TY - JOUR

T1 - Nanomolar EP4 receptor potency and expression of eicosanoid-related enzymes in normal appearing colonic mucosa from patients with colorectal neoplasia

AU - Feddersen, Ulrike Ries

AU - Hendel, Sebastian Kjærgaard

AU - Berner-Hansen, Mark Alexander

AU - Jepps, Thomas Andrew

AU - Bindslev, Niels

N1 - Correction: https://bmcgastroenterol.biomedcentral.com/articles/10.1186/s12876-022-02339-1

PY - 2022

Y1 - 2022

N2 - Background: Aberrations in cyclooxygenase and lipoxygenase (LOX) pathways in non-neoplastic, normal appearing mucosa from patients with colorectal neoplasia (CRN), could hypothetically qualify as predisposing CRN-markers. Methods: To test this hypothesis, biopsies were obtained during colonoscopy from macroscopically normal colonic mucosa from patients with and without CRN. Prostaglandin E2 (PGE2) receptors, EP1-4, were examined in Ussing-chambers by exposing biopsies to selective EP receptor agonists, antagonists and PGE2. Furthermore, mRNA expression of EP receptors, prostanoid synthases and LOX enzymes were evaluated with qPCR. Results: Data suggest that PGE2 binds to both high and low affinity EP receptors. In particular, PGE2 demonstrated EP4 receptor potency in the low nanomolar range. Similar results were detected using EP2 and EP4 agonists. In CRN patients, mRNA-levels were higher for EP1 and EP2 receptors and for enzymes prostaglandin-I synthase, 5-LOX, 12-LOX and 15-LOX. Conclusions: In conclusion, normal appearing colonic mucosa from CRN patients demonstrates deviating expression in eicosanoid pathways, which might indicate a likely predisposition for early CRN development and furthermore that PGE2 potently activates high affinity EP4 receptor subtypes, supporting relevance of testing EP4 antagonists in colorectal neoplasia management.

AB - Background: Aberrations in cyclooxygenase and lipoxygenase (LOX) pathways in non-neoplastic, normal appearing mucosa from patients with colorectal neoplasia (CRN), could hypothetically qualify as predisposing CRN-markers. Methods: To test this hypothesis, biopsies were obtained during colonoscopy from macroscopically normal colonic mucosa from patients with and without CRN. Prostaglandin E2 (PGE2) receptors, EP1-4, were examined in Ussing-chambers by exposing biopsies to selective EP receptor agonists, antagonists and PGE2. Furthermore, mRNA expression of EP receptors, prostanoid synthases and LOX enzymes were evaluated with qPCR. Results: Data suggest that PGE2 binds to both high and low affinity EP receptors. In particular, PGE2 demonstrated EP4 receptor potency in the low nanomolar range. Similar results were detected using EP2 and EP4 agonists. In CRN patients, mRNA-levels were higher for EP1 and EP2 receptors and for enzymes prostaglandin-I synthase, 5-LOX, 12-LOX and 15-LOX. Conclusions: In conclusion, normal appearing colonic mucosa from CRN patients demonstrates deviating expression in eicosanoid pathways, which might indicate a likely predisposition for early CRN development and furthermore that PGE2 potently activates high affinity EP4 receptor subtypes, supporting relevance of testing EP4 antagonists in colorectal neoplasia management.

KW - Colorectal cancer

KW - EP receptors

KW - Lipoxygenase

KW - mRNA expression

KW - Short circuit current

U2 - 10.1186/s12876-022-02311-z

DO - 10.1186/s12876-022-02311-z

M3 - Journal article

C2 - 35549670

AN - SCOPUS:85130637443

VL - 22

SP - 1

EP - 11

JO - B M C Gastroenterology

JF - B M C Gastroenterology

SN - 1471-230X

IS - 1

M1 - 234

ER -