Preoperative chemoradiotherapy for rectal cancer: the sensitizer role of the association between miR-375 and c-Myc

Raquel Conde-Muiño,Antonio Herrera,Carlos Cano,Victoria Sánchez-Martín,Marta Cuadros,Pablo Palma,Pedro P Medina,Ana Comino

doi:10.18632/oncotarget.19393

Abstract

Administration of chemoradiation before tumor resection has revolutionized the management of locally advanced rectal cancer, but many patients have proven resistant to this preoperative therapy. Our group recently reported a negative correlation between c-Myc gene expression and this resistance. In the present study, integrated analysis of miRNA and mRNA expression profiles was conducted in 45 pre-treatment rectal tumors in order to analyze the expressions of miRNAs and c-Myc and their relationship with clinicopathological factors and patient survival. Twelve miRNAs were found to be differentially expressed by responders and non-responders to the chemoradiation. Functional classification revealed an association between the differentially expressed miRNAs and c-Myc. Quantitative real-time PCR results showed that miRNA-148 and miRNA-375 levels were both significantly lower in responders than in non-responders. Notably, a significant negative correlation was found between miRNA-375 expression and c-Myc expression. According to these findings, miRNA-375 and its targeted c-Myc may be useful as a predictive biomarker of the response to neoadjuvant treatment in patients with locally advanced rectal cancer.

Highlights

Standard treatment of locally advanced rectal cancer (LARC) includes 5-fluorouracil (5-FU) based neoadjuvant chemoradiotherapy (CT/RT) followed by surgery [1]
Administration of chemoradiation before tumor resection has revolutionized the management of locally advanced rectal cancer, but many patients have proven resistant to this preoperative therapy
Questions have been raised about this approach, given that a pathological complete response is reported in only a minority of patients

Summary

Introduction

Standard treatment of locally advanced rectal cancer (LARC) includes 5-fluorouracil (5-FU) based neoadjuvant chemoradiotherapy (CT/RT) followed by surgery [1]. The clinical effectiveness of 5-FU is limited by drug resistance [3], and novel strategies are required to increase its therapeutic effect and to determine the molecular mechanisms underlying the therapeutic response. This may enable the identification of patients who would respond to this treatment. MiRNAs act as negative regulators for mRNA expression via sequencecomplementary targeting of 3′-untranslated regions (3′UTRs) and other regions in order to repress translation or mediation of mRNA [6, 7] Because their target genes can control multiple biological processes, including apoptosis, proliferation, and differentiation, some miRNAs have been characterized as tumor suppressor genes or protooncogenes [8]. There is a very small overlap among reported sets of dysregulated markers, with only miR-21 [13, 16, 19] and miR-630 [15, 20] being described in common across published molecular signatures

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Conclusion