cPLA2, COX-2 and PPAR-gamma in Cholangiocarcinoma

描述（申请人提供）：胆管癌是胆道树的高度恶性上皮肿瘤，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。根据我们实验室发表的数据和新的初步发现，我们假设胞质磷脂酶A2 （cPLA2）和环氧化酶2 （COX-2）控制的前列腺素（PG）通过激活EP1受体和Akt来促进胆管癌的生长。因此，阻断这些促进生长的PG信号通路可能为化学预防和治疗人类胆管癌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，通过培养原代和肿瘤性胆道上皮细胞、实验动物模型和人体组织评估来检验上述假设。目的：我将检验cPLA2和COX-2是两个限速关键酶的假设，介导PG的产生和胆道有丝分裂原HGF和il -6诱导的细胞增殖和侵袭。目的II旨在评估PG和PPARgamma协同调节胆管癌发生的假设，同时靶向COX-2和PPARgamma是化学预防和治疗人类胆管癌的一种新的治疗策略。我们将详细研究它们的作用机制，预计cPLA2和COX-2控制的PGE2通过EP1受体介导的Akt激活促进细胞生长，而PPARgamma配体通过诱导p53/p21/GADD45和抑制COX-2/PGE2信号传导来阻止细胞生长。Aim III将检测cPLA2、COX-2、PPARgamma及其下游信号分子在人胆管癌和癌前组织中的表达和磷酸化。这些研究将有助于了解cPLA2和cox -2控制的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.