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Farnesoid X Receptor Expression Is Decreased in Colonic Mucosa of Patients with Primary Sclerosing Cholangitis and Colitis-associated Neoplasia

Torres, Joana MD*,†; Bao, Xiuliang MS*; Iuga, Alina C. MD; Chen, Anli MS*; Harpaz, Noam MD, PhD; Ullman, Thomas MD*; Cohen, Benjamin L. MD*; Pineton de Chambrun, Guillaume MD§,‖; Asciutti, Stefania MD, PhD; Odin, Joseph A. MD**; Sachar, David B. MD*; Gaskins, H. Rex PhD††; Setchell, Kenneth PhD‡‡; Colombel, Jean-Frédéric MD, PhD*,§§; Itzkowitz, Steven H. MD*

doi: 10.1097/MIB.0b013e318286ff2e
Original Basic Science Articles

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.

Article first published online 23 January 2013

*Dr. Henry D. Janowitz Division of Gastroenterology, Mount Sinai School of Medicine, New York, New York, USA

Gastroenterology Service, Surgery Department, Hospital Beatriz Ângelo, Loures, Portugal

Division of Gastrointestinal Pathology, Mount Sinai School of Medicine, New York, New York, USA

§Inserm Unit 995, Université Lille Nord de France, Lille, France

Department of Medicine, School of Medicine, UCSD, San Diego, California, USA

Department of Oncological Sciences, Mount Sinai School of Medicine, New York, New York, USA

**Division of Liver Disease and Recanati/Miller Transplantation Institute, The Mount Sinai Hospita Mount Sinai School of Medicine, New York, New York, USA

††Departments of Animal Sciences and Pathobiology, Division of Nutritional Sciences, Institute for Genomic Biology. University of Illinois at Urbana-Champaign, Urbana, Illinois, USA

‡‡Department of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio USA

§§Department of Hepatogastroenterology, Hôpital Claude Huriez and Centre d'Investigation Clinique, Centre Hospitalier Universitaire de Lille, Université Lille Nord de France, Lille, France

Reprints: Steven Itzkowitz, MD, GI Division, Box 1069, Mount Sinai School of Medicine, One Gustave Levy Place, New York, NY 10029 (e-mail: steven.itzkowitz@mountsinai.org).

Joana Torres received a Travel Grant from International Organization for the study of Inflammatory Bowel Disease (IOIBD) and a grant from the Burrill B. Crohn Research Foundation. This work was supported in part by the Gastric Cancer and Peptic Ulcer Disease Foundation and the Chemotherapy Foundation.

Received May 16, 2012

Accepted May 31, 2012

© Crohn's & Colitis Foundation of America, Inc.
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