Association of microRNA-31 with BRAF mutation, colorectal cancer survival and serrated pathway

Katsuhiko Nosho, Hisayoshi Igarashi, Masanori Nojima, Miki Ito, Reo Maruyama, Shinji Yoshii, Takafumi Naito, Yasutaka Sukawa, Masashi Mikami, Wakana Sumioka, Eiichiro Yamamoto, Sei Kurokawa, Yasushi Adachi, Hiroaki Takahashi, Hiroyuki Okuda, Takaya Kusumi, Masao Hosokawa, Masahiro Fujita, Tadashi Hasegawa, Kenji OkitaKoichi Hirata, Hiromu Suzuki, Hiroyuki Yamamoto, Yasuhisa Shinomura

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Abstract

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 nonserrated 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.

Original languageEnglish
Pages (from-to)776-783
Number of pages8
JournalCarcinogenesis
Volume35
Issue number4
DOIs
Publication statusPublished - 2014
Externally publishedYes

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MicroRNAs
Colorectal Neoplasms
Mutation
Tumor Biomarkers
Polyps
Adenoma
Colonic Neoplasms
Reverse Transcription

ASJC Scopus subject areas

  • Cancer Research

Cite this

Nosho, K., Igarashi, H., Nojima, M., Ito, M., Maruyama, R., Yoshii, S., ... Shinomura, Y. (2014). Association of microRNA-31 with BRAF mutation, colorectal cancer survival and serrated pathway. Carcinogenesis, 35(4), 776-783. https://doi.org/10.1093/carcin/bgt374

Association of microRNA-31 with BRAF mutation, colorectal cancer survival and serrated pathway. / Nosho, Katsuhiko; Igarashi, Hisayoshi; Nojima, Masanori; Ito, Miki; Maruyama, Reo; Yoshii, Shinji; Naito, Takafumi; Sukawa, Yasutaka; Mikami, Masashi; Sumioka, Wakana; Yamamoto, Eiichiro; Kurokawa, Sei; Adachi, Yasushi; Takahashi, Hiroaki; Okuda, Hiroyuki; Kusumi, Takaya; Hosokawa, Masao; Fujita, Masahiro; Hasegawa, Tadashi; Okita, Kenji; Hirata, Koichi; Suzuki, Hiromu; Yamamoto, Hiroyuki; Shinomura, Yasuhisa.

In: Carcinogenesis, Vol. 35, No. 4, 2014, p. 776-783.

Research output: Contribution to journalArticle

Nosho, K, Igarashi, H, Nojima, M, Ito, M, Maruyama, R, Yoshii, S, Naito, T, Sukawa, Y, Mikami, M, Sumioka, W, Yamamoto, E, Kurokawa, S, Adachi, Y, Takahashi, H, Okuda, H, Kusumi, T, Hosokawa, M, Fujita, M, Hasegawa, T, Okita, K, Hirata, K, Suzuki, H, Yamamoto, H & Shinomura, Y 2014, 'Association of microRNA-31 with BRAF mutation, colorectal cancer survival and serrated pathway', Carcinogenesis, vol. 35, no. 4, pp. 776-783. https://doi.org/10.1093/carcin/bgt374
Nosho, Katsuhiko ; Igarashi, Hisayoshi ; Nojima, Masanori ; Ito, Miki ; Maruyama, Reo ; Yoshii, Shinji ; Naito, Takafumi ; Sukawa, Yasutaka ; Mikami, Masashi ; Sumioka, Wakana ; Yamamoto, Eiichiro ; Kurokawa, Sei ; Adachi, Yasushi ; Takahashi, Hiroaki ; Okuda, Hiroyuki ; Kusumi, Takaya ; Hosokawa, Masao ; Fujita, Masahiro ; Hasegawa, Tadashi ; Okita, Kenji ; Hirata, Koichi ; Suzuki, Hiromu ; Yamamoto, Hiroyuki ; Shinomura, Yasuhisa. / Association of microRNA-31 with BRAF mutation, colorectal cancer survival and serrated pathway. In: Carcinogenesis. 2014 ; Vol. 35, No. 4. pp. 776-783.
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AU - Nosho, Katsuhiko

AU - Igarashi, Hisayoshi

AU - Nojima, Masanori

AU - Ito, Miki

AU - Maruyama, Reo

AU - Yoshii, Shinji

AU - Naito, Takafumi

AU - Sukawa, Yasutaka

AU - Mikami, Masashi

AU - Sumioka, Wakana

AU - Yamamoto, Eiichiro

AU - Kurokawa, Sei

AU - Adachi, Yasushi

AU - Takahashi, Hiroaki

AU - Okuda, Hiroyuki

AU - Kusumi, Takaya

AU - Hosokawa, Masao

AU - Fujita, Masahiro

AU - Hasegawa, Tadashi

AU - Okita, Kenji

AU - Hirata, Koichi

AU - Suzuki, Hiromu

AU - Yamamoto, Hiroyuki

AU - Shinomura, Yasuhisa

PY - 2014

Y1 - 2014

N2 - 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 nonserrated 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.

AB - 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 nonserrated 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.

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