title: MicroRNA-17 is downregulated in esophageal adenocarcinoma cancer stem-like cells and promotes a radioresistant phenotype.
abstract: Resistance to neoadjuvant chemoradiation therapy (CRT) remains a critical barrier to the effective treatment of esophageal adenocarcinoma (EAC). Cancer stem-like cells (CSCs) are a distinct subpopulation of cells implicated in the resistance of tumors to anti-cancer therapy. However, their role in the resistance of EAC to CRT is largely unknown. In this study, using a novel in vitro isogenic model of radioresistant EAC, we demonstrate that radioresistant EAC cells have enhanced tumorigenicity in vivo, increased expression of CSC-associated markers and enhanced holoclone forming ability. Further investigation identified a subpopulation of cells that are characterised by high aldehyde dehydrogenase (ALDH) activity, enhanced radioresistance and decreased expression of miR-17-5p. In vitro, miR-17-5p was demonstrated to significantly sensitise radioresistant cells to X-ray radiation and promoted the repression of genes with miR-17-5p binding sites, such as C6orf120. In vivo, miR-17-5p was significantly decreased, whilst C6orf120 was significantly increased, in pre-treatment EAC tumour samples from patients who demonstrated a poor response to neoadjuvant CRT. This study sheds novel insights into the role of CSCs in the resistance of EAC to CRT and highlights miR-17-5p as a potential biomarker of CRT sensitivity and novel therapeutic target in treatment resistant EAC.
authors.affiliation: Trinity Translational Medicine Institute, Department of Surgery, Trinity College Dublin, St James's Hospital, Dublin 8, Ireland.
authors.forename: Niamh
authors.initials: N
authors.lastname: Lynam-Lennon
authors.affiliation: Trinity Translational Medicine Institute, Department of Surgery, Trinity College Dublin, St James's Hospital, Dublin 8, Ireland.
authors.forename: Susan
authors.initials: S
authors.lastname: Heavey
authors.affiliation: Trinity Translational Medicine Institute, Department of Surgery, Trinity College Dublin, St James's Hospital, Dublin 8, Ireland.
authors.forename: Gary
authors.initials: G
authors.lastname: Sommerville
authors.affiliation: Cancer Biology and Therapeutics Lab, School of Life Sciences, University of Hull, Hull, United Kingdom.
authors.forename: Becky A S
authors.initials: BA
authors.lastname: Bibby
authors.affiliation: Department of Histopathology, Trinity College Dublin, Sir Patrick Dun Laboratory, Central Pathology Laboratory, St James's Hospital, Dublin 8, Ireland.|Molecular Pathology Laboratory, Coombe Women and Infant's University Hospital, Dublin 8, Ireland.
authors.forename: Brendan
authors.initials: B
authors.lastname: Ffrench
authors.affiliation: Trinity Translational Medicine Institute, Department of Surgery, Trinity College Dublin, St James's Hospital, Dublin 8, Ireland.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Quinn
authors.affiliation: Department of Histopathology, Trinity College Dublin, Sir Patrick Dun Laboratory, Central Pathology Laboratory, St James's Hospital, Dublin 8, Ireland.|Molecular Pathology Laboratory, Coombe Women and Infant's University Hospital, Dublin 8, Ireland.
authors.forename: Claudia
authors.initials: C
authors.lastname: Gasch
authors.affiliation: Department of Histopathology, Trinity College Dublin, Sir Patrick Dun Laboratory, Central Pathology Laboratory, St James's Hospital, Dublin 8, Ireland.|Molecular Pathology Laboratory, Coombe Women and Infant's University Hospital, Dublin 8, Ireland.
authors.forename: John J
authors.initials: JJ
authors.lastname: O'Leary
authors.affiliation: Department of Histopathology, Trinity College Dublin, Sir Patrick Dun Laboratory, Central Pathology Laboratory, St James's Hospital, Dublin 8, Ireland.|Molecular Pathology Laboratory, Coombe Women and Infant's University Hospital, Dublin 8, Ireland.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Gallagher
authors.affiliation: Trinity Translational Medicine Institute, Department of Surgery, Trinity College Dublin, St James's Hospital, Dublin 8, Ireland.
authors.forename: John V
authors.initials: JV
authors.lastname: Reynolds
authors.affiliation: Trinity Translational Medicine Institute, Department of Surgery, Trinity College Dublin, St James's Hospital, Dublin 8, Ireland.|Cancer Biology and Therapeutics Lab, School of Life Sciences, University of Hull, Hull, United Kingdom.
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Maher
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D045744:Cell Line, Tumor; D002469:Cell Separation; D015536:Down-Regulation; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D064593:Heterografts; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D016133:Polymerase Chain Reaction; D011836:Radiation Tolerance / Q000235:genetics*; D059467:Transcriptome
chemical_list: C524941:MIRN17 microRNA, human; D035683:MicroRNAs
keywords: cancer stem-like cells; esophageal adenocarcinoma; microRNA; predictive biomarker; radioresistance