Farnesoid X receptor expression is decreased in colonic mucosa of patients with primary sclerosing cholangitis and colitis-associated neoplasia

Background: The expression and distribution of farnesoid X receptor (FXR) in colitis and colitis-associated neoplasia (CAN) is unknown. We investigated FXR expression in neoplastic and nonneoplastic tissue from ulcerative colitis (UC) patients, with or without primary sclerosing cholangitis (PSC), as well as the role of DNA methylation in FXR expression in colorectal cancer (CRC) cell lines. Methods: Samples from the right (RC) and left (LC) colon of patients with UC, with and without PSC, and with or without CAN, were stained by immunohistochemistry and scored semiquantitatively for nuclear FXR expression. FXR expression was analyzed by western blot and polymerase chain reaction (PCR) in nine different CRC cell lines before and after demethylation with 5-azacytidine. Results: In nondysplastic samples, FXR expression demonstrated a diminishing expression from proximal to distal colon (strong FXR expression: 39% RC samples vs. 14% LC samples; P 1/4 0.007). With moderate-to-severe inflammation, FXR expression was almost always absent or weak in both UC and PSC-UC, regardless of location. With quiescent/mild inflammation, 56% of UC samples in the RC retained strong FXR expression versus 24% of PSC-UC samples (P1/4 0.017). FXR was absent in 72% of the neoplastic samples, with an inverse association with the grade of dysplasia. FXR expression was absent in all CRC cell lines, in some cases due to DNA methylation. Conclusions: FXR expression is inversely correlated with neoplastic progression and severity of inflammation in UC. Patients with PSC-UC have diminished FXR expression in the proximal colon compared to UC patients. This finding could contribute to the higher risk of proximal neoplasia in PSC patients.