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  • Hypoxia-inducible factor-1α mediates reflux-induced epithelial-mesenchymal plasticity in Barrett’s oesophagus patients

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Oesophagus
Original research
Hypoxia-inducible factor-1α mediates reflux-induced epithelial-mesenchymal plasticity in Barrett’s oesophagus patients
  1. Qiuyang Zhang1,2,
  2. Kerry B Dunbar3,4,
  3. Robert D Odze5,6,
  4. Agoston T Agoston7,
  5. Xuan Wang8,
  6. Tianhong Su9,
  7. Anh D Nguyen1,2,
  8. Xi Zhang1,2,
  9. Stuart Jon Spechler1,2,
  10. Rhonda F Souza1,2
  1. 1 Department of Medicine, Baylor University Medical Center, Dallas, Texas, USA
  2. 2 Center for Esophageal Research, Baylor Scott & White Research Institute, Dallas, Texas, USA
  3. 3 Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA
  4. 4 Internal Medicine, VA North Texas Health Care System, Dallas, Texas, USA
  5. 5 Department of Pathology, Tufts Medical Center, Boston, Massachusetts, USA
  6. 6 Robert D Odze Pathology, LLC, Boston, Massachusetts, USA
  7. 7 Department of Pathology, Brigham and Womens Hospital, Boston, Massachusetts, USA
  8. 8 Biostatistics Core, Baylor Scott & White Research Insitute, Dallas, Texas, USA
  9. 9 Department of Oncology, Sun Yat-sen University First Affiliated Hospital, Guangzhou, Guangdong, China
  1. Correspondence to Dr Rhonda F Souza, Center for Esophageal Research, Baylor University Medical Center, Dallas, Texas 75246, USA; rhonda.souza{at}verizon.net

Abstract

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.

  • GASTROESOPHAGEAL REFLUX DISEASE
  • BARRETT'S METAPLASIA
  • CANCER
  • CELL MIGRATION

Data availability statement

Data are available on reasonable request.

https://doi.org/10.1136/gutjnl-2023-331467

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    Data availability statement

    Data are available on reasonable request.

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    Footnotes

    • Contributors QZ: study design; technical and material support; analysis and interpretation of data; critical revision of manuscript; important intellectual content; drafting of manuscript; KD: technical and material support; analysis and interpretation of data; critical revision of manuscript; important intellectual content; RO: technical and material support; analysis and interpretation of data; critical revision of manuscript; important intellectual content; ATA: technical and material support; analysis and interpretation of data; critical revision of manuscript; important intellectual content; XW: analysis and interpretation of data; drafting of manuscript; important intellectual content; TS: technical and material support; analysis and interpretation of data; critical revision of manuscript; important intellectual content; AN: technical and material support; critical revision of manuscript; important intellectual content; XZ: technical and material support; important intellectual content; critical revision of manuscript; SJS: study concept; analysis and interpretation of data; critical revision of manuscript; important intellectual content; RFS: study concept/design; analysis and interpretation of data; critical revision of manuscript; important intellectual content; drafting of manuscript. RFS is the guarantor.

    • Funding This work was supported by the National Institutes of Health (R01-DK124185, R01-DK103598 to RFS and SJS), Baylor Scott & White Research Institute, the Merit Review Award CX001668 from the US Department of Veterans Affairs (VA) Clinical Science Research Program (to KD) and resources at the Dallas VA Medical Center.

    • Competing interests None declared.

    • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.