دورية أكاديمية
Hypoxia-inducible factor-1α mediates reflux-induced epithelial-mesenchymal plasticity in Barrett's oesophagus patients.
| العنوان: | Hypoxia-inducible factor-1α mediates reflux-induced epithelial-mesenchymal plasticity in Barrett's oesophagus patients. |
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| المؤلفون: | Zhang Q; Department of Medicine, Baylor University Medical Center, Dallas, Texas, USA.; Center for Esophageal Research, Baylor Scott & White Research Institute, Dallas, Texas, USA., Dunbar KB; Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA.; Internal Medicine, VA North Texas Health Care System, Dallas, Texas, USA., Odze RD; Department of Pathology, Tufts Medical Center, Boston, Massachusetts, USA.; Robert D Odze Pathology, LLC, Boston, Massachusetts, USA., Agoston AT; Department of Pathology, Brigham and Womens Hospital, Boston, Massachusetts, USA., Wang X; Biostatistics Core, Baylor Scott & White Research Insitute, Dallas, Texas, USA., Su T; Department of Oncology, Sun Yat-sen University First Affiliated Hospital, Guangzhou, Guangdong, China., Nguyen AD; Department of Medicine, Baylor University Medical Center, Dallas, Texas, USA.; Center for Esophageal Research, Baylor Scott & White Research Institute, Dallas, Texas, USA., Zhang X; Department of Medicine, Baylor University Medical Center, Dallas, Texas, USA.; Center for Esophageal Research, Baylor Scott & White Research Institute, Dallas, Texas, USA., Spechler SJ; Department of Medicine, Baylor University Medical Center, Dallas, Texas, USA.; Center for Esophageal Research, Baylor Scott & White Research Institute, Dallas, Texas, USA., Souza RF; Department of Medicine, Baylor University Medical Center, Dallas, Texas, USA rhonda.souza@verizon.net.; Center for Esophageal Research, Baylor Scott & White Research Institute, Dallas, Texas, USA. |
| المصدر: | Gut [Gut] 2024 Jul 11; Vol. 73 (8), pp. 1269-1279. Date of Electronic Publication: 2024 Jul 11. |
| نوع المنشور: | Clinical Study; Journal Article; Research Support, Non-U.S. Gov't; Research Support, N.I.H., Extramural |
| اللغة: | English |
| بيانات الدورية: | Publisher: British Medical Assn Country of Publication: England NLM ID: 2985108R Publication Model: Electronic Cited Medium: Internet ISSN: 1468-3288 (Electronic) Linking ISSN: 00175749 NLM ISO Abbreviation: Gut Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: London, British Medical Assn. |
| مواضيع طبية MeSH: | Barrett Esophagus*/pathology , Barrett Esophagus*/metabolism , Barrett Esophagus*/genetics , Epithelial-Mesenchymal Transition* , Hypoxia-Inducible Factor 1, alpha Subunit*/metabolism , Proton Pump Inhibitors*/pharmacology, Aged ; Female ; Humans ; Male ; Middle Aged ; Cell Movement ; Esophagitis, Peptic/pathology ; Esophagitis, Peptic/metabolism ; Esophagitis, Peptic/etiology ; Gastroesophageal Reflux/metabolism ; Gastroesophageal Reflux/complications ; Gastroesophageal Reflux/pathology ; MicroRNAs/genetics ; MicroRNAs/metabolism ; Vascular Endothelial Growth Factor A/metabolism ; Zinc Finger E-box-Binding Homeobox 1/metabolism ; Zinc Finger E-box-Binding Homeobox 1/genetics |
| مستخلص: | Introduction: Epithelial-mesenchymal plasticity (EMP), the process through which epithelial cells acquire mesenchymal features, is needed for wound repair but also might contribute to cancer initiation. Earlier, in vitro studies showed that Barrett's cells exposed to acidic bile salt solutions (ABS) develop EMP. Now, we have (1) induced reflux oesophagitis in Barrett's oesophagus (BO) patients by stopping proton pump inhibitors (PPIs), (2) assessed their biopsies for EMP and (3) explored molecular pathways underlying reflux-induced EMP in BO cells and spheroids. Methods: 15 BO patients had endoscopy with biopsies of Barrett's metaplasia while on PPIs, and 1 and 2 weeks after stopping PPIs; RNA-seq data were assessed for enrichments