ErbB Receptor Signaling in DEN-induced Murine Hepatocarcinogenesis

描述（由申请人提供）：我们实验室的长期目标是了解控制肝脏生长、分化和再生的机制。肝细胞生长和分化紊乱最深刻的后果之一是肝细胞癌（HCC）的发展。HCC是全球第五大常见癌症和第三大癌症死亡原因，每年导致100多万人死亡。它的发病率正在上升，特别是在美国，在过去的25年里它增加了70%。没有有效的二级预防或系统治疗。我们对表皮生长因子（EGF）及其同源物和ErbB酪氨酸激酶受体（包括EGF受体，EGFr）在控制肝细胞生长和分化中的作用有着长期的兴趣。吉非替尼是一种EGFr酪氨酸激酶的小分子抑制剂，可减少暴露于N-亚硝基二乙胺（DEN）的大鼠HCC的发展，DEN可诱导肝损伤、肝硬化，最终导致HCC。吉非替尼和其他EGFr酪氨酸激酶抑制剂最近在治疗人类HCC中显示出前景，表明ErbB蛋白在肝细胞癌变中的重要作用以及人类HCC动物模型的相关性。我们已经证明，在正常情况下，只有三种ErbB蛋白在肝脏中表达（EGFr， ErbB2和ErbB3），并且它们在肝细胞中的表达存在发育调节模式。虽然它们经常被单独研究，但ErbB蛋白是高度相互作用的，并形成信号同源和异源二聚体。在人类HCC中，ErbB3是217种持续上调的蛋白之一（在所检测的9000种蛋白中）；EGFr或ErbB2（但不是两者都）倾向于与ErbB3一起上调。正在研究的假设是ErbB酪氨酸激酶对DEN啮齿动物模型中HCC的发展至关重要。我们建议对肝细胞中这些分子基因缺失的后果进行系统研究，以评估它们在HCC发生和进展中的重要性。我们已经产生了肝细胞特异性的单基因和双基因ErbB敲除小鼠。这些动物发育正常，是分析从肝炎到肝硬化再到肝细胞癌（HCC）在ErbB丢失情况下进展的理想遗传模型。我们还获得了一种携带EGFr超态等位基因dsk5的小鼠，该等位基因对配体激活的反应更为强烈。我们期望确定特定的ErbB受体和下游途径参与肝癌的发生。这些研究应该有助于开发用于预防或治疗人类HCC干预的分子靶点。

DESCRIPTION (provided by applicant): The long-term goal of our laboratory is to understand the mechanisms that control the growth, differentiation, and regeneration of the liver. Among the most profound consequences of disordered hepatocellular growth and differentiation is the development of hepatocellular carcinoma (HCC). HCC is the fifth most common cancer and the third leading cause of cancer deaths worldwide, resulting in over 1 million deaths per year. Its incidence is rising, particularly in the United States, where it has increased by 70% over the last 25 years. No effective secondary prevention or systemic treatments are available. We have a longstanding interest in the role of epidermal growth factor (EGF and its homologs), and the ErbB tyrosine kinase receptors (including the EGF receptor, EGFr) in the control of hepatocellular growth and differentiation. Gefitinib, a small molecule inhibitor of the EGFr tyrosine kinase, will reduce the development of HCC in rats exposed to N- nitrosodiethylamine (DEN), which induces liver injury, cirrhosis, and ultimately HCC. Gefitinib and other EGFr tyrosine kinase inhibitors have recently shown promise in the treatment of human HCC, indicating an important role for the ErbB proteins in hepatocellular carcinogenesis and the relevance of animal models for human HCC. We have shown that only three ErbB proteins are expressed in liver under normal circumstances (EGFr, ErbB2 and ErbB3), and that there is a developmentally-regulated pattern in their expression by hepatocytes. Although they are frequently studied in isolation, the ErbB proteins are highly interactive and form signaling homo- and heterodimers. In human HCC, ErbB3 is one of 217 proteins (out of 9000 examined) that is consistently upregulated; either EGFr or ErbB2 (but not both) tend to be upregulated along with ErbB3. The hypothesis under investigation is that ErbB tyrosine kinases are critical to development of HCC in the DEN rodent model. We propose a systematic study of the consequences of genetic deletion of these molecules in hepatocytes in order to assess their importance in the initiation and progression of HCC. We have generated hepatocyte-specific single and double gene ErbB knockout mice. These animals develop normally and are ideal genetic models to analyze the progression from hepatitis to cirrhosis to hepatocellular carcinoma (HCC) in the setting of ErbB loss. We also have access to a mouse bearing a hypermorphic allele of the EGFr, dsk5, that signals more robustly in response to ligand activation. We expect to identify the specific ErbB receptors and downstream pathways involved in liver carcinogenesis. These studies should assist in the development of molecular targets for interventions to prevent or treat HCC in humans. PUBLIC HEALTH RELEVANCE: Hepatocellular carcinoma (HCC), or liver cell cancer, is the fifth most common cancer, and is the third leading cause of cancer death; the incidence of HCC has risen by over 70% over the past 25 years in the United States. There is significant evidence that a family of proteins called the ErbB tyrosine kinases play a role in the development of liver cancer; they would be extremely good targets for the control of HCC. Using genetically altered mice in which the hepatic ErbB proteins have been rendered nonfunctional or hyperfunctional, we expect to identify key targets for the development of novel chemotherapy to treat HCC.