Deoxycholic Acid Could Induce Apoptosis and Trigger Gastric Carcinogenesis on Gastric Epithelial Cells by Quantitative Proteomic Analysis

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Abstract

Background. Pathologic duodenogastric reflux can induce or aggravate gastritis because of the presence of bile acids. Bile reflux has been generally considered to be associated with intestinal metaplasia and gastric cancer. However, the pathogenic mechanisms of the effects of bile acids on gastric mucosa are still unknown. Methods. To explore the mechanisms by which bile acids induce gastric mucosal lesions, we examined cell apoptosis in the gastric epithelial cell line GES-1 and investigated the changes in protein profiles of GES-1 cells in response to a bile acid deoxycholic acid using a proteomics approach. Changes in the profiles of the differently expressed proteins were analyzed using the DAVID and STRING programs. Results. We found apoptosis was significantly induced in GES-1 cells by deoxycholic acid. Using liquid chromatographic/tandem mass spectrometric (LC-MS/MS) methods, 134 upregulated proteins and 214 downregulated proteins were identified in the bile acid treated GES-1 cells. Bioinformatics analysis revealed the interactions and signaling networks of these differentially expressed proteins. Conclusion. These findings may improve the understanding of the molecular mechanisms underlying the pathogenicity of bile acids on gastric mucosa.

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Most cited references 38

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Gastric cancer is one of the world's most common cancers. Its carcinogenic pathway is mainly associated with Helicobacter pylori infection, subsequent inflammation and tissue regeneration. During the regeneration process, cells deviate from the normal pathway of gastric differentiation to an 'intestinal phenotype', which is thought to be precancerous and associated with the intestinal type of gastric cancer. Inappropriate activation of intestine-specific transcription factors could contribute to the occurrence of the intestinal-type cancer of the stomach.

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The nuclear factor kappaB (NF-kappaB) transcription factor is responsive to specific cytokines and stress and is often activated in association with cell damage and growth arrest in eukaryotes. NF-kappaB is a heterodimeric protein, typically composed of 50- and 65-kilodalton subunits of the Rel family, of which RelA(p65) stimulates transcription of diverse genes. Specific cyclin-dependent kinases (CDKs) were found to regulate transcriptional activation by NF-kappaB through interactions with the coactivator p300. The transcriptional activation domain of RelA(p65) interacted with an amino-terminal region of p300 distinct from a carboxyl-terminal region of p300 required for binding to the cyclin E-Cdk2 complex. The CDK inhibitor p21 or a dominant negative Cdk2, which inhibited p300-associated cyclin E-Cdk2 activity, stimulated kappaB-dependent gene expression, which was also enhanced by expression of p300 in the presence of p21. The interaction of NF-kappaB and CDKs through the p300 and CBP coactivators provides a mechanism for the coordination of transcriptional activation with cell cycle progression.

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Bile acid toxicity has been shown in the gastric, colonic, and hepatic tissues; the effect on oesophageal mucosa is less well known. To determine the spectrum of bile acids refluxing in patients with gastro-oesophageal reflux disease and its relation to oesophageal pH using a new technique of combined oesophageal aspiration and pH monitoring. Ten asymptomatic subjects and 30 patients with symptoms of gastro-oesophageal reflux disease (minimal mucosal injury, erosive oesophagitis (grade 2 or 3 Savary-Miller), Barrett's oesophagus/stricture; n=10 in each group) underwent 15 hour continuous oesophageal aspiration with simultaneous pH monitoring. Bile acid assay of the oesophageal samples was performed using modified high performance liquid chromatography. The peak bile acid concentration and DeMeester acid scores were significantly higher in the patients with oesophagitis (median bile acid concentration 124 micromol/l; acid score 20.2) and Barrett's oesophagus/stricture (181 micromol/l; 43. 3) than patients with minimal injury (14 micromol/l; 12.5) or controls (0 micromol/l; 11.1). The predominant bile acids detected were cholic, taurocholic, and glycocholic acids but there was a significantly greater proportion of secondary bile acids, deoxycholic and taurodeoxycholic acids, in patients with erosive oesophagitis and Barrett's oesophagus/stricture. Although bile acid reflux episodes occurred at variable pH, a temporal relation existed between reflux of taurine conjugates and oesophageal acid exposure (r=0.58, p=0.009). Toxic secondary bile acid fractions have been detected in patients with extensive mucosal damage. Mixed reflux is more harmful than acid reflux alone with possible toxic synergism existing between the taurine conjugates and acid.

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Author and article information

Journal

Journal ID (nlm-ta): Gastroenterol Res Pract

Journal ID (iso-abbrev): Gastroenterol Res Pract

Journal ID (publisher-id): GRP

Title: Gastroenterology Research and Practice

Publisher: Hindawi Publishing Corporation

ISSN (Print): 1687-6121

ISSN (Electronic): 1687-630X

Publication date (Print): 2016

Publication date (Electronic): 14 December 2016

Volume: 2016

Electronic Location Identifier: 9638963

Affiliations

¹Research Center of Clinical Epidemiology, Peking University Third Hospital, Beijing 100191, China

²Department of Gastroenterology, Peking University Third Hospital, Beijing 100191, China

³Department of Microbiology, Peking University Health Science Center, Beijing 100191, China

Author notes

*Shigang Ding: dingshigang222@ 123456163.com

Academic Editor: Daiming Fan

Author information

Yanyan Shi http://orcid.org/0000-0003-0247-371X

Ting Zhang http://orcid.org/0000-0002-2862-7644

Shigang Ding http://orcid.org/0000-0002-0831-0965

Article

DOI: 10.1155/2016/9638963

PMC ID: 5192292

PubMed ID: 28070185

SO-VID: 21df9b17-f0ac-410a-b679-0dc3de8fe9a0

License:

This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

History

Date received : 2 August 2016

Date revision received : 10 October 2016

Date accepted : 23 October 2016

Funding

Funded by: Beijing Key Laboratory

Award ID: BZ0371

Funded by: National Natural Science Foundation of China

Award ID: 81270475

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