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，每年导致超过60万例死亡。肝硬化，无论是化学或病毒诱导的，是HCC发展的主要诱发因素。长期饮酒已被确定为患者发生肝硬化和进展为HCC的重要风险因素，无论是其本身还是病毒或化学损伤后的协同因素。我们对酒精摄入后受影响的细胞和生物化学途径的理解的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）是介导酒精在肝脏和其他器官中的有害影响的主要因素。这些发现导致建议使用全身抗氧化剂来抑制包括HCC在内的几种肝脏疾病的发展和进展。这些研究已经导致S-腺苷甲硫氨酸（SAMe）作为潜在的治疗剂的出现。虽然在啮齿动物模型中有效，但其在人类临床试验中的有效性越来越受到关注。几千年来，天然抗氧化剂一直用于治疗肝脏疾病。尽管它们可以在非处方药上买到，但对它们的功效和作用机制知之甚少。我们实验室以前的研究表明，G蛋白在体外介导HCC的有丝分裂中起着重要作用。此外，用酒精处理增强这些促有丝分裂途径。虽然相当多的研究已经确定了在慢性饮酒的情况下肝细胞转化过程中的重要事件，但关于酒精对易形成肿瘤的肝脏中HCC进展速度的影响，我们知之甚少。目前的建议假设长期饮酒会增加病灶发展和HCC进展的速率和发生率。 为了检验这一假设，将在经历慢性饮酒的动物中使用进行性病灶发展和HCC进展的体内鼠模型进行研究。此外，该提案将解决水飞蓟宾，一种常用的黄酮类化合物，从牛奶蓟植物，通过其作用，以抑制肿瘤进展的速度在临床相关的模型中的HCC在慢性酒精摄入的存在和不存在的机制的影响。具体来说，这些研究将集中在确定特定的，促有丝分裂的信号级联的作用，证明是重要的肝细胞癌增殖，酒精治疗的影响在体外。鉴于酒精在社会中的广泛使用和滥用，以及对目前治疗HCC的治疗药物疗效的担忧，我们认为探索替代方法势在必行。虽然广泛可用，并且轶事有效，但对植物来源的抗氧化剂在治疗肝脏疾病中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.