MicroRNA-17 is downregulated in esophageal adenocarcinoma cancer stem-like cells and promotes a radioresistant phenotype

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// Niamh Lynam-Lennon 1 , Susan Heavey 1 , Gary Sommerville 1 , Becky A.S. Bibby 2 , Brendan Ffrench 3, 4 , Jennifer Quinn 1 , Claudia Gasch 3, 4 , John J. O’Leary 3, 4 , Michael F. Gallagher 3, 4 , John V. Reynolds 1 , Stephen G. Maher 1, 2 1 Trinity Translational Medicine Institute, Department of Surgery, Trinity College Dublin, St James’s Hospital, Dublin 8, Ireland 2 Cancer Biology and Therapeutics Lab, School of Life Sciences, University of Hull, Hull, United Kingdom 3 Department of Histopathology, Trinity College Dublin, Sir Patrick Dun Laboratory, Central Pathology Laboratory, St James's Hospital, Dublin 8, Ireland 4 Molecular Pathology Laboratory, Coombe Women and Infant's University Hospital, Dublin 8, Ireland Correspondence to: Stephen G. Maher, email: maherst@tcd.ie Keywords: esophageal adenocarcinoma, radioresistance, cancer stem-like cells, microRNA, predictive biomarker Received: July 28, 2016 Accepted: November 21, 2016 Published: December 15, 2016 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.