cPLA2, COX-2 and PPAR-gamma in Cholangiocarcinoma

描述（由申请方提供）：胆管癌是高度恶性的胆管上皮肿瘤，死亡率高。胆管癌发生的确切分子机制尚未完全确定，目前没有有效的治疗或化学预防。基于我们实验室已发表的数据和新的初步发现，我们假设胞浆磷脂酶A2（cPLA 2）和环氧合酶-2（考克斯-2）控制的前列腺素（PG）通过激活EP 1受体和Akt促进胆管癌生长。因此，阻断这些促生长的PG信号通路可能为胆管癌的化学预防和治疗提供有希望的潜在治疗靶点。本申请提出了三个相互关联的具体目标，以使用培养的原代和肿瘤性胆管上皮细胞、实验动物模型和人体组织评估来检验上述假设。目的探讨cPLA 2和考克斯-2是介导PG生成和胆汁促分裂素HGF和IL-6诱导的细胞增殖和侵袭的两个限速酶的假说。目的II：探讨PG和PPARgamma协同调控胆管癌的发生，同时靶向考克斯-2和PPARgamma是胆管癌化学预防和治疗的新策略。将详细研究其作用机制，预期cPLA 2和考克斯-2控制的PGE 2通过EP 1受体介导的Akt活化促进细胞生长，而PPARgamma配体通过诱导p53/p21/GADD 45和抑制考克斯-2/PGE 2信号传导防止生长。目的III检测cPLA 2、考克斯-2、PPARgamma及其下游信号分子在人胆管癌及癌前组织中的表达及磷酸化水平。这些研究将有助于了解cPLA 2和考克斯-2调控的PG代谢在胆管癌生长中的病理生物学功能和分子机制，并提供重要的治疗意义。

DESCRIPTION (provided by applicant): Cholangiocarcinomas are highly malignant epithelial neoplasms of the biliary tree with a high rate of mortality. The exact molecular mechanism of cholangiocarcinogenesis is not completely defined and currently there is no effective treatment or chemoprevention. On the basis of published data from our laboratory and new preliminary findings, we hypothesize that the cytosolic phospholipase A2 (cPLA2) and cyclooxygenase-2 (COX-2)-controlled prostaglandin (PG) promotes cholangiocarcinoma growth through activation of EP1 receptor and Akt. Thus, interruption of these growth-promoting PG signaling pathways may provide promising potential therapeutic targets for the chemoprevention and treatment of human cholangiocarcinoma. This application proposes three interrelated specific aims to examine the above hypotheses using cultured primary and neoplastic biliary epithelial cells, experimental animal models and evaluation of human tissues. Aim I will examine the hypothesis that the cPLA2 and COX-2 are two rate-limiting key enzymes that mediate PG production and biliary mitogen HGF and IL-6-induced cell proliferation and invasion. Aim II is proposed to evaluate the hypothesis that PG and PPARgamma coordinately modulate cholangiocarcinogenesis and simultaneous targeting of COX-2 and PPARgamma is a novel therapeutic strategy for the chemoprevention and treatment of human cholangiocarcinoma. The mechanisms for their actions will be examined in detail, with the expectation that the cPLA2 and COX-2-controlled PGE2 promotes cell growth via EP1 receptor-mediated Akt activation, whereas PPARgamma ligands prevent growth through induction of p53/p21/GADD45 and inhibition of COX-2/PGE2 signaling. Aim III will examine the expression and phosphorylation of cPLA2, COX-2, PPARgamma and their downstream signaling molecules in human cholangiocarcinoma and pre-cancerous tissues. The proposed studies will help understand the pathobiological functions and molecular mechanisms of cPLA2 and COX-2-controlled PG metabolism in cholangiocarcinoma growth and provide important therapeutic implications.