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，对其预防知之甚少。基于我们实验室已发表的数据和令人兴奋的新的初步发现，我们假设胞浆磷脂酶A2（cPLA 2）和环氧合酶-2（考克斯-2），这两个最重要的限速关键酶在前列腺素合成的控制，重要的是通过EP 1受体介导的Akt的激活，促进肝癌的发生。因此，阻断该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。本申请提出了三个具体目标来评估上述假设。目的利用肝癌发生的动物模型，验证cPLA 2和考克斯-2介导的前列腺素信号通路促进肝癌发生的假说。将使用肝脏中cPLA 2和考克斯-2破坏或靶向过表达的小鼠来检查自发性或肝致癌物诱导的肝癌发展。目的II研究cPLA 2和考克斯-2过表达或反义/siRNA去除对体外和SCID小鼠肝癌生长的影响。目的III：探讨EP 1受体激活Akt是介导cPLA 2和考克斯-2诱导肝癌生长的关键信号通路的假说。这些研究将有助于了解cPLA 2和考克斯-2调控前列腺素代谢在肝癌发生、发展中的病理生物学功能和分子机制。该结果将为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.