{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T15:37:32Z","timestamp":1776958652923,"version":"3.51.4"},"reference-count":42,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2020,10,28]],"date-time":"2020-10-28T00:00:00Z","timestamp":1603843200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001602","name":"Science Foundation Ireland","doi-asserted-by":"publisher","award":["SFI-RFP\/BMT2781"],"award-info":[{"award-number":["SFI-RFP\/BMT2781"]}],"id":[{"id":"10.13039\/501100001602","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Bile acids (BAs) have been implicated in the development of oesophagitis, Barrett\u2019s oesophagus and oesophageal adenocarcinoma (OAC). However, whether BAs promote cancer invasiveness has not been elucidated. We evaluated the role of BAs, in particular deoxycholic acid (DCA), in OAC invasion. Migration and invasiveness in untreated and BA-treated oesophageal SKGT-4 cancer cells were evaluated. Activity and expression of different matrix metalloproteinases (MMPs) were determined by zymography, ELISA, PCR and Western blot. Finally, human OAC tissues were stained for MMP-10 by immunohistochemistry. It was found that SKGT-4 cells incubated with low concentrations of DCA had a significant increase in invasion. In addition, MMP-10 mRNA and protein expression were also increased in the presence of DCA. MMP-10 was found to be highly expressed both in-vitro and in-vivo in neoplastic OAC cells relative to non-neoplastic squamous epithelial cells. Our results show that DCA promotes OAC invasion and MMP-10 overexpression. This study will advance our understanding of the pathophysiological mechanisms involved in human OAC and shows promise for the development of new therapeutic strategies.<\/jats:p>","DOI":"10.3390\/ijms21218042","type":"journal-article","created":{"date-parts":[[2020,10,28]],"date-time":"2020-10-28T11:43:06Z","timestamp":1603885386000},"page":"8042","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Impact of Deoxycholic Acid on Oesophageal Adenocarcinoma Invasion: Effect on Matrix Metalloproteinases"],"prefix":"10.3390","volume":"21","author":[{"given":"Fran","family":"Quilty","sequence":"first","affiliation":[{"name":"School of Pharmacy and Pharmaceutical Sciences, Trinity Biomedical Sciences Institute, Trinity College Dublin, 2 Dublin, Ireland"},{"name":"School of Medicine, Trinity Translational Medicine Institute, Trinity College Dublin, Trinity Centre for Health Sciences, St James\u2019s Hospital, 8 Dublin, Ireland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anne-Marie","family":"Byrne","sequence":"additional","affiliation":[{"name":"School of Pharmacy and Pharmaceutical Sciences, Trinity Biomedical Sciences Institute, Trinity College Dublin, 2 Dublin, Ireland"},{"name":"School of Medicine, Trinity Translational Medicine Institute, Trinity College Dublin, Trinity Centre for Health Sciences, St James\u2019s Hospital, 8 Dublin, Ireland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John","family":"Aird","sequence":"additional","affiliation":[{"name":"Department of Histopathology and Morbid Anatomy, School of Medicine, Trinity College Dublin, 2 Dublin, Ireland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sheeren","family":"El Mashad","sequence":"additional","affiliation":[{"name":"Cork Cancer Research Centre, BioSciences Institute, University College, T12 YN60 Cork, Ireland"},{"name":"National Liver Institute, Menoufiya University, Shebin El Kom, Egypt"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adolfo","family":"Parra-Blanco","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham NG11 8NF, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aideen","family":"Long","sequence":"additional","affiliation":[{"name":"School of Medicine, Trinity Translational Medicine Institute, Trinity College Dublin, Trinity Centre for Health Sciences, St James\u2019s Hospital, 8 Dublin, Ireland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John F","family":"Gilmer","sequence":"additional","affiliation":[{"name":"School of Pharmacy and Pharmaceutical Sciences, Trinity Biomedical Sciences Institute, Trinity College Dublin, 2 Dublin, Ireland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carlos","family":"Medina","sequence":"additional","affiliation":[{"name":"School of Pharmacy and Pharmaceutical Sciences, Trinity Biomedical Sciences Institute, Trinity College Dublin, 2 Dublin, Ireland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,10,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1698","DOI":"10.1007\/s00268-017-3957-z","article-title":"From Heartburn to Barrett\u2019s Esophagus, and Beyond","volume":"41","author":"Schlottmann","year":"2017","journal-title":"World J. Surg."