Role of COX Downstream Signaling Pathways in Cancer

结直肠癌（CRC）是大多数工业化国家的重大健康问题。在过去的十年中，在确定用于预防和治疗结直肠癌的药物靶点方面做出了重大努力。流行病学，实验和临床研究表明，服用非甾体抗炎药（NSAID）的人患结直肠癌的风险显著降低。大量的遗传学和生物化学证据表明，环氧合酶-2（考克斯-2）酶是预防结直肠癌的有希望的NSAID靶点。在考克斯-2依赖性途径中，NSAID通过抑制前列腺素的形成来抑制结肠癌的发生。 本课题组的研究表明：1）合成的PPARdelta激动剂增加Min小鼠中息肉的数量和大小; 2）考克斯-2衍生的PGE 2诱导PPARdelta反式激活; 3）PGE 2通过EGFR-PI 3 k-Akt途径诱导结肠癌细胞迁移/侵袭; 4）NSAIDs下调一个新基因NRG-1（NSAIDregulatedgene-1），该基因在人结直肠肿瘤组织中高度表达，并被Ras上调。然而，非甾体抗炎药对结直肠癌发生的作用是考克斯-2依赖性的还是非依赖性的，其确切机制尚不清楚。我们在这里提出的实验将进一步探讨这些问题，并试图了解NSAIDs影响结直肠生物学的机制。我们的实验方法将集中在以下三个具体目标：1）确定PPARdelta在肠息肉形成中的生物学功能; 2）表征考克斯-2衍生的PGE 2在结直肠癌生物学中的下游通路; 3）表征NSAID调节基因-1（NRG-1）在结直肠癌形成中的生物学功能。

Colorectal cancer (CRC) is a significant health concern in most industrialized countries. A significant effort has been made in the identification of drug targets for both the prevention and treatment of colorectal cancer over the past decade. Epidemiological, experimental, and clinical studies have demonstrated that there is a significant reduction in risk for colorectal cancer in persons who take nonsteroidal anti-inflammatory drugs (NSAIDs). A large body of genetic and biochemical evidence has demonstrated that the cyclooxygenase-2 (COX-2) enzyme is a promising NSAID target for prevention of colorectal cancer. In COX-2-dependent pathways, NSAIDs suppress colon carcinogenesis through the inhibition of prostaglandin formation. Studies by our group have demonstrated that 1) a synthetic PPARdelta agonist increases the number and size of polyps in Min mice; 2) COX-2 derived PGE2 induces PPARdelta transactivation; 3) PGE2 induces colon cancer cell migration/invasion through a EGFR-PI3k-Akt pathway; 4) NSAIDs downregulate a novel gene NRG-1 (NSAID regulated gene-1), which is highly expressed in human colorectal tumor tissue and is up-regulated by Ras. However, the precise mechanisms for the COX-2-dependent or -independent effects of NSAIDs on colorectal carcinogenesis are not clear. The experiments we propose here will explore these issues further and attempt to understand the mechanisms by which NSAIDs affect colorectal biology. Our experimental approaches will focus on the following three specific aims: 1) Determine the biologic function of PPARdelta in the intestinal polyp formation; 2) Characterize downstream pathways of COX-2 derived PGE2 in colorectal cancer biology; and 3) Characterize the biologic function of the NSAID-regulated gene-1 (NRG-1) in colorectal cancer formation.