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 = 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 (P= 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.
Dr Henry D Janowitz Division of Gastroenterology, Mount Sinai School of Medicine, New York, New York 10029, USA.
Joana
J
Torres
Xiuliang
X
Bao
Alina C
AC
Iuga
Anli
A
Chen
Noam
N
Harpaz
Thomas
T
Ullman
Benjamin L
BL
Cohen
Guillaume
G
Pineton de Chambrun
Stefania
S
Asciutti
Joseph A
JA
Odin
David B
DB
Sachar
H Rex
HR
Gaskins
Kenneth
K
Setchell
Jean-Frédéric
JF
Colombel
Steven H
SH
Itzkowitz
D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D018938:Caco-2 Cells; D015209:Cholangitis, Sclerosing / Q000150:complications / Q000378:metabolism*; D003093:Colitis, Ulcerative / Q000150:complications / Q000378:metabolism*; D003106:Colon / Q000378:metabolism*; D003110:Colonic Neoplasms / Q000209:etiology / Q000378:metabolism*; D019175:DNA Methylation; D005260:Female; D045325:HCT116 Cells; D056945:Hep G2 Cells; D006801:Humans; D007150:Immunohistochemistry; D007413:Intestinal Mucosa / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D060888:Real-Time Polymerase Chain Reaction; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D012189:Retrospective Studies; D000099150:Receptor, Farnesoid X-Activated
D015415:Biomarkers; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated