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

Joana Torres, Xiuliang Bao, Alina C. Iuga, Anli Chen, Noam Harpaz, Thomas A. Ullman, Benjamin L. Cohen, Guillaume Pineton De Chambrun, Stefania Asciutti, Joseph A. Odin, David B. Sachar, H. Rex Gaskins, Kenneth Setchell, Jean Frédéric Colombel, Steven H. Itzkowitz

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)275-282
Number of pages8
JournalInflammatory Bowel Diseases
Volume19
Issue number2
DOIs
StatePublished - Feb 1 2013
Externally publishedYes

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Sclerosing Cholangitis
Colitis
Ulcerative Colitis
Mucous Membrane
Neoplasms
Colorectal Neoplasms
Colon
DNA Methylation
Inflammation
Cell Line
Azacitidine
Western Blotting
Immunohistochemistry
Polymerase Chain Reaction

Keywords

  • Colorectal neoplasia
  • Farnesoid X receptor
  • Primary sclerosing cholangitis

ASJC Scopus subject areas

  • Immunology and Allergy
  • Gastroenterology

Cite this

Farnesoid X receptor expression is decreased in colonic mucosa of patients with primary sclerosing cholangitis and colitis-associated neoplasia. / Torres, Joana; Bao, Xiuliang; Iuga, Alina C.; Chen, Anli; Harpaz, Noam; Ullman, Thomas A.; Cohen, Benjamin L.; De Chambrun, Guillaume Pineton; Asciutti, Stefania; Odin, Joseph A.; Sachar, David B.; Gaskins, H. Rex; Setchell, Kenneth; Colombel, Jean Frédéric; Itzkowitz, Steven H.

In: Inflammatory Bowel Diseases, Vol. 19, No. 2, 01.02.2013, p. 275-282.

Research output: Contribution to journalArticle

Torres, J, Bao, X, Iuga, AC, Chen, A, Harpaz, N, Ullman, TA, Cohen, BL, De Chambrun, GP, Asciutti, S, Odin, JA, Sachar, DB, Gaskins, HR, Setchell, K, Colombel, JF & Itzkowitz, SH 2013, 'Farnesoid X receptor expression is decreased in colonic mucosa of patients with primary sclerosing cholangitis and colitis-associated neoplasia', Inflammatory Bowel Diseases, vol. 19, no. 2, pp. 275-282. https://doi.org/10.1097/MIB.0b013e318286ff2e
Torres, Joana ; Bao, Xiuliang ; Iuga, Alina C. ; Chen, Anli ; Harpaz, Noam ; Ullman, Thomas A. ; Cohen, Benjamin L. ; De Chambrun, Guillaume Pineton ; Asciutti, Stefania ; Odin, Joseph A. ; Sachar, David B. ; Gaskins, H. Rex ; Setchell, Kenneth ; Colombel, Jean Frédéric ; Itzkowitz, Steven H. / Farnesoid X receptor expression is decreased in colonic mucosa of patients with primary sclerosing cholangitis and colitis-associated neoplasia. In: Inflammatory Bowel Diseases. 2013 ; Vol. 19, No. 2. pp. 275-282.
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abstract = "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.",
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T1 - Farnesoid X receptor expression is decreased in colonic mucosa of patients with primary sclerosing cholangitis and colitis-associated neoplasia

AU - Torres, Joana

AU - Bao, Xiuliang

AU - Iuga, Alina C.

AU - Chen, Anli

AU - Harpaz, Noam

AU - Ullman, Thomas A.

AU - Cohen, Benjamin L.

AU - De Chambrun, Guillaume Pineton

AU - Asciutti, Stefania

AU - Odin, Joseph A.

AU - Sachar, David B.

AU - Gaskins, H. Rex

AU - Setchell, Kenneth

AU - Colombel, Jean Frédéric

AU - Itzkowitz, Steven H.

PY - 2013/2/1

Y1 - 2013/2/1

N2 - 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.

AB - 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.

KW - Colorectal neoplasia

KW - Farnesoid X receptor

KW - Primary sclerosing cholangitis

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