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.
This study, building upon the large PLCO screening arm population and a Cleveland colonoscopy screening cohort, addresses the hypothesis that 15-PGDH is a novel susceptibility gene for human colon neoplasia, and genetic variants and tissue expression levels of 15-PGDH may work jointly with non-steroidal anti-inflammatory drug use (NSAIDs) and circulating levels of vitamin D to impact the development of early colorectal neoplasia.
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