MicroRNA-193a-3p is specifically down-regulated and acts as a tumor suppressor in BRAF-mutated colorectal cancer

Hidekazu Takahashi,Kota Ouchi,Masanobu Takahashi,Yasuhide Yamada,Shin Takahashi,Yuki Yoshino,Shinobu Ohnuma,Michiaki Unno,Hideki Shimodaira,Chikashi Ishioka

doi:10.1186/s12885-017-3739-x

Abstract

BackgroundThe aim of this study was to identify miRNAs specifically dysregulated in BRAF-mutated colorectal cancer, which could lead to a better understanding of the molecular mechanisms underlying oncogenesis of this malignant subtype of colorectal cancer.MethodsCandidate dysregulated miRNAs were selected in genome-wide miRNA expression array analysis using a screening set composed of 15 BRAF-mutated and 15 non-KRAS/BRAF-mutated colorectal cancers. The miRNA expressions were validated in another set of patients. The functional roles of the miRNAs were analyzed by cell growth and invasion assays. The association between miRNA expression status and the clinical outcome of patients treated with various chemotherapies was analyzed.ResultsWithin the top five of the miRNAs screened, we validated miRNA-31 (miR-31) and miR-135b as up-regulated, while miR-193a-3p was down-regulated in BRAF-mutated cancer. Moreover, miR-193a-3p inhibited cell growth, and invasion of colorectal cancer cells. Low miR-193a-3p expression was associated with shorter progression-free survival in patients who received anti-EGFR therapy.ConclusionsOur results disclose a novel tumor suppressive role of miR-193a-3p in colorectal cancer. These results could lead to novel therapeutic strategies for colorectal cancer, particularly in BRAF-mutated colorectal cancer.

Highlights

The aim of this study was to identify miRNAs dysregulated in BRAF-mutated colorectal cancer, which could lead to a better understanding of the molecular mechanisms underlying oncogenesis of this malignant subtype of colorectal cancer
We aimed to identify miRNAs that are dysregulated in BRAF-mutant colorectal cancer using a genome-wide miRNA expression analysis, and to clarify whether these miRNAs play a role in colorectal tumorigenesis as an oncogene or a tumor-suppressor through functional assays using colorectal cancer cell lines
Screening of BRAF-mutant specific miRNAs We first analyzed the mutational status of KRAS and BRAF in colorectal cancers from our cohort of patients

Summary

Introduction

The aim of this study was to identify miRNAs dysregulated in BRAF-mutated colorectal cancer, which could lead to a better understanding of the molecular mechanisms underlying oncogenesis of this malignant subtype of colorectal cancer. RAF family kinases, including BRAF and RAF1, function downstream of RAS as critical regulators of the MEK-ERK MAP kinase signaling pathway [1]. This RAS-RAF-MEKERK cascade is a key pathway, which contributes to human oncogenesis controlling the cell cycle, proliferation, differentiation, angiogenesis, apoptosis, migration, and metastasis [2,3,4]. Several lines of evidence suggest that colorectal cancer containing a BRAF p.V600E mutation possesses more malignant potential when compared with other genotypes of colorectal cancer, including the KRAS/BRAF-wild-type tumor and the KRAS-mutated tumor. A similar tendency has been observed in studies of metastatic or recurrent colorectal cancer, where BRAF mutations are associated

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