in hypoxia-inducible factors (HIFs), angiogenesis and EMP pathways. In BO biopsies, cell lines and spheroids, EMP features (motility) and markers (vascular endothelial growth factor (VEGF), ZEB1, miR-200a&b) were evaluated by morphology, migration assays, immunostaining and qPCR; HIF-1α was knocked down with siRNA or shRNA. Results: At 1 and/or 2 weeks off PPIs, BO biopsies exhibited EMP features and markers, with significant enrichment for HIF-1α, angiogenesis and EMP pathways. In BO cells, ABS induced HIF-1α activation, which decreased miR-200a&b while increasing VEGF, ZEB1 and motility; HIF-1α knockdown blocked these effects. After ABS treatment, BO spheroids exhibited migratory protrusions showing nuclear HIF-1α, increased VEGF and decreased miR-200a&b. Conclusions: In BO patients, reflux oesophagitis induces EMP changes associated with increased HIF-1α signalling in Barrett's metaplasia. In Barrett's cells, ABS trigger EMP via HIF-1α signalling. Thus, HIF-1α appears to play a key role in mediating reflux-induced EMP that might contribute to cancer in BO. Trial Registration Number: NCT02579460. Competing Interests: Competing interests: None declared. (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.) |
| References: | PLoS One. 2012;7(12):e50165. (PMID: 23272057) Gut. 2002 Sep;51(3):316-22. (PMID: 12171950) Toxicol In Vitro. 2020 Jun;65:104787. (PMID: 32004541) Mol Cells. 2010 May;29(5):435-42. (PMID: 20396958) Cell Mol Gastroenterol Hepatol. 2018 Jun 27;6(4):389-404. (PMID: 30186929) J Physiol. 2008 Sep 1;586(17):4055-9. (PMID: 18599532) Clin Gastroenterol Hepatol. 2014 Mar;12(3):405-10. (PMID: 23891922) Dis Esophagus. 2007;20(3):256-64. (PMID: 17509124) Am J Gastroenterol. 2015 Oct;110(10):1412-9. (PMID: 26346864) World J Gastroenterol. 2011 Feb 28;17(8):1036-44. (PMID: 21448356) Gastroenterology. 2019 Jan;156(1):130-144.e10. (PMID: 30268789) Nat Rev Cancer. 2021 May;21(5):325-338. (PMID: 33547455) Nat Rev Genet. 2023 Sep;24(9):590-609. (PMID: 37169858) Carcinogenesis. 2008 Dec;29(12):2267-78. (PMID: 18791199) Am J Physiol Gastrointest Liver Physiol. 2022 Jun 1;322(6):G598-G614. (PMID: 35380457) Exp Cell Res. 2010 Feb 15;316(4):554-67. (PMID: 20006606) Nature. 2021 Jan;589(7842):448-455. (PMID: 33328637) Oncogene. 2009 Aug;28 Suppl 1:S14-23. (PMID: 19680292) Gut. 2017 Sep;66(9):1542-1554. (PMID: 27694141) Gastrointest Endosc. 2012 Jul;76(1):32-40. (PMID: 22482920) Cancer Res. 2015 Jul 1;75(13):2749-59. (PMID: 25948589) Am J Gastroenterol. 2011 Nov;106(11):1899-908; quiz 1909. (PMID: 21826111) Nature. 2018 Apr;556(7702):463-468. (PMID: 29670281) Nat Rev Mol Cell Biol. 2020 Jun;21(6):341-352. (PMID: 32300252) Oncotarget. 2015 Mar 30;6(9):6472-98. (PMID: 25762624) PLoS One. 2010 Sep 30;5(9):. (PMID: 20927195) EMBO Mol Med. 2009 Sep;1(6-7):303-14. (PMID: 20049734) J Clin Oncol. 2003 Oct 15;21(20):3798-807. (PMID: 12953099) |
| معلومات مُعتمدة: | I01 CX001668 United States CX CSRD VA; P30 CA006516 United States CA NCI NIH HHS; R01 DK103598 United States DK NIDDK NIH HHS; R01 DK124185 United States DK NIDDK NIH HHS |
| فهرسة مساهمة: | Keywords: BARRETT'S METAPLASIA; CANCER; CELL MIGRATION; GASTROESOPHAGEAL REFLUX DISEASE |
| سلسلة جزيئية: | ClinicalTrials.gov NCT02579460 |
| المشرفين على المادة: | 0 (HIF1A protein, human) 0 (Hypoxia-Inducible Factor 1, alpha Subunit) 0 (MicroRNAs) 0 (MIRN200 microRNA, human) 0 (Proton Pump Inhibitors) 0 (Vascular Endothelial Growth Factor A) 0 (ZEB1 protein, human) 0 (Zinc Finger E-box-Binding Homeobox 1) |
| تواريخ الأحداث: | Date Created: 20240419 Date Completed: 20240711 Latest Revision: 20240805 |
| رمز التحديث: | 20240806 |
| مُعرف محوري في PubMed: | PMC11239289 |
| DOI: | 10.1136/gutjnl-2023-331467 |
| PMID: | 38641363 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 1468-3288 |
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| DOI: | 10.1136/gutjnl-2023-331467 |