cPLA2, COX-2 and PPAR-gamma in Cholangiocarcinoma

描述(申请人提供)：胆管癌是一种高度恶性的胆系上皮性肿瘤，死亡率高。胆管癌变的确切分子机制尚未完全明确，目前还没有有效的治疗或化学预防措施。根据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(CPLA2)和环氧合酶-2(COX-2)控制的前列腺素(PG)通过激活EP1受体和Akt促进胆管癌细胞的生长。因此，阻断这些促进生长的PG信号通路可能为胆管细胞癌的化学预防和治疗提供潜在的治疗靶点。本申请提出了三个相互关联的具体目标，以检验上述假设，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。目的验证cPLA2和COX-2是介导PG产生和胆汁有丝分裂原HGF和IL-6诱导的细胞增殖和侵袭的两个限速关键酶的假设。目的评价PG和PPAR-γ协同调控胆管癌变的假说，同时靶向COX-2和PPAR-γ是预防和治疗胆管癌的一种新的治疗策略。他们的作用机制将被详细研究，期望cPLA2和COX-2控制的PGE2通过EP1受体介导的Akt激活来促进细胞生长，而PPARγ配体通过诱导p53/p21/GADD45和抑制COX-2/PGE2信号来抑制细胞生长。目的研究cPLA2、COX-2、PPAR-γ及其下游信号分子在胆管癌及癌前病变组织中的表达和磷酸化情况。这些研究将有助于理解cPLA2和COX-2调控的PG代谢在胆管癌细胞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.