮食（HFD）模型，我将研究Id 1的缺乏是否预防肥胖相关的HCC。