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

描述(申请人提供)：肝细胞癌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，肥胖会导致包括肝癌在内的癌症风险的大幅增加。因此，肥胖通过增加IL-6和肿瘤坏死因子等炎性细胞因子的循环水平来促进小鼠的肝脏炎症和肿瘤形成。因此，在肥胖相关癌症中，理想的分子靶点是其抑制应该a)抑制癌细胞增殖，b)减少身体肥胖和循环中的炎性细胞因子。ID1(Inhibitor Of DNA Binding1)是一种螺旋-环-螺旋(HLH)转录因子，对碱性螺旋-环-螺旋(BHLH)转录因子起负调控作用。ID1促进细胞增殖，抑制细胞分化。研究表明，Id1在包括肝细胞癌在内的多种人类肿瘤中均有过表达，但其在肝细胞癌发生发展中的具体作用尚不清楚。最近，我发现Id1在脂肪组织中高表达，尤其是在棕色脂肪组织(BAT)中，Id1缺乏导致小鼠产热增强，这是因为诱导了产热的关键调节因子PGC1和UCP1的表达。这些研究表明，Id1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，我推测Id1基因的缺失通过两种机制抑制肥胖相关的肝细胞癌：1.Id1基因是癌细胞增殖所必需的，Id1基因缺失抑制了肝肿瘤的生长。2.Id1基因缺失可促进产热，减少体脂和循环炎性细胞因子，从而预防肝脏炎症，从而促进肝肿瘤的生长。本研究的目的是探讨Id1在肥胖相关肝肿瘤发生中的特殊作用。为了追求 提出了这两个具体目标。目的1：探讨Id1基因缺失在BAT介导的产热过程中对Pgc1和UCP1调控的影响。为此，我建立了Id1fl/fl条件性基因敲除小鼠，并通过与aP2Cre小鼠杂交，实现了脂肪组织特异性的Id1缺失，这将使我能够研究Id1缺失在生热途径和身体肥胖调节中的影响。目的2：研究Id1基因缺失和过表达在肝肿瘤发生中的作用，寻找Id1基因在肝细胞癌发生发展中的潜在合作伙伴。为此，我将使用Id1fl/flAlbCre小鼠，并建立一个新的转基因模型(Alb-Id1Tg)，以评估肝脏特异性缺失和Id1过表达对肝细胞癌发生和发展的影响。此外，通过脂肪组织和肝脏中Id1基因的联合缺失，以及利用肥胖的高脂模型，我将研究Id1基因的缺失是否可以预防肥胖相关的肝细胞癌。

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.