The Role of EGF in Human Hepatocellular Transformation

描述（由申请人提供）：在动物模型中，肝脏中表皮生长因子（EGF）的过度表达诱导转化为肝细胞癌（HCC）。在EGF基因中发现了一个单核苷酸多态性（位置61的A到G过渡）。我们已经证明，在肝癌细胞系和原代人肝细胞中，G等位基因的mRNA稳定性增加，这可能是G/G基因型个体血清和肝组织水平增加的机制。我们对马萨诸塞州和法国肝硬化人群中等位基因频率分布的分析显示，相对于A/A基因型，G/G基因型与HCC风险显著相关。目前，过量EGF的来源尚不清楚。大多数hcc是在肝硬化的情况下发生的。因此，Specific Aim 1的目标是研究肝硬化对血清和各种肝细胞群中EGF表达的影响，因为监测EGF水平可用于识别HCC高危的肝硬化患者。HCC的发病率在美国和世界范围内都在增加。鉴于缺乏成功的HCC治疗方案，高危患者的化学预防已被提出作为一种替代策略。我们对导致肝细胞转化的分子途径知之甚少。因此，Specific Aim 2的目标是研究egf诱导转化过程中启动的信号通路，作为识别潜在治疗靶点的一种手段。小分子EGF受体（EGFR）酪氨酸激酶抑制剂在大鼠肝细胞癌模型中被证明是有效的化学预防剂。特异性目的3的目标是确定残留肿瘤的耐药机制，以便设计更有效的化学预防策略。该建议的长期目标是开发化学预防疗法，可用于降低EGF水平和/或抑制EGF诱导的肝细胞转化。从这些实验中获得的数据具有广泛的意义，因为EGFR的过表达是肿瘤转化的常见事件，我们假设靶向EGF通路可能是化学预防的新策略。

DESCRIPTION (provided by applicant): 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 worldwide. 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.