Prostaglandin Signaling Pathway in Liver Cancer

描述（申请人提供）：原发性肝癌是人类最常见的恶性肿瘤，死亡率高。然而，肝癌发生的确切分子机制尚未完全确定，对其预防也知之甚少。根据我们实验室发表的数据和令人兴奋的新初步发现，我们假设胞质磷脂酶A2 （cPLA2）和环氧化酶2 （COX-2）是控制前列腺素合成的两个最重要的限速关键酶，它们通过EP1受体介导的Akt活化在肝癌发生中起重要作用。因此，阻断前列腺素相关信号通路可能为人类肝癌的化学预防和治疗提供有希望的潜在治疗靶点。本应用程序提出了三个具体目标来评估上述假设。目的：我将利用肝癌发生的动物模型来检验cPLA2和cox -2介导的前列腺素信号通路促进肝癌发展的假设。肝脏中cPLA2和COX-2被破坏或靶向过表达的小鼠将被用于检测自发性或肝癌诱导的肝癌发展。Aim II将在体外和SCID小鼠中评估cPLA2和COX-2过表达或反义/siRNA缺失对肝癌生长的影响。Aim III旨在评估EP1受体激活Akt是介导cPLA2和COX-2诱导肝癌生长的关键信号通路的假设。本研究将有助于了解cPLA2和cox -2控制的前列腺素代谢在肝癌促进和进展中的病理生物学功能和分子机制。该结果将为人类肝癌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 most common malignant tumor in human with high mortality. However, the exact molecular mechanism of liver carcinogenesis is not completely defined and little is known about its prevention. On the basis of published data from our laboratory and exciting new preliminary findings, we hypothesize that cytosolic phospholipase A2 (cPLA2) and cyclooxygenase-2 (COX-2), the two most important rate-limiting key enzymes in the control of prostaglandin synthesis, importantly contribute to liver carcinogenesis through EP1 receptor-mediated activation of Akt. Therefore, interruption of the prostaglandin-associated signaling pathways may provide promising potential therapeutic targets for the chemoprevention and treatment of human liver cancer. This application proposes three specific aims to evaluate the above hypotheses. Aim I will examine the hypothesis that the cPLA2 and COX-2-mediated prostaglandin signaling pathways promote liver cancer development by utilizing animal models of hepatocarcinogenesis. Mice with disruption or targeted overexpression of cPLA2 and COX-2 in liver will be utilized to examine the spontaneous or hepatic carcinogen-induced liver cancer development. Aim II will evaluate the effect of overexpression or antisense/siRNA depletion of cPLA2 and COX-2 on liver cancer growth, in vitro and in SCID mice. Aim III is proposed to evaluate the hypothesis that activation of Akt by EP1 receptor is a key signaling pathway that mediates the cPLA2 and COX-2- induced liver cancer growth. The proposed studies will help understand the pathobiological functions and molecular mechanisms of cPLA2 and COX-2-controlled prostaglandin metabolism in liver cancer promotion and progression. The results will provide important therapeutic implications for the chemoprevention and treatment of human liver cancer.