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1053\/gast.2000.9302","article-title":"Is there publication bias in the reporting of cancer risk in Barrett\u2019s esophagus?","volume":"119","author":"Shaheen","year":"2000","journal-title":"Gastroenterology"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1111\/j.1572-0241.1999.00776.x","article-title":"Adenocarcinoma of the esophagus and Barrett\u2019s esophagus: a population-based study","volume":"94","author":"Bytzer","year":"1999","journal-title":"Am. J. Gastroenterol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1042\/bj0890057","article-title":"The Function of Bile Sats in Fat Absorption. The Solvent Properties of Dilute Micellar Solutions of Conjugated Biles Salts","volume":"89","author":"Hofmann","year":"1963","journal-title":"Biochem. J."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1016\/S0022-2275(20)43070-6","article-title":"Bacterial 7-dehydroxylation of cholic acid and allocholic acid","volume":"10","author":"Bokkenheuser","year":"1969","journal-title":"J. Lipid Res."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Straub, D., Elferink, R.P.J.O., Jansen, P.L.M., Bergman, J.J.G.H.M., Parikh, K., and Krishnadath, K.K. (2019). Glyco-conjugated bile acids drive the initial metaplastic gland formation from multi-layered glands through crypt-fission in a murine model. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0220050"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1111\/j.1365-2036.2011.04709.x","article-title":"Systematic review: the role of bile acids in the pathogenesis of gastro-oesophageal reflux disease and related neoplasia","volume":"34","author":"McQuaid","year":"2011","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1257","DOI":"10.1111\/j.1572-0241.2005.41338.x","article-title":"Proinflammatory Cytokine and Nuclear Factor Kappa-B Expression along the Inflammation-Metaplasia-Dysplasia-Adenocarcinoma Sequence in the Esophagus","volume":"100","author":"Ravi","year":"2005","journal-title":"Am. J. Gastroenterol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1232","DOI":"10.1136\/jcp.2006.043976","article-title":"Immunohistochemical study of nuclear factor-kappaB activity and interleukin-8 abundance in oesophageal adenocarcinoma; a useful strategy for monitoring these biomarkers","volume":"60","author":"Jenkins","year":"2007","journal-title":"J. Clin. Pathol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1042","DOI":"10.1136\/gutjnl-2013-305533","article-title":"In oesophageal squamous cells exposed to acidic bile salt medium, omeprazole inhibits IL-8 expression through effects on nuclear factor-\u03baB and activator protein-1","volume":"63","author":"Huo","year":"2014","journal-title":"Gut"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"G278","DOI":"10.1152\/ajpgi.00092.2011","article-title":"Deoxycholic acid causes DNA damage while inducing apoptotic resistance through NF-\u03baB activation in benign Barrett\u2019s epithelial cells","volume":"301","author":"Huo","year":"2011","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1007\/s11605-007-0174-3","article-title":"The Pathogenesis of Barrett\u2019s Esophagus: Secondary Bile Acids Upregulate Intestinal Differentiation Factor CDX2 Expression in Esophageal Cells","volume":"11","author":"Hu","year":"2007","journal-title":"J. Gastrointest. Surg."