Association of microRNA-31 with BRAF mutation, colorectal cancer survival and serrated pathway.
BRAF is an important gene in colorectal cancers (CRCs) that is associated with molecular characterization and resistance to targeted therapy. Although microRNAs (miRNAs) are useful biomarkers of various cancers, the association between miRNA and BRAF in CRCs is undefined. Therefore, this study was conducted to identify a relationship between specific miRNA molecules and BRAF mutation in CRCs and serrated lesions. miRNA array was used for the measurement of 760 miRNAs in 29 CRCs. To assess the identified miRNAs, quantitative reverse transcription-PCR was performed on 721 CRCs, 381 serrated lesions and 251 non-serrated adenomas. Moreover, proliferation and invasion assays were conducted using cell lines. miRNA array analysis revealed that microRNA-31 (miR-31)-5p was the most up-regulated miRNA in CRCs with mutated BRAF (V600E) compared with CRCs possessing wild-type BRAF (including cases with KRAS mutation). High miR-31 expression was associated with BRAF and KRAS mutations and proximal location (P < 0.0001). High miR-31 expression was related to cancer-specific mortality [multivariate hazard ratio = 2.06, 95% confidence interval: 1.36-3.09, P = 0.0008]. Functional analysis demonstrated that miR-31 inhibitor decreased cell invasion and proliferation. With regard to serrated lesions, high miR-31 expression was less frequently detected in hyperplastic polyps compared with other serrated lesions. In conclusion, associations were identified between miR-31, BRAF and prognosis in CRC. Transfection of miR-31 inhibitor had an antitumour effect. Thus, miR-31 may be a promising diagnostic biomarker and therapeutic target in colon cancers. Moreover, high miR-31 expression in serrated lesions suggested that miR-31 may be a key molecule in serrated pathway.
Department of Gastroenterology, Rheumatology and Clinical Immunology, Sapporo Medical University School of Medicine, Sapporo, Japan.
Katsuhiko
K
Nosho
Hisayoshi
H
Igarashi
Masanori
M
Nojima
Miki
M
Ito
Reo
R
Maruyama
Shinji
S
Yoshii
Takafumi
T
Naito
Yasutaka
Y
Sukawa
Masashi
M
Mikami
Wakana
W
Sumioka
Eiichiro
E
Yamamoto
Sei
S
Kurokawa
Yasushi
Y
Adachi
Hiroaki
H
Takahashi
Hiroyuki
H
Okuda
Takaya
T
Kusumi
Masao
M
Hosokawa
Masahiro
M
Fujita
Tadashi
T
Hasegawa
Kenji
K
Okita
Koichi
K
Hirata
Hiromu
H
Suzuki
Hiroyuki
H
Yamamoto
Yasuhisa
Y
Shinomura
D000368:Aged; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D005260:Female; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016019:Survival Analysis
C534612:MIRN31 microRNA, human; D035683:MicroRNAs; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf