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.
Highlights
In recent decades, there has been a dramatic epidemiological shift in the incidence of esophageal adenocarcinoma (EAC), with rates rising by 600% over the last 30 years in Western populations [1]
We demonstrate for the first time the dysregulated expression of miR-187 in EAC tumors from patients resistant to neoadjuvant chemoradiation therapy (CRT) and importantly demonstrate a functional role for miR-187 in modulating the response of EAC to radiation and cisplatin
In this study, we performed global miRNA profiling of EAC patient tumors to identify miRNAs that may be involved in tumor resistance to neoadjuvant CRT
Summary
There has been a dramatic epidemiological shift in the incidence of esophageal adenocarcinoma (EAC), with rates rising by 600% over the last 30 years in Western populations [1]. EAC is the predominant histological subtype of esophageal cancer in Europe and the United States [2]. This increase is linked to lifestyle factors, such as obesity, and incidence is expected to increase at a similar rate in the coming decades [3]. Tumor response to neoadjuvant CRT is the best predictor of overall and disease-free survival, with the attainment of a complete pathological response (pCR) associated with a 5-year survival rate of up to 60% [5]. A pCR is observed in only approximately 30% of patients receiving neoadjuvant CRT [6]. There are currently no alternative treatment strategies for this majority of EAC patients
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