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1111\/j.1432-0436.2006.00074.x","article-title":"The intestine-specific homeobox gene Cdx2 induces expression of the basic helix\u2013loop\u2013helix transcription factor Math1","volume":"74","author":"Mutoh","year":"2006","journal-title":"Differentiation"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1046\/j.1365-2559.1999.00791.x","article-title":"Expression of MUC1 and MUC2 mucin gene products in Barrett\u2019s metaplasia, dysplasia and adenocarcinoma: An immunopathological study with clinical correlation","volume":"35","author":"Chinyama","year":"1999","journal-title":"Histopathology"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Wu, J., Gong, J., Geng, J., and Song, Y. (2008). Deoxycholic acid induces the overexpression of intestinal mucin, MUC2, via NF-kB signaling pathway in human esophageal adenocarcinoma cells. BMC Cancer, 8.","DOI":"10.1186\/1471-2407-8-333"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1097\/01.sla.0000130850.31178.8c","article-title":"Impact of the Biliary Diversion Procedure on Carcinogenesis in Barrett\u2019s Esophagus Surgically Induced by Duodenoesophageal Reflux in Rats","volume":"240","author":"Nishijima","year":"2004","journal-title":"Ann. Surg."},{"key":"ref_17","first-page":"1384","article-title":"Bile acids but not acidic acids induce Barrett\u2019s esophagus","volume":"8","author":"Sun","year":"2015","journal-title":"Int. J. Clin. Exp. Pathol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1007\/BF03032599","article-title":"The role of matrix metalloproteinases in tumor angiogenesis and tumor metastasis","volume":"7","author":"John","year":"2001","journal-title":"Pathol. Oncol. Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"609","DOI":"10.2174\/156652411797536705","article-title":"Roles of Metalloproteases in Metastatic Niche","volume":"11","author":"Sanita","year":"2011","journal-title":"Curr. Mol. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1016\/S1055-3207(18)30071-1","article-title":"The Role of Matrix Metalloproteinases in Tumor Invasion, Metastasis, and Angiogenesis","volume":"10","year":"2001","journal-title":"Surg. Oncol. Clin. North Am."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12885-019-5996-3","article-title":"Silencing microRNA-330-5p increases MMP1 expression and promotes an invasive phenotype in oesophageal adenocarcinoma","volume":"19","author":"Bibby","year":"2019","journal-title":"BMC Cancer"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1186\/1479-5876-8-99","article-title":"MMP-1 is a (pre-)invasive factor in Barrett-associated esophageal adenocarcinomas and is associated with positive lymph node status","volume":"8","author":"Grimm","year":"2010","journal-title":"J. Transl. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1779","DOI":"10.3892\/or.2017.5426","article-title":"Interleukin-17A promotes esophageal adenocarcinoma cell invasiveness through ROS-dependent, NF-\u03baB-mediated MMP-2\/9 activation","volume":"37","author":"Liu","year":"2017","journal-title":"Oncol. Rep."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e13683","DOI":"10.14814\/phy2.13683","article-title":"Matrix metalloproteinase (MMP)-7 in Barrett\u2019s esophagus and esophageal adenocarcinoma: Expression, metabolism, and functional significance","volume":"6","author":"Garalla","year":"2018","journal-title":"Physiol. Rep."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1002\/mc.21840","article-title":"MMP9 expression in oesophageal adenocarcinoma is upregulated with visceral obesity and is associated with poor tumour differentiation","volume":"52","author":"Allott","year":"2013","journal-title":"Mol. Carcinog."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1669","DOI":"10.1093\/carcin\/bgq130","article-title":"Nitric oxide-mediated invasion in Barrett\u2019s high-grade dysplasia and adenocarcinoma","volume":"31","author":"Clemons","year":"2010","journal-title":"Carcinogenesis"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1042\/bj3490189","article-title":"Lithocholic acid and sulphated lithocholic acid differ in the ability to promote matrix metalloproteinase secretion in the human colon cancer cell line CaCo-2","volume":"349","author":"Halvorsen","year":"2000","journal-title":"Biochem. J."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"598","DOI":"10.1136\/gut.44.5.598","article-title":"Toxic bile acids in gastro-oesophageal reflux disease: Influence of gastric acidity","volume":"44","author":"Nehra","year":"1999","journal-title":"Gut"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1930","DOI":"10.1111\/j.1742-4658.2006.05206.x","article-title":"The calcium-binding domain of the stress protein SEP53 is required for survival in response to deoxycholic acid-mediated injury","volume":"273","author":"Darragh","year":"2006","journal-title":"FEBS J."