15-Hydroxyprostaglandin Dehydrogenase, NSAIDs, Vitamin D, and Coloretcal Neoplasi

描述（由申请人提供）：前列腺素信号通路在结肠肿瘤发生中起重要作用。抑制考克斯-2导致前列腺素E2（PGE 2）水平降低是非甾体抗炎药（NSAID）结肠化学预防作用的关键机制。15-羟基前列腺素脱氢酶（15-PGDH）是考克斯-2的下游代谢拮抗剂，最近被确定为一种新的结肠肿瘤抑制剂。NSAID通过“夹心”方式对PGE 2途径发挥抗肿瘤作用，同时抑制考克斯-2和上调15-PGDH。新出现的证据表明，维生素D还通过其对PGE 2信号传导途径的作用，通过下调考克斯-2、上调15-PGDH和抑制EP 1-EP 4（PGE 2的受体）来发挥抗肿瘤作用。我们在一项结肠腺瘤预防试验中发现，在接受塞来昔布治疗时发生新腺瘤的个体结肠15-PGDH表达水平也较低。此外，我们最近在15-PGDH基因的启动子区域中鉴定了一个SNP，该SNP与人类结肠癌风险增加和结肠组织中15-PGDH表达降低相关。这些导致了我们的中心假设，即15-PGDH是人类结肠肿瘤的易感基因，NSAID和维生素D的循环水平可能与15-PGDH相互作用，影响结肠肿瘤的发生。该提案建立在PLCO试验和克利夫兰的既定结肠筛查人群基础上，其中来自病例和对照子集的正常结肠组织很容易获得。具体而言，目标1使用3阶段设计（发现、组织表达验证和复制）来询问整个15-PGDH基因座（跨越100 kb上游和下游），以寻找15-PGDH的结直肠肿瘤易感遗传变体。目的2检测309例大肠腺瘤患者和327例正常对照者的正常结肠组织中PE 2信号通路关键基因的表达水平，并评估其与大肠腺瘤风险的关系。目的3综合SNP、基因表达和暴露数据，评估15-PGDH、NSAID和血清维生素D水平对结直肠肿瘤风险的联合作用。我们提出的研究将为15-PGDH在结肠癌发生中的病因学作用提供新的见解，并将为个体化策略提供信息，以最大限度地发挥NSAID和维生素D的15-PGDH依赖性化学预防作用，并最大限度地减少迄今为止阻碍人群广泛使用NSAID进行化学预防的不良胃肠道和心脏效应。

DESCRIPTION (provided by applicant): Prostaglandin signaling pathway plays an important role in colon tumorigenesis. Inhibition of COX-2 with resultant decreased levels of prostaglandin E2 (PGE2) is a key mechanism underlying the colon chemo- preventive effects of non-steroidal anti-inflammatory drugs (NSAIDs). 15-hydroxyprostaglandin dehydrogenase (15-PGDH), a downstream metabolic antagonist of COX-2, has recently been established as a novel colon neoplasia suppressor. NSAIDs exert anti-neoplastic effects through a 'sandwiched' manner on the PGE2 pathway by concomitant suppression of COX-2 and up-regulation of 15-PGDH. Emerging evidence suggests that vitamin D also exerts anti-neoplastic effects through its actions on the PGE2 signaling pathway by down- regulating COX-2, up-regulating 15-PGDH, and inhibiting EP1-EP4, the receptors for PGE2. We have shown in a colon adenoma prevention trial that individuals who developed new adenomas while receiving celecoxib also had low colonic 15-PGDH expression levels. Furthermore, we have recently identified a SNP in the promoter region of 15-PGDH gene that is associated with both an increased risk of colon cancer and decreased colonic tissue expression of 15-PGDH in humans. These lead to our central hypothesis that 15-PGDH is a susceptibility gene for human colon neoplasia, and NSAIDs and circulating levels of vitamin D may interact with 15-PGDH to impact colon tumorigenesis. This proposal builds upon the PLCO trial and an established colon screening population in Cleveland, where normal colonic tissues from a subset of cases and controls are readily available. Specifically, Aim 1 uses a 3-stage design (discovery, tissue expression validation, and replication) to interrogate the entire 15-PGDH gene locus (spanning 100kb upstream and downstream) for colorectal neoplasia predisposing genetic variants of 15-PGDH. Aim 2 examines PE2 signaling pathway key gene expression levels in normal colonic tissues from a set of 309 adenoma cases and 327 controls, and assesses their associations with risk of colorectal adenoma. Aim 3 synthesizes SNP, gene expression, and exposure data to assess the joint effects of 15-PGDH, NSAIDs, and serum levels of vitamin D on risk of colorectal neoplasia. Our proposed study will provide novel insight into the etiological role of 15-PGDH in colon carcinogenesis, and will inform individualized strategies to maximize the 15-PGDH dependent chemoprevention effects of NSAIDs and vitamin D, and minimize the adverse gastrointestinal and cardiac effects that have thus far hampered population-wide use of NSAIDs for chemoprevention.