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

• Published in: Oncotarget 2017-02, Vol.8 (7), p.11400-11413
• Main Authors: Lynam-Lennon, Niamh, Heavey, Susan, Sommerville, Gary, Bibby, Becky A S, Ffrench, Brendan, Quinn, Jennifer, Gasch, Claudia, O'Leary, John J, Gallagher, Michael F, Reynolds, John V, Maher, Stephen G
• Format: Article
• Language: English
• Subjects: Adenocarcinoma - genetics; Adenocarcinoma - metabolism; Adenocarcinoma - pathology; Animals; Cell Line, Tumor; Cell Separation; Down-Regulation; Esophageal Neoplasms - genetics; Esophageal Neoplasms - metabolism; Esophageal Neoplasms - pathology; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic - genetics; Heterografts; Humans; Mice; Mice, Inbred NOD; Mice, SCID; MicroRNAs - biosynthesis; MicroRNAs - genetics; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Polymerase Chain Reaction; Radiation Tolerance - genetics; Research Paper; Transcriptome
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.13940

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.