Expression of bile acid receptor TGR5 in gastric adenocarcinoma

Abstract

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, whether the G protein-coupled bile acid receptor TGR5 is expressed in this tumor is not known. In this study, we determined the expression of TGR5 in gastric adenocarcinoma and examined the role of TGR5 in cell proliferation. Strong TGR5 staining was present in 12% of cases of intestinal metaplasia but in no cases of normal gastric epithelium (P Ͻ 0.01). Moderate to strong TGR5 membranous and cytoplasmic staining was present in 52% of the intestinal but in only 25% of the diffuse subtype of adenocarcinomas (P Ͻ 0.001). KaplanMeier univariate survival analysis revealed that moderate to strong TGR5 staining was associated with decreased patient survival (P Ͻ 0.05). Treatment with taurodeoxycholic acid (TDCA, a bile acid) significantly increased thymidine incorporation in the AGS gastric adenocarcinoma cell line, suggesting that bile acids may increase cell proliferation. This increase was significantly decreased by knockdown of TGR5 with TGR5 small-interfering RNA (siRNA). In addition, overexpression of TGR5 significantly enhanced TDCA-induced increases in thymidine incorporation. TGR5 is coupled with Gq␣ and G␣i-3 proteins. TDCA-induced increase in thymidine incorporation was significantly decreased by knockdown of Gq␣ and G␣i-3 with their siRNAs. We conclude that TGR5 is overexpressed in most gastric intestinal-type adenocarcinomas, and moderate to strong TGR5 staining is associated with decreased patient survival in all gastric adenocarcinomas. Bile acids increase cell proliferation via activation of TGR5 receptors and Gq␣ and G␣i-3 proteins.

GPBA: a GPCR for bile acids and an emerging therapeutic target for disorders of digestion and sensation

“…siRNA knockdown indicated that DCA-stimulation of ERK1/2 required expression of GPBA and activation of the membrane protease ADAM17, which liberates membrane-tethered heparin-binding EGF-like growth factor, an agonist of the EGF receptor. GPBA is also highly expressed in metastatic gastric adenocarcinoma and taurodeoxycholic acid (TDCA)-induced proliferation of ACS cells requires expression of GPBA (Cao et al, 2013). In the oesophageal adenocarcinoma cell line FLO, GPBA mediates TDCA-stimulated expression of the NADPH oxidase NOX5-S, which is required for the generation of reactive oxygen species and cell proliferation (Hong et al, 2010).…”

“…In the oesophageal adenocarcinoma cell line FLO, GPBA mediates TDCA-stimulated expression of the NADPH oxidase NOX5-S, which is required for the generation of reactive oxygen species and cell proliferation (Hong et al, 2010). In gastric and oesophageal adenocarcinoma cell lines GPBA couples to Gαq, which appears to be necessary for BA-stimulated proliferation (Hong et al, 2010;Cao et al, 2013). GPBA signalling has also been implicated in BA-induced apoptosis of hepatocytes, which can occur during cholestasis.…”

The bile acid receptor GPBAR1 (TGR5) is expressed in human gastric cancers and promotes epithelial-mesenchymal transition in gastric cancer cell lines

“…Thus, GPBAR1 could be a marker of tumor aggressiveness. Consistent with this view, Cao et al [20] have shown that moderate to strong GPBAR1 staining in gastric adenocarcinomas associates with decreased patient survival.…”

“…By immunohistochemistry GPBAR1 expression in non-neoplastic samples was found to be overexpressed in some patients with intestinal metaplasia [20] when compared with normal gastric epithelium ( Figure 1A). However, the expression of the receptor was not constantly upregulated in gastric adenocarcinoma cells (intestinal and diffuse type), indicating that neither the presence of metaplasia or histologic subtype of the tumor was associated with a specific pattern of GPBAR1 gene expression.…”

Membrane Bile Acid Receptor Tgr5 - A New Target in the Study of Metabolic, Inflammatory and Neoplastic Diseases

“…Активация TGR5 способна ин-дуцировать метаплазию эпителия, выявляемую при таком предраковом процессе, как пищевод Барретта [28,31]. Недавнее клиническое исследование по изучению выживаемости пациентов с аденокарциномой желуд-ка, проанализированное с помощью кривых Каплана-Мейера, показало, что чем больше иммунореактивность TGR5 в биоптатах аденокарциномы, тем хуже выжи-ваемость [32]. Приведенные данные свидетельствует о негативном влиянии TGR5 -опосредованных меха-низмов на процессы канцерогенеза верхних отделов же-лудочно-кишечного тракта.…”