Combined activity of COX-1 and COX-2 is increased in non-neoplastic colonic mucosa from colorectal neoplasia patients

Abstract

BackgroundCyclooxygenase (COX) activity is increased in endoscopic normal colonic mucosa from patients with colorectal neoplasia (CRN). COX-2 is thought to be the predominant COX isozyme involved in neoplasia. Meanwhile, relative contributions of COX-1 and COX-2 isoforms are unknown. Knowledge about their mutual activity in colonic mucosa is important for diagnostics and targeted therapy for CRN. The aim of this study was to assess the relative function, expression and localization of COX-1 and COX-2 enzymes in colonic non-neoplastic human mucosa and thereby to potentially reveal a mucosal disease predisposition for better treatment.MethodsBiopsies were pinched from normal appearing colonic mucosa in patients undergoing endoscopy. Ussing chamber technique was applied for an indirect assessment of epithelial activity, RT-qPCR for expression and immunohistochemistry for localization of COX-1 and COX-2 enzymes in patients without (ctrls) and with a history of CRN (CRN-pts).ResultsCombined COX-1 and COX-2 activity was higher in CRN-pts, p = 0.036. COX-2 was primarily localized in absorptive cells, while COX-1 appeared to be restricted to nonenteroendocrine tuft cells of the colonic epithelium.ConclusionsIn biopsies from endoscopic normal appearing colonic mucosa, combined activity of COX-1 and COX-2 enzymes is increased in CRN-pts compared with ctrls. This indicates that COX-1 and COX-2 together contribute to an increased proliferation process. Of note, in colonic epithelial cell lining, the COX-1 enzyme seems localized in tuft cells.

Possible predisposition for colorectal carcinogenesis due to altered gene expressions in normal appearing mucosa from patients with colorectal neoplasia

“…Thus, despite we did not observe up-regulation of COX-1 and -2 enzyme mRNA, a higher substrate level may yield a higher PGE 2 -concentration. This corroborates with previous reports demonstrating higher sensitivity to indomethacin in CRN patients versus controls [3, 16, 31]. In terms of the resulting mucosal content of active PGE 2 , our assay indicates that the mean concentration is lifted (26%) in CRN patients.…”

“…COX-1 was selectively expressed in a small subset of cells in the epithelial cell layer where the enzyme displayed a reticular, intracellular localization associated with the perinuclear area. We believe that these COX-1 expressing cells represent epithelial tuft cells [15, 16]. β-catenin showed expression throughout the epithelial layer and was mainly associated with lateral membranes of the epithelial cells.…”

Eicosanoids in carcinogenesis

“…This goes in line with the findings that inhibiting 5-LOX and Cox-2 blocks colon cancer proliferation, migration, as well as invasion in vitro [231]. This may explain why NSAID intake might result in some 50% reduction of the relative CRC risk [232,233] as the combined Cox-1 and Cox-2 activity is increased in CRC [234]. The non-enteroendocrine "tuft cells" which are referred to chemosensory cells showed mainly Cox-1 overexpression while Cox-2 was primarily found in absorptive cells and are "rather constitute a distinct entity with transcription factor requirements for differentiation that differ from those of enterocytes, enteroendocrine, Paneth, and goblet cells" [supplemental material Inhibiting 5-LOX and the 5-lipoxygenase-activating protein (FLAP) by the tobacco carcinogen, 4-methylni-trosamino-1-(3-pyridyl)-1-butanone suppresses carcinogenesis [238] and modulating LOX by clearly defining proand anti-carcinogenic effects depend on which metabolite is used and may be an option in anticancer treatment [181].…”

Glucocorticoids promote the development of azoxymethane and dextran sulfate sodium-induced colorectal carcinoma in mice

“…When activated NF-κB translocates to the nucleus, it can regulate the expression of multiple target genes, including COX-2. It is widely accepted that the deregulation of the COX-2 signalling pathway took a vital effect in the progression of CRC [39]. Therefore, we investigated the expression of COX-2 by IHC analysis.…”