Prostaglandin Signaling Pathway in Liver Cancer

描述(申请人提供)：原发性肝癌是人类常见的恶性肿瘤，死亡率高。在慢性炎症性肝病的背景下，肿瘤通常在存在持续的肝脏炎症和上皮再生的情况下发展。我们实验室最近的研究表明，胞浆磷脂酶A21(CPLA21)和环氧合酶-2(COX-2)控制的前列腺素信号转导通路在肝癌发生中起着重要作用。因此，抑制前列腺素途径可能是阻断炎症、异型增生和恶性转化过程的一种有效的治疗方法。然而，由于长期使用某些COX-2抑制剂可能引起的心血管副作用，利用药理学COX-2抑制剂进行肝癌化学预防和治疗的努力一直受到阻碍。因此，迫切需要寻找COX-2下游的新的、更安全的治疗靶点，例如那些抑制前列腺素E2(PGE2)信号转导的靶点，以便在副作用较小的情况下进行有效的化学预防。在这一后续应用中，我们假设前列腺素受体EP1和EGFR/2-catenin之间的相互作用在肝癌的发生中起关键作用，同时抑制这些关键分子可能协同预防肝癌的发生并提供有效的抗肿瘤治疗。这一假说将通过利用培养的肝癌细胞和肝癌发生的动物模型的互补方法在三个特定目标上进行评估。目的1研究前列腺素与EGFR/2-连环蛋白信号通路在体外培养的肝癌细胞和cPLA21和COX-2转基因及基因敲除小鼠肝细胞癌组织中的相互作用。在目标2中，将建立肝脏中COX-2或cPLA21过表达并缺失EGFR或2-连环蛋白的小鼠，以确定肝致癌物质诱导的肿瘤发生，以期通过缺失EGFR/2-连环蛋白来阻止COX-2或cPLA21诱导的肝癌的发生。目的3旨在评估阻断前列腺素受体EP1并同时抑制EGFR或2-连环蛋白可能是一种有效和安全的肝癌化学预防和治疗的治疗策略的假说。这些拟议的研究有望为人类肝癌的化学预防和治疗提供重要的治疗意义。公共卫生相关性：目前的继续提案将描述前列腺素和EGFR/2-连环蛋白信号通路在肝癌细胞和肝癌发生的动物模型中的相互作用。同时抑制前列腺素受体EP1和EGFR/2-连环蛋白对肝肿瘤生长的影响将在体外和在肝癌发生的动物模型中进行检测。拟议的研究将确定导致肝癌生长的分子机制，并为未来有效的化学预防和治疗提供重要的治疗意义。

DESCRIPTION (provided by applicant): Primary liver cancer is the common malignant neoplasm in human with high mortality. The tumor usually develops in the presence of continuous hepatic inflammation and epithelial regeneration in the setting of chronic inflammatory liver diseases. Recent studies from our laboratory have shown an important role of the cytosolic phospholipase A21 (cPLA21) and cyclooxygenase-2 (COX-2)-controlled prostaglandin signaling cascade in liver carcinogenesis. Therefore, inhibiting prostaglandin pathway may represent an effective therapeutic approach to disrupt the inflammation, dysplasia and malignant transformation processes. However, the effort for utilizing pharmacological COX-2 inhibitors for liver cancer chemoprevention and treatment in patients has been hindered by the potential cardiovascular side effect associated with long-term use of some COX-2 inhibitors. Thus, there is an urgent and practical need to identify novel and safer therapeutic targets downstream of COX-2, such as those inhibiting prostaglandin E2 (PGE2) signaling, for effective chemoprevention with lesser side effect. In this continuation application, we hypothesize that the interaction between the prostaglandin receptor, EP1, and EGFR/2-catenin is crucial for hepatocarcinogenesis and that simultaneous inhibition of these key molecules may synergistically prevent hepatocarcinogenesis and provide effective anti-tumor therapy. This hypothesis will be evaluated in three specific aims by utilizing complementary approaches of cultured liver cancer cells and animal models of hepatocarcinogenesis. Aim 1 is designed to delineate the interplays between prostaglandin and EGFR/2-catenin signaling pathways in cultured liver cancer cells and in hepatocellular cancer tissues from the cPLA21 and COX-2 transgenic and knockout mice. In Aim 2, mice with overexpression of COX-2 or cPLA21 plus deletion of EGFR or 2-catenin in the liver will be developed to determine hepatic carcinogen-induced tumor development, with the expectation that deletion of EGFR/2- catenin will prevent COX-2 or cPLA21-induced hepatocarcinogenesis. Aim 3 is designed to evaluate the hypothesis that blocking the prostaglandin receptor EP1 with concomitant inhibition of EGFR or 2-catenin may represent an effective and safe therapeutic strategy for the chemoprevention and treatment of liver cancer. The proposed studies are expected to provide important therapeutic implications for the chemoprevention and treatment of human liver cancer. PUBLIC HEALTH RELEVANCE: The current continuation proposal will delineate the interplays between prostaglandin and EGFR/2-catenin signaling pathways in liver cancer cells and in animal models of hepatocarcinogenesis. The effect of simultaneous inhibition of the prostaglandin receptor EP1 and EGFR/2-catenin on liver tumor growth will be examined in vitro and in animal models of hepatocarcinogenesis. The proposed studies will define the molecular mechanisms responsible for liver cancer growth and provide important therapeutic implications for future effective chemoprevention and treatment.