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，肿瘤通常在持续的肝脏炎症和上皮再生的存在下发展。本实验室最近的研究表明，胞浆磷脂酶A21（cPLA 21）和环氧化酶-2（考克斯-2）控制的前列腺素信号级联在肝癌发生中起重要作用。因此，抑制前列腺素途径可能是一种有效的治疗方法，以破坏炎症，发育不良和恶性转化过程。然而，利用药理学考克斯-2抑制剂用于肝癌化学预防和治疗患者的努力受到与长期使用某些考克斯-2抑制剂相关的潜在心血管副作用的阻碍。因此，迫切需要鉴定考克斯-2下游的新的和更安全的治疗靶点，例如抑制前列腺素E2（PGE 2）信号传导的靶点，以实现有效的化学预防和更小的副作用。在本延续申请中，我们假设前列腺素受体、EP 1和EGFR/2-连环蛋白之间的相互作用对肝癌发生至关重要，同时抑制这些关键分子可能协同预防肝癌发生并提供有效的抗肿瘤治疗。本研究将利用培养的肝癌细胞和肝癌发生的动物模型的互补方法，从三个具体目标对这一假说进行评估。目的1旨在描述前列腺素和EGFR/2-catenin信号通路在培养的肝癌细胞和来自cPLA 21和考克斯-2转基因和敲除小鼠的肝癌组织中的相互作用。在目标2中，将开发肝脏中过表达考克斯-2或cPLA 21加上EGFR或2-连环蛋白缺失的小鼠，以确定肝癌原诱导的肿瘤发展，期望EGFR/2-连环蛋白缺失将防止考克斯-2或cPLA 21诱导的肝癌发生。目的3旨在评估阻断前列腺素受体EP 1并同时抑制EGFR或2-连环蛋白可能代表肝癌化学预防和治疗的有效和安全的治疗策略的假设。这些研究为肝癌的化学预防和治疗提供了重要的理论依据。公共卫生相关性：目前的延续计划将描述前列腺素和EGFR/2-连环蛋白信号通路在肝癌细胞和肝癌发生动物模型中的相互作用。同时抑制前列腺素受体EP 1和EGFR/2-连环蛋白对肝肿瘤生长的影响将在体外和肝癌发生的动物模型中进行检查。拟议的研究将确定负责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.