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Abstract
Oxylipins derived from arachidonic acid (ARA) have been implicated in the development of colorectal adenomas and colorectal cancer. The primary purpose of this work was to determine the relationship between plasma levels of oxylipins and colorectal adenoma characteristics at study entry, as well as with the development of a new adenoma during follow-up within a Phase III adenoma prevention clinical trial with selenium (Sel). Secondarily, we sought to determine whether the selenium intervention influenced plasma oxylipin levels. Four oxylipins were quantified in stored plasma samples from a subset of Sel study subjects (n = 256) at baseline and at 12-months. There were significantly lower odds of an advanced adenoma at baseline with higher prostaglandin E2 (PGE2), with an OR (95% CI) of 0.55 (0.33–0.92), and with 5-hydroxyeicosatetraenoic acid (5-HETE) ((0.53 (0.33–0.94)); and of a large adenoma with higher PGE2 ((0.52 (0.31–0.87)). In contrast, no associations were observed between any oxylipin and the development of a new adenoma during follow-up. Selenium supplementation was associated with a significantly smaller increase in 5-HETE after 12 months compared to the placebo, though no other results were statistically significant. The ARA-derived oxylipins may have a role in the progression of non-advanced adenoma to advanced, but not with the development of a new adenoma.
Highlights
Oxylipins are the oxygenated lipid metabolites of ω-3 and ω-6 fatty acids
Participants with an advanced or nonadvanced adenoma at baseline were similar in terms of sex, age, education level, body mass index (BMI), smoking status, nonsteroidal anti-inflammatory drugs (NSAIDs), and aspirin use, as well as relatives with colorectal cancer (CRC) and history of polyps or cancer (Table 1)
These results show that those above the median for prostaglandin E2 (PGE2) were statistically significantly less likely to have an advanced adenoma at baseline, with an OR of 0.55 (0.33–0.92) compared to those below the median
Summary
Oxylipins are the oxygenated lipid metabolites of ω-3 and ω-6 fatty acids. Enzymatic production of oxylipins is achieved via the cyclooxygenase(COX), lipoxygenase (LOX), and cytochrome P450 (CYP450) enzymes. While oxylipins have a broad range of potent biological activities, many of the oxylipins produced from the ω-6 fatty acid, arachidonic acid (ARA) are pro-inflammatory and pro-tumorigenic with prostaglandin E2 (PGE2) being the most thoroughly studied in relation to colorectal and other cancers [1]. Further supporting the role of PGE2 in colorectal carcinogenesis is that the prostaglandin E2 metabolite (PGEM) was observed to be associated with increased risk for advanced adenoma among women, but not nonadvanced, in a nested case-control of the Tennessee Colorectal Polyp Study; there was no reduction in risk for men [5]. The PGEM was related to significantly greater odds for high-risk adenoma in a nested case control in the Nurses’ Health Study, and regular use of NSAIDs was associated with significant reduction in risk among women with high baseline PGEM [6]. In a nested case control study conducted within the Shanghai Women’s Health Study, the relative risks of developing CRC were significantly elevated with increasing quartiles of urinary PGEM levels [7]
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