Journal Article

Sodium taurocholate inhibits intestinal adenoma formation in APC<i><sup>Min/+</sup></i> mice, potentially through activation of the farnesoid X receptor

Darcey L.H. Smith, Pavitra Keshavan, Uri Avissar, Kashif Ahmed and Stephen D. Zucker

in Carcinogenesis

Volume 31, issue 6, pages 1100-1109
Published in print June 2010 | ISSN: 0143-3334
Published online March 2010 | e-ISSN: 1460-2180 | DOI:
Sodium taurocholate inhibits intestinal adenoma formation in APCMin/+ mice, potentially through activation of the farnesoid X receptor

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In light of clinical and biological evidence that bile constituents exert preventive effects against colorectal cancer, we evaluated the influence of oral bilirubin and sodium taurocholate (NaTC) on intestinal tumor formation in APCMin/+ mice. Mice received bilirubin and/or bovine serum albumin (BSA) and NaTC in the drinking water for 8 weeks, after which the number, size and location of intestinal adenomas were determined. Tissue specimens were analyzed by light microscopy, TUNEL staining, immunohistochemistry for β-catenin and Ki-67 and quantitative polymerase chain reaction for farnesoid X receptor (FXR)-dependent gene expression. Colon tumor formation also was assessed in azoxymethane (AOM)-treated hyperbilirubinemic Gunn (j/j) and wild-type (+/+) rats. Compared with untreated APCMin/+ mice, the mean number of intestinal adenomas was markedly lower in both bilirubin (10.5 ± 0.9 versus 37.0 ± 5.2; ±SEM; P < 0.001) and NaTC plus BSA (14.3 ± 5.4; P = 0.01)-treated animals. Both treatment groups exhibited reduced levels of cellular proliferation in the ileum (by Ki-67 staining), but no differences in TUNEL staining or the percentage of β-catenin-positive crypts. Bilirubin feeding reduced intestinal inducible nitric oxide synthase expression, but did not alter adenoma multiplicity in APCMin/+ mice or in AOM-treated j/j versus +/+ rats. Mice receiving NaTC manifested increased intestinal expression of the FXR-regulated genes, Shp, FGF15 and IBABP, and a concomitant decrease in cyclin D1 message. Administering NaTC to APCMin/+ mice causes a marked reduction in intestinal adenomas. We postulate that this effect is mediated through activation of FXR, leading to increased Shp expression and consequent downregulation of cyclin D1.

Journal Article.  5285 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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