(PQA 2) Obesity & Obstructive Sleep Apnea in Hepatocellular Carcinoma Progression

描述（由申请人提供）：原发性肝癌是全球第五大常见癌症，也是癌症死亡率的第三大原因。肝细胞癌（HCC）的发病率在过去二十年中增加了80%，现在占所有原发性肝癌的85%。肥胖使女性患肝癌的风险增加2倍，男性增加5倍。肥胖常见的合并症包括非酒精性脂肪性肝炎（NASH）、肝脏炎症和脂质蓄积，这些合并症增加了发生HCC的风险。阻塞性睡眠呼吸暂停（OSA），一种在肥胖个体中常见的慢性间歇性缺氧状态，也会增加NASH的发病率。美国人口约33%肥胖，OSA为30- 50%，我们估计肥胖和OSA的共同发病率为整个美国人口的10-16.5%。饮食诱导的肥胖或间歇性缺氧诱导肝脏脂质积聚，最近显示饮食诱导的肥胖促进HCC肿瘤发展。我们建立了一种慢性间歇性缺氧的小鼠模型，以研究饮食诱导的肥胖和慢性间歇性缺氧对HCC进展的联合作用。我们将应用一种新开发的磁共振成像技术，在实验过程中平行地非侵入性地重复监测肿瘤发展和肝脏甘油三酯含量。我们假设肥胖、慢性间歇性缺氧及其组合将加速肝脏脂质积聚和HCC肿瘤进展。肥胖和间歇性缺氧都会增加HIF- 1？，从而促进肝脏脂质积聚，并与HCC的发展和预后相关。使用肝脏特异性缺失HIF- 1 <$的小鼠，我们将检验HIF- 1 <$激活对于促进由饮食诱导的肥胖和/或慢性间歇性缺氧诱导的HCC肿瘤发生是必不可少的假设。这项研究是表征可能解释肥胖相关HCC的机制的重要临床前步骤，并将确定疾病预防的靶点。除了体重明显减轻 还没有确定的用于逆转NASH的疗法。此外，没有HCC的预防剂。重要的是，HIF- 1抑制剂正在进行临床前测试，用于治疗已建立的癌症。这里的成功将提供必要的科学证据，以证明继续进行针对HIF- 1的药物的临床前测试以预防HCC。

DESCRIPTION (provided by applicant): Primary liver cancer is the fifth most common cancer worldwide and the third highest cause of cancer mortality. The incidence of hepatocellular carcinoma (HCC) has increased 80% in the past two decades and now comprises 85% of all primary liver cancer. Obesity increases the risk of developing HCC two-fold in women and five-fold in men. Co-morbidities common to obesity including non-alcoholic steatohepatitis (NASH), hepatic inflammation, and lipid accumulation increase the risk of developing HCC. Obstructive sleep apnea (OSA), a state of chronic intermittent hypoxia which is common in obese individuals, also increases the incidence of NASH. With a U.S. population that is approximately 33% obese, having OSA at 30-50%, we estimate the co-incidence of obesity and OSA is 10-16.5% of the entire U.S. population. Diet- induced obesity or intermittent hypoxia induces hepatic lipid accumulation and diet-induced obesity was recently shown to promote HCC tumor development. We have developed a mouse model of chronic intermittent hypoxia to study the combined effects of diet-induced obesity and chronic intermittent hypoxia on HCC progression. We will apply a newly developed magnetic resonance imaging technique to non-invasively and repeatedly monitor tumor development and hepatic triglyceride content in parallel over the course of the experiments. We hypothesize that obesity, chronic intermittent hypoxia, and their combination will hasten hepatic lipid accumulation and HCC tumor progression. Both obesity and intermittent hypoxia increase HIF- 1¿, which promotes hepatic lipid accumulation and is associated with the development and prognosis of HCC. Using mice with liver specific deletion of HIF- 1¿, we will test the hypothesis that HIF- 1¿ activation is essential for promotion of HCC tumorigenesis induced by diet-induced obesity and/or chronic intermittent hypoxia. This study is a significant preclinical step in characterizing mechanisms that may explain obesity associated HCC and will identify targets for disease prevention. With the exception of significant weight loss there are no established therapies for reversal of NASH. Further, there are no prevention agents for HCC. Importantly, HIF- 1¿ inhibitors are in preclinical testing for the treatment of establishe cancers. Success here will provide the necessary scientific evidence to justify moving forward with preclinical testing of drugs that target HIF- 1¿ to prevent HCC.