The Role of EGF in Human Hepatocellular Transformation

表皮生长因子（EGF）在肝脏中的过度表达诱导向肝细胞转化 肝癌（HCC）动物模型。单核苷酸多态性（第61位的A到G转换）具有 EGF基因的作用我们已经证明了G等位基因的mRNA稳定性增加， 肝癌细胞系和原代人肝细胞，这可能是个体 与G/G基因型有增加的血清和肝组织水平。我们分析了等位基因的分布， 来自马萨诸塞州和法国的肝硬化人群的G/G基因型频率显示， 相对于A/A基因型，与HCC风险显著相关。目前，过剩的来源 EGF未知大多数肝细胞癌发生于肝硬化。因此，具体目标 目的1探讨肝硬化对血清及肝细胞EGF表达的影响 监测EGF水平可用于识别肝硬化患者的HCC高风险。 HCC在美国和全美国的发病率都在增加。由于缺乏成功的 肝癌的治疗选择，在高危患者中的化学预防已被提出作为一种替代方案 战略导致肝细胞转化的分子途径知之甚少。 因此，特异性目的2的目标是检查EGF诱导的细胞凋亡过程中启动的信号通路。 转化作为鉴定潜在治疗靶点的手段。小分子表皮生长因子受体（EGFR） 酪氨酸激酶抑制剂已被证明在HCC的大鼠模型中作为化学预防剂是有效的。目标 的具体目标3是确定残留肿瘤的耐药机制，以设计更有效的 化学预防策略该提案的广泛长期目标是开发化学预防药物， 可用于降低EGF水平和/或抑制EGF诱导的肝细胞转化的疗法。 从这些实验中获得的数据具有广泛的意义，因为EGFR的过表达是一种免疫抑制剂。 肿瘤转化中的常见事件，我们假设EGF途径的靶向可能是一种治疗肿瘤的方法。 化学预防的新策略。 相关性（参见说明）： 迫切需要新的和有效的筛查和治疗选择，以诊断和预防 肝癌在这里，我们将分析肝脏和血清EGF水平作为一种新的技术，以监测肝脏风险 研究EGF的致癌机制。此外，EGFR酪氨酸 激酶抑制剂埃罗替尼将被测试其作为肝癌的化学预防策略的功效。

Overexpression of epidermal growth factor (EGF) in the liver induces transformation to hepatocellular carcinoma (HCC) in animal models. A single nucleotide polymorphism (A to G transition at position 61) has been identified in the EGF gene. We have demonstrated increased mRNA stability of the G allele both in hepatoma cell lines and primary human hepatocytes which may serve as a mechanism by which individuals with the G/G genotype have increased serum and liver tissue levels. Our analysis of the distribution of allelic frequencies in cirrhosis populations from both Massachusetts and France revealed that the G/G genotype was significantly associated with risk of HCC relative to the A/A genotype. Currently, the source of excess EGF is unknown. The majority of HCCs develop in the setting of cirrhosis. Therefore, the goal of Specific Aim 1 is to investigate the effects of cirrhosis on EGF expression in serum and the various liver cell populations as monitoring of EGF levels could be used to identify cirrhosis patients at high-risk for HCC. HCC is increasing in incidence both in the United States and worlwide. Given the lack of successful treatment options for HCC, chemoprevention in high-risk patients has been proposed as an alternative strategy. Exceedingly little is known about the molecular pathways leading to hepatocellular transformation. Therefore, the goal of Specific Aim 2 is to examine the signaling pathways initiated during EGF-induced transformation as a means to identify potential therapeutic targets. Small molecule EGF receptor (EGFR) tyrosine kinase inhibitors have proven effective as chemopreventive agents in a rat model of HCC. The goal of Specific Aim 3 is to identify resistance mechanisms in the residual tumors in order to design more effective chemoprevention strategies. The broad long-term objective of this proposal is to develop chemopreventive therapies that can be used to lower EGF levels and/or inhibit EGF-induced hepatocellular transformation. The data obtained from these experiments have broad implications as overexpression of the EGFR is a common event in neoplastic transformation, and we hypothesize that targeting of the EGF pathway may be a novel strategy for chemoprevention. RELEVANCE (See instructions): Novel and effective screening and treatment options are urgently needed for the diagnosis and prevention of liver cancer. Here we will analyze liver and serum EGF levels as a novel technique to monitor risk of liver cancer and also study the mechanisms by which EGF induces carcinogenesis. Further, the EGFR tyrosine kinase inhibitor, eriotinib, will be tested for its efficacy as a chemoprevention strategy for liver cancer.