title: Low miR-187 expression promotes resistance to chemoradiation therapy in vitro and correlates with treatment failure in patients with esophageal adenocarcinoma.
abstract: Esophageal adenocarcinoma (EAC) has a poor prognosis and is increasing in incidence in many western populations. Neoadjuvant chemoradiation therapy (CRT) followed by surgery is increasingly the standard of care for locally advanced EAC; however, resistance to treatment is a significant clinical problem. The identification of both novel biomarkers predicting response to treatment and novel therapeutic targets to enhance the efficacy of CRT are key to improving survival rates in EAC. In this study we performed global microRNA (miRNA) profiling of pre-treatment EAC biopsies and identified 67 miRNA significantly altered in patients who are resistant to CRT. One of these miRNA, miR-187, was significantly decreased in pre-treatment EAC tumors from patients having a poor response to neoadjuvant CRT, highlighting downregulation of miR-187 as a potential mechanism of treatment resistance in EAC. In vitro, miR-187 was demonstrated to play a functional role in modulating sensitivity to X-ray radiation and cisplatin in EAC and its dysregulation was demonstrated to be due to chromosomal alterations. In vitro, miR-187 altered expression of a diverse array of pathways, including the immune regulator complement component 3 (C3), serum levels of which we have previously demonstrated to predict patient response to CRT. In vivo, expression of C3 was significantly increased in tumors from patients having a poor response to CRT. This study highlights for the first time a role for miR-187 as a novel biomarker of response to CRT and a potential therapeutic target for enhancing the efficacy of CRT in EAC.
authors.affiliation: University of Dublin Trinity College, Dublin, Ireland.
authors.forename: Niamh
authors.initials: N
authors.lastname: Lynam-Lennon
authors.affiliation: University of Hull, Hull, Kingston upon Hull, United Kingdom of Great Britain and Northern Ireland.
authors.forename: Becky A
authors.initials: BA
authors.lastname: Bibby
authors.affiliation: University of Dublin Trinity College, Dublin, Ireland.
authors.forename: Ann Marie
authors.initials: AM
authors.lastname: Mongan
authors.affiliation: University of Dublin Trinity College, Dublin, Ireland.
authors.forename: Laure
authors.initials: L
authors.lastname: Marignol
authors.affiliation: Arup Institute for Clinical and Experimental Pathology, United States.
authors.forename: Christian N
authors.initials: CN
authors.lastname: Paxton
authors.affiliation: University of Utah and ARUP Laboratories, United States.|Arup Institute for Clinical and Experimental Pathology, United States.
authors.forename: Katherine
authors.initials: K
authors.lastname: Geiersbach
authors.affiliation: University of Utah and ARUP Laboratories, United States.|Arup Institute for Clinical and Experimental Pathology, United States.
authors.forename: Mary P
authors.initials: MP
authors.lastname: Bronner
authors.affiliation: University of Dublin Trinity College, Dublin, Ireland.
authors.forename: Jacintha
authors.initials: J
authors.lastname: O'Sullivan
authors.affiliation: University of Dublin Trinity College, Dublin, Ireland.
authors.forename: John
authors.initials: J
authors.lastname: Reynolds
authors.affiliation: University of Dublin Trinity College, Dublin, Ireland.|University of Hull, Hull, Kingston upon Hull, United Kingdom of Great Britain and Northern Ireland.
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Maher
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics* / Q000532:radiotherapy; D000328:Adult; D000368:Aged; D045744:Cell Line, Tumor; D059248:Chemoradiotherapy; D002945:Cisplatin / Q000494:pharmacology*; D003176:Complement C3 / Q000235:genetics*; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D004938:Esophageal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000532:radiotherapy; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged
chemical_list: C038245:C3 protein, human; D003176:Complement C3; C571843:MIRN187 microRNA, human; D035683:MicroRNAs; D002945:Cisplatin
keywords: Chemoradiation Therapy; Predictive biomarker; gastroenterology; microRNA; oncology