Primary bile acid activates Egr‑1 expression through the MAPK signaling pathway in gastric cancer

Lee,Su-Mi; Park,Moon Sik; Park,Seon-Young; Choi,Yoo-Duk; Chung,Jin Ook; Kim,Dong Hyun; Jung,Young Do; Kim,Hyun Soo

doi:10.3892/mmr.2022.12646

Primary bile acid activates Egr‑1 expression through the MAPK signaling pathway in gastric cancer

Authors:
- Su-Mi Lee
- Moon Sik Park
- Seon-Young Park
- Yoo-Duk Choi
- Jin Ook Chung
- Dong Hyun Kim
- Young Do Jung
- Hyun Soo Kim
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Affiliations: Division of Gastroenterology, Department of Internal Medicine, Chonnam National University Medical School, Gwangju 61469, Republic of Korea, Department of Pathology, Chonnam National University Medical School, Gwangju 61469, Republic of Korea, Division of Endocrinology, Department of Internal Medicine, Chonnam National University Medical School, Gwangju 61469, Republic of Korea, Research Institute of Medical Sciences, Chonnam National University Medical School, Gwangju 61469, Republic of Korea
Published online on: February 15, 2022 https://doi.org/10.3892/mmr.2022.12646
Article Number: 129
Copyright: © Lee et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Bile acids have been linked to pathomechanism and prognosis in various types of cancers. The present study aimed to investigate the effect of bile acids on the molecular change in gastric epithelial cancer cells and to evaluate gastric bile acid concentration in patients with early gastric cancer (EGC). Human gastric cancer cells (AGS and NCI‑N87 cell lines) were treated with several bile acid types to determine their effect on molecular changes in the cells. Gastric levels of individual bile acids were measured (primary unconjugated or conjugated bile acids and secondary bile acids) in 39 participants (20 controls and 19 patients with EGC). Exposing gastric epithelial cancer cells to primary bile acids in vitro upregulated the expression of early growth response factor 1 (Egr‑1) and the oncogenes including c‑Jun, c‑Myc and Snail, whereas a p42/44 MAPK inhibitor exposure reduced their expression. There was a significant difference in age and presence of atrophic gastritis with intestinal metaplasia in background mucosa between controls and patients with EGC. There were significant differences in the levels of unconjugated or conjugated primary bile acids between controls and EGC patients except lithocholic acid. After adjustment of age and presence of atrophic gastritis with intestinal metaplasia, the levels of cholic acid [adjusted odds ratio (aOR) 4.3; 95% confidence interval (CI): 1.2‑16.2; P=0.029] and glycochenodeoxycholic acid [aOR 9.9; 95% CI: 1.3‑75.3; P=0.027] were significantly higher in patients with EGC compared with controls. In conclusion, bile acids upregulate Egr‑1 in gastric cancer cells via the MAPK signaling pathway, and higher gastric levels of primary bile acids are associated with EGC. Therefore, exposure of gastric cells to primary bile acids may play a role in gastric carcinogenesis.

