Slc10a2-null mice uncover colon cancer-promoting actions of endogenous fecal bile acids.

Abstract:

:Although epidemiological evidence in humans and bile acid feeding studies in rodents implicate bile acids as tumor promoters, the role of endogenous bile acids in colon carcinogenesis remains unclear. In this study, we exploited mice deficient in the ileal apical sodium-dependent bile acid transporter (ASBT, encoded by SLC10A2) in whom fecal bile acid excretion is augmented more than 10-fold. Wild-type and Asbt-deficient (Slc10a2 (-/-) ) male mice were treated with azoxymethane (AOM) alone to examine the development of aberrant crypt foci, the earliest histological marker of colon neoplasia and a combination of AOM and dextran sulfate sodium to induce colon tumor formation. Asbt-deficient mice exhibited a 54% increase in aberrant crypt foci, and 70 and 59% increases in colon tumor number and size, respectively. Compared to littermate controls, Asbt-deficient mice had a striking, 2-fold increase in the number of colon adenocarcinomas. Consistent with previous studies demonstrating a role for muscarinic and epidermal growth factor receptor signaling in bile acid-induced colon neoplasia, increasing bile acid malabsorption was associated with M3 muscarinic and epidermal growth factor receptor expression, and activation of extracellular signal-related kinase, a key post-receptor signaling molecule.

journal_name

Carcinogenesis

journal_title

Carcinogenesis

authors

Raufman JP,Dawson PA,Rao A,Drachenberg CB,Heath J,Shang AC,Hu S,Zhan M,Polli JE,Cheng K

doi

10.1093/carcin/bgv107

subject

Has Abstract

pub_date

2015-10-01 00:00:00

pages

1193-200

issue

10

eissn

0143-3334

issn

1460-2180

pii

bgv107

journal_volume

36

pub_type

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