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

描述(申请人提供)：原发性肝癌是全球第五大常见癌症，也是导致癌症死亡的第三大原因。在过去的二十年中，肝细胞癌的发病率上升了80%，目前占所有原发性肝癌的85%。肥胖使女性罹患肝癌的风险增加两倍，男性增加五倍。肥胖常见的并发症包括非酒精性脂肪性肝炎(NASH)、肝脏炎症和脂肪堆积增加了发生肝细胞癌的风险。阻塞性睡眠呼吸暂停(OSA)是一种慢性间歇性低氧状态，在肥胖人群中很常见，也会增加NASH的发生率。美国大约33%的人口肥胖，OSA在30%-50%，我们估计肥胖和OSA的共同发病率占美国总人口的10%-16.5%。饮食诱导的肥胖或间歇性低氧导致肝脏脂肪堆积，最近发现饮食诱导的肥胖促进了肝癌的发展。我们建立了一种慢性间歇性低氧小鼠模型，以研究饮食诱导的肥胖和慢性间歇性低氧在肝癌进展中的联合作用。我们将应用一种新开发的磁共振成像技术来非侵入性地重复监测实验过程中肿瘤的发展和肝脏甘油三酯的含量。我们假设肥胖、慢性间歇性低氧以及它们的组合将加速肝脏脂质堆积和肝癌的进展。肥胖和间歇性低氧均使HIF-1升高，HIF-1促进肝脏脂质堆积，与肝细胞癌的发生、发展及预后有关。利用肝脏特异缺失HIF-1的小鼠，我们将检验这一假设，即HIF-1的激活对于促进饮食诱导的肥胖和/或慢性间歇性低氧诱导的肝细胞癌的发生至关重要。这项研究是在确定肥胖与肝细胞癌相关的机制方面迈出的重要的临床前步骤，并将确定疾病预防的目标。除了体重显著下降之外 目前还没有逆转NASH的既定疗法。此外，目前还没有预防肝细胞癌的药物。重要的是，HIF-1抑制剂正在进行临床前试验，用于治疗已确定的癌症。这方面的成功将提供必要的科学证据，证明有必要推进针对HIF-1的药物的临床前测试，以预防肝细胞癌。

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.