MicroRNA-31 modulates tumour sensitivity to radiation in oesophageal adenocarcinoma.
Chemoradiation therapy (CRT) prior to surgery is increasingly the standard of care for locally advanced oesophageal cancer. Radiation therapy is important for local tumour control; however, tumour resistance to radiation is a substantial clinical problem. The mechanism(s) of radioresistance are still poorly understood, however, mounting evidence supports a role for microRNA (miRNA) in modulating key cellular pathways mediating response to radiation. Global miRNA profiling of an established isogenic model of radioresistance in oesophageal adenocarcinoma demonstrated a significant downregulation of miR-31 in radioresistant cells, both basally and in response to radiation. Ectopic re-expression of miR-31 significantly re-sensitised radioresistant cells to radiation. miR-31 was demonstrated to alter the expression of 13 genes involved in DNA repair, which is a critical cellular defence against radiation-induced DNA damage. In oesophageal tumours, miR-31 expression was significantly reduced in patients demonstrating poor histomorphologic response to neoadjuvant CRT, whilst expression of the miR-31-regulated DNA repair genes was significantly increased. Our data suggest a possible mechanism for resistance to CRT, potentially via enhanced DNA repair. This study demonstrates, for the first time, a role for miR-31 in modulating radioresistance and highlights the need for further study investigating the potential role of miR-31 as both a predictive marker of response and a novel therapeutic agent with which to enhance the efficacy of radiation therapy.
Department of Surgery, Trinity College Dublin, Trinity Centre for Health Sciences, St. James's Hospital, Dublin 8, Ireland.
Niamh
N
Lynam-Lennon
John V
JV
Reynolds
Laure
L
Marignol
Orla M
OM
Sheils
Graham P
GP
Pidgeon
Stephen G
SG
Maher
D000230:Adenocarcinoma / Q000235:genetics* / Q000532:radiotherapy*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000532:radiotherapy*; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics / Q000528:radiation effects; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D011836:Radiation Tolerance
C468783:H2AX protein, human; D006657:Histones; C534612:MIRN31 microRNA, human; D035683:MicroRNAs