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1	Ferlay J, Colombet M, Soerjomataram I, Mathers C, Parkin DM, Piñeros M, Znaor A and Bray F: Estimating the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods. Int J Cancer. 144:1941–1953. 2019. View Article : Google Scholar : PubMed/NCBI
2	Di Ciaula A, Wang DQ, Molina-Molina E, Lunardi Baccetto R, Calamita G, Palmieri VO and Portincasa P: Bile acids and cancer: Direct and environmental-dependent effects. Ann Hepatol. 16 (Suppl 1: s3-e105):S87–S105. 2017. View Article : Google Scholar
3	Matsuhisa T, Arakawa T, Watanabe T, Tokutomi T, Sakurai K, Okamura S, Chono S, Kamada T, Sugiyama A, Fujimura Y, et al: Relation between bile acid reflux into the stomach and the risk of atrophic gastritis and intestinal metaplasia: A multicenter study of 2283 cases. Dig Endosc. 25:519–525. 2013. View Article : Google Scholar : PubMed/NCBI
4	Li D, Zhang J, Yao WZ, Zhang DL, Feng CC, He Q, Lv HH, Cao YP, Wang J, Qi Y, et al: The relationship between gastric cancer, its precancerous lesions and bile reflux: A retrospective study. J Dig Dis. 21:222–229. 2020. View Article : Google Scholar : PubMed/NCBI
5	Cao W, Tian W, Hong J, Li D, Tavares R, Noble L, Moss SF and Resnick MB: Expression of bile acid receptor TGR5 in gastric adenocarcinoma. Am J Physiol Gastrointest Liver Physiol. 304:G322–G327. 2013. View Article : Google Scholar : PubMed/NCBI
6	Hong J, Behar J, Wands J, Resnick M, Wang LJ, DeLellis RA, Lambeth D, Souza RF, Spechler SJ and Cao W: Role of a novel bile acid receptor TGR5 in the development of oesophageal adenocarcinoma. Gut. 59:170–180. 2010. View Article : Google Scholar : PubMed/NCBI
7	Yu JH, Zheng JB, Qi J, Yang K, Wu YH, Wang K, Wang CB and Sun XJ: Bile acids promote gastric intestinal metaplasia by upregulating CDX2 and MUC2 expression via the FXR/NF-κB signalling pathway. Int J Oncol. 54:879–892. 2019.PubMed/NCBI
8	Thiel G and Cibelli G: Regulation of life and death by the zinc finger transcription factor Egr-1. J Cell Physiol. 193:287–292. 2002. View Article : Google Scholar : PubMed/NCBI
9	Wang B, Guo H, Yu H, Chen Y, Xu H and Zhao G: The role of the transcription factor EGR1 in cancer. Front Oncol. 11:6425472021. View Article : Google Scholar : PubMed/NCBI
10	Steele NG, Chakrabarti J, Wang J, Biesiada J, Holokai L, Chang J, Nowacki LM, Hawkins J, Mahe M, Sundaram N, et al: An organoid-based preclinical model of human gastric cancer. Cell Mol Gastroenterol Hepatol. 7:161–184. 2019. View Article : Google Scholar : PubMed/NCBI
11	Schlemper RJ, Riddell RH, Kato Y, Borchard F, Cooper HS, Dawsey SM, Dixon MF, Fenoglio-Preiser CM, Fléjou JF, Geboes K, et al: The Vienna classification of gastrointestinal epithelial neoplasia. Gut. 47:251–255. 2000. View Article : Google Scholar : PubMed/NCBI
12	Carino A, Graziosi L, D'Amore C, Cipriani S, Marchianò S, Marino E, Zampella A, Rende M, Mosci P, Distrutti E, et al: The bile acid receptor GPBAR1 (TGR5) is expressed in human gastric cancers and promotes epithelial-mesenchymal transition in gastric cancer cell lines. Oncotarget. 7:61021–61035. 2016. View Article : Google Scholar : PubMed/NCBI
13	Park SY, Kim JY, Lee SM, Chung JO, Lee KH, Jun CH, Park CH, Kim HS, Choi SK, Rew JS, et al: Expression of early growth response gene-1 in precancerous lesions of gastric cancer. Oncol Lett. 12:2710–2715. 2016. View Article : Google Scholar : PubMed/NCBI
14	Allen K, Kim ND, Moon JO and Copple BL: Upregulation of early growth response factor-1 by bile acids requires mitogen-activated protein kinase signaling. Toxicol Appl Pharmacol. 243:63–67. 2010. View Article : Google Scholar : PubMed/NCBI
15	Shibata W, Maeda S, Hikiba Y, Yanai A, Sakamoto K, Nakagawa H, Ogura K, Karin M and Omata M: c-Jun NH2-terminal kinase 1 is a critical regulator for the development of gastric cancer in mice. Cancer Res. 68:5031–5039. 2008. View Article : Google Scholar : PubMed/NCBI
16	Chen R, Masuo K, Yogo A, Yokoyama S, Sugiyama A, Seno H, Yoshizawa A and Takaishi S: SNAIL regulates gastric carcinogenesis through CCN3 and NEFL. Carcinogenesis. 42:190–201. 2021. View Article : Google Scholar : PubMed/NCBI
17	Zhao A, Wang S, Chen W, Zheng X, Huang F, Han X, Ge K, Rajani C, Huang Y, Yu H, et al: Increased levels of conjugated bile acids are associated with human bile reflux gastritis. Sci Rep. 10:116012020. View Article : Google Scholar : PubMed/NCBI
18	Lee W, Um J, Hwang B, Lee YC, Chung BC and Hong J: Assessing the progression of gastric cancer via profiling of histamine, histidine, and bile acids in gastric juice using LC-MS/MS. J Steroid Biochem Mol Biol. 197:1055392020. View Article : Google Scholar : PubMed/NCBI
19	Goldman A, Shahidullah M, Goldman D, Khailova L, Watts G, Delamere N and Dvorak K: A novel mechanism of acid and bile acid-induced DNA damage involving Na+/H+ exchanger: Implication for Barrett's oesophagus. Gut. 59:1606–1616. 2010. View Article : Google Scholar : PubMed/NCBI
20	Souza RF: The role of acid and bile reflux in oesophagitis and Barrett's metaplasia. Biochem Soc Trans. 38:348–352. 2010. View Article : Google Scholar : PubMed/NCBI
21	Hyun JJ, Yeom SK, Shim E, Cha J, Choi I, Lee SH, Chung HH, Cha SH and Lee CH: Correlation between bile reflux gastritis and biliary excreted contrast media in the stomach. J Comput Assist Tomogr. 41:696–701. 2017. View Article : Google Scholar : PubMed/NCBI
22	Matsuhisa T and Tsukui T: Relation between reflux of bile acids into the stomach and gastric mucosal atrophy, intestinal metaplasia in biopsy specimens. J Clin Biochem Nutr. 50:217–221. 2012. View Article : Google Scholar : PubMed/NCBI
23	Xu X, Cheng J, Luo S, Gong X, Huang D, Xu J, Qian Y, Wan X and Zhou H: Deoxycholic acid-stimulated macrophage-derived exosomes promote spasmolytic polypeptide-expressing metaplasia in the stomach. Biochem Biophys Res Commun. 524:649–655. 2020. View Article : Google Scholar : PubMed/NCBI
24	Weis VG, Sousa JF, LaFleur BJ, Nam KT, Weis JA, Finke PE, Ameen NA, Fox JG and Goldenring JR: Heterogeneity in mouse spasmolytic polypeptide-expressing metaplasia lineages identifies markers of metaplastic progression. Gut. 62:1270–1279. 2013. View Article : Google Scholar : PubMed/NCBI