The Role of Bile Acid in the Development of Gastric Adenocarcinoma Via Activation of a Novel Bile Acid Receptor TGR5
W Cao, W Tian, J Hong, LJ Wang, R DeLellis, S Moss, M Resnick. Rhode Island Hospital, Providence, RI
Background: Bile reflux is a risk factor in the development of intestinal metaplasia in the stomach and is believed to function as an initiator of gastric carcinogenesis. However, the mechanisms whereby bile reflux promotes gastric tumor formation are not fully understood. In this study we determined the expression of a novel G-protein coupled bile acid receptor TGR5 in gastric adenocarcinoma and examined the role of TGR5 in cell proliferation.
Design: Tissue microarrays were created from paraffinized blocks from 171 patients with gastric adenocarcinomas (86 intestinal and 85 diffuse subtypes). In addition, cores of normal mucosa and intestinal metaplasia were taken from most cases. The microarrays were stained for TGR5, and the intensity of staining was determined using a 3-point scale. Cell proliferation was measured in the gastric adenocarcinoma cell line AGS treated with taurodeoxycholic acid (TDCA, a bile acid). The effects of TGR5 knockdown by siRNA and overexpression on cell proliferation were also determined.
Results: Strong TGR5 membranous staining was present in 12% of the cores with intestinal metaplasia but was not detected in normal gastric epithelium (p<0.01). Moderate to strong TGR5 membranous staining was present in 52% of the intestinal but in only 25% of the diffuse subtype of adenocarcinomas (p<0.001). Kaplan-Meier univariate survival analysis revealed that moderate to strong TGR5 staining was associated with decreased patient survival (p<0.05). TDCA treatment significantly increased thymidine incorporation in AGS cells. This increase was significantly decreased by knockdown of TGR5 with TGR5 siRNA. In addition, overexpression of TGR5 significantly enhanced TDCA-induced increase in thymidine incorporation.
Conclusions: TGR5 is moderately to strongly expressed in most gastric intestinal-type adenocarcinomas and is also associated with poor prognosis. Bile acid may activate TGR5 receptors and thereby increase cell proliferation, thus contributing to the development of gastric adenocarcinoma, particularly the intestinal type. Supported by NIH NIDDK R01 DK080703.
Monday, March 22, 2010 9:30 AM
Poster Session I Stowell-Orbison/Surgical Pathology/Autopsy Awards Poster Session # 89, Monday Morning