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1093\/carcin\/bgt332","article-title":"Mechanisms of platelet-stimulated colon cancer invasion: Role of clusterin and thrombospondin 1 in regulation of the P38MAPK-MMP-9 pathway","volume":"35","author":"Corbalan","year":"2014","journal-title":"Carcinogenesis"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2156","DOI":"10.1091\/mbc.e03-12-0894","article-title":"Deoxycholic acid activates beta-catenin signaling pathway and increases colon cell cancer growth and invasiveness","volume":"15","author":"Pai","year":"2004","journal-title":"Mol. Biol. Cell"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1007\/s00441-009-0892-9","article-title":"Interstitial cell migration: Integrin-dependent and alternative adhesion mechanisms","volume":"339","author":"Schmidt","year":"2010","journal-title":"Cell Tissue Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1069","DOI":"10.1083\/jcb.201210152","article-title":"Physical limits of cell migration: Control by ECM space and nuclear deformation and tuning by proteolysis and traction force","volume":"201","author":"Wolf","year":"2013","journal-title":"J. Cell Biol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/j.cell.2010.03.015","article-title":"Matrix metalloproteinases: Regulators of the tumor microenvironment","volume":"141","author":"Kessenbrock","year":"2010","journal-title":"Cell"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1147","DOI":"10.1158\/1535-7163.MCT-17-0646","article-title":"Matrix Metalloproteinase Inhibitors in Cancer Therapy: Turning Past Failures into Future Successes","volume":"17","author":"Winer","year":"2018","journal-title":"Mol. Cancer Ther."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Kim, T.-D., Song, K.-S., Li, G., Choi, H., Park, H.-D., Lim, K., Hwang, B.-D., and Yoon, W.-H. (2006). Activity and expression of urokinase-type plasminogen activator and matrix metalloproteinases in human colorectal cancer. BMC Cancer, 6.","DOI":"10.1186\/1471-2407-6-211"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"936","DOI":"10.1093\/carcin\/bgq036","article-title":"An integrative genomic approach in oesophageal cells identifies TRB3 as a bile acid responsive gene, downregulated in Barrett\u2019s oesophagus, which regulates NF-\u03baB activation and cytokine levels","volume":"31","author":"Duggan","year":"2010","journal-title":"Carcinogenesis"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1186\/1479-5876-8-91","article-title":"Increased matrix metalloproteinase activation in esophageal squamous cell carcinoma","volume":"8","author":"Mukherjee","year":"2010","journal-title":"J. Transl. Med."},{"key":"ref_39","first-page":"63","article-title":"Esophageal cancer: Matrix metalloproteinase 10 is associated with survival in patients with esophageal squamous cell carcinoma","volume":"9","author":"Greenhill","year":"2012","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1038\/bjc.1989.252","article-title":"Appraisal of the MTT assay as a rapid test of chemosensitivity in acute myeloid leukaemia","volume":"60","author":"Sargent","year":"1989","journal-title":"Br. J. Cancer"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method","volume":"25","author":"Livak","year":"2001","journal-title":"Methods"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1111\/bph.13712","article-title":"Inhibition of matrix metalloproteinase-9 by a barbiturate-nitrate hybrid ameliorates dextran sulphate sodium-induced colitis: Effect on inflammation-related genes","volume":"174","author":"Wang","year":"2017","journal-title":"Br. J. Pharmacol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/21\/8042\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:30:06Z","timestamp":1760178606000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/21\/8042"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,10,28]]},"references-count":42,"journal-issue":{"issue":"21","published-online":{"date-parts":[[2020,11]]}},"alternative-id":["ijms21218042"],"URL":"https:\/\/doi.org\/10.3390\/ijms21218042","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,10,28]]}}}