EFFECT OF ALCOHOL ON HEPATOCELLULAR CARCINOMA PROGRESSION IN VIVO

描述（由申请人提供）：肝细胞癌（HCC）的发病率在美国和全球范围内急剧增加，每年死亡人数超过60万。无论是化学还是病毒诱导的肝硬化，都是HCC发生的主要诱发因素。慢性饮酒已被确定为发展为肝硬化和进展为HCC的患者的重要危险因素，无论是其本身还是病毒或化学损伤后的协同因素。我们对酒精摄入后影响的细胞和生化途径的理解取得了进展，已经确定乙醇代谢（以及相关的活性氧（ROS）生成/氧化应激）是介导酒精对肝脏和其他器官有害影响的主要因素。这些发现导致建议使用全身性抗氧化剂来抑制包括HCC在内的几种肝脏疾病的发生和进展。这些研究导致s -腺苷型蛋氨酸（SAMe）作为一种潜在的治疗剂出现。虽然在啮齿动物模型中有效，但其在人体临床试验中的有效性越来越受到关注。几千年来，天然抗氧化剂一直被用于治疗肝病。尽管它们的非处方可用性相对较少，但人们对它们的功效和作用机制知之甚少。我们实验室先前的研究表明，g蛋白在体外介导肝癌细胞有丝分裂发生中发挥了核心作用。此外，酒精治疗增强了这些促有丝分裂途径。虽然相当多的研究已经确定了慢性饮酒背景下肝细胞转化过程中的重要事件，但对于酒精对易形成肿瘤的肝脏中HCC进展速度的影响，我们所知相对较少。目前的建议假设长期饮酒会增加灶发展和HCC进展的速度和发生率。为了验证这一假设，研究将在长期饮酒的动物体内进行渐进式病灶发展和HCC进展的小鼠模型。此外，本研究还将探讨水飞蓟宾（一种从水飞蓟植物中提取的常用类黄酮）在没有和存在慢性酒精摄入的HCC临床相关模型中抑制肿瘤进展速率的机制作用。具体来说，这些研究将集中于鉴定特异性的促有丝分裂信号级联的作用，这些信号级联在体外酒精治疗影响的HCC增殖中被证明是重要的。鉴于酒精在社会上的广泛使用和滥用，以及对当前治疗HCC药物疗效的担忧，我们认为有必要探索替代方法。虽然植物源性抗氧化剂广泛使用，而且疗效显著，但人们对其治疗肝病的作用机制知之甚少。

DESCRIPTION (provided by applicant): The incidence of hepatocellular carcinoma (HCC) is increasing dramatically in the US and globally, and accounts for more than 600,000 deaths/year. Cirrhosis of the liver, whether chemically or virally induced, is the major predisposing factor to the development of HCC. Chronic alcohol consumption has been identified as a significant risk factor in patients developing cirrhosis and progression to HCC, both in its own right and as a synergistic factor following viral or chemical insult. Advances in our understanding of the cellular and biochemical pathways affected following alcohol ingestion have identified ethanol metabolism (and associated reactive oxygen species (ROS) generation/oxidative stress) as a major factor in mediating the deleterious effects of alcohol in the liver and other organs. These findings have led to the proposed use of systemic antioxidants to inhibit the development and progression of several hepatic diseases including HCC. These studies have led to the emergence of S-adenosyl methionine (SAMe) as a potential therapeutic agent. While efficacious in rodent models, there is increasing concern regarding its effectiveness in human clinical trials. For several millennia natural antioxidants have been used in the treatment of liver disease. Despite their over-the-counter availability relatively little is known about their efficacy and mechanisms of action. Previous studies by our laboratory demonstrate a central role for G-proteins in mediating mitogenesis in HCC in vitro. Furthermore, treatment with alcohol enhances these pro-mitogenic pathways. While considerable research has identified important events during hepatic cell transformation in the setting of chronic alcohol consumption, relatively little is known about the effects of alcohol on the rate of HCC progression in livers predisposed to tumor formation. The current proposal hypothesizes that chronic alcohol consumption increases the rate and incidence of foci development and HCC progression. To test this hypothesis studies will be performed using in vivo murine models of progressive foci development and HCC progression in animals undergoing chronic alcohol consumption. In addition this proposal will address the mechanistic effects by which silibinin, a commonly used flavanoid derived from the milk thistle plant, acts to inhibit the rate of tumor progression in a clinically relevant model of HCC in the absence and presence of chronic alcohol intake. Specifically, these studies will focus on identifying the role of specific, pro-mitogenic signaling cascades demonstrated to be important in HCC proliferation that are affected by alcohol treatment in vitro. Given the widespread use and abuse of alcohol in society, and concerns regarding the efficacy of current therapeutic agents for the treatment of HCC, we believe it is imperative to explore alternative approaches. While widely available, and anecdotally effective, little is understood about the mechanisms of action of plant- derived antioxidants in the treatment of hepatic disease.