MicroRNA-17 is downregulated in esophageal adenocarcinoma cancer stem-like cells and promotes a radioresistant phenotype
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Niamh Lynam-Lennon1, Susan Heavey1, Gary Sommerville1, Becky A.S. Bibby2, Brendan Ffrench3,4, Jennifer Quinn1, Claudia Gasch3,4, John J. O’Leary3,4, Michael F. Gallagher3,4, John V. Reynolds1, Stephen G. Maher1,2
1Trinity Translational Medicine Institute, Department of Surgery, Trinity College Dublin, St James’s Hospital, Dublin 8, Ireland
2Cancer Biology and Therapeutics Lab, School of Life Sciences, University of Hull, Hull, United Kingdom
3Department of Histopathology, Trinity College Dublin, Sir Patrick Dun Laboratory, Central Pathology Laboratory, St James's Hospital, Dublin 8, Ireland
4Molecular Pathology Laboratory, Coombe Women and Infant's University Hospital, Dublin 8, Ireland
Stephen G. Maher, email: firstname.lastname@example.org
Keywords: esophageal adenocarcinoma, radioresistance, cancer stem-like cells, microRNA, predictive biomarker
Received: July 28, 2016 Accepted: November 21, 2016 Published: December 15, 2016
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.
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