title: MicroRNA Expression Signatures Associated With BRAF-Mutated Versus KRAS-Mutated Colorectal Cancers.
abstract: BRAF and KRAS genes are known to play a similar role in the activation of RAS-RAF-MEK-ERK signaling pathway in colorectal tumorigenesis. However, BRAF-mutated colorectal cancers (CRCs) have distinct clinicopathologic characteristics different from those of the KRAS mutated ones as in comparison the BRAF-mutated CRCs are associated with a much worse prognosis for the afflicted patients. This study aimed to determine the different miRNA expression signatures associated with BRAF-mutated CRCs in comparison to KRAS-mutated ones, and to identify the specific miRNAs possibly mediating the aggressive phenotype of the BRAF-mutated CRCs. We screened 535 formalin-fixed paraffin-embedded CRC tissue samples for the BRAF V600E mutation, and selected 7 BRAF-mutated and 7 KRAS-mutated CRCs that were tumor size, stage, and microsatellite status-matched. Affymetrix GeneChip® miRNA 4.0 Array was used for detection of miRNA expression differences in the selected samples. We validated the array results by quantitative reverse transcription polymerase chain reaction (qRT-PCR) for selected miRNAs. A total of 10 differentially expressed (DE) miRNAs associated with BRAF-mutated CRCs were obtained, including miR-31-5p, miR-877-5p, miR-362-5p, and miR-425-3p. miR-31-5p showed the highest fold change (8.3-fold) among all of the miRNAs analyzed. From the analyses of GO biological processes, the DE-miRNAs were functionally relevant to cellular proliferation such as positive regulation of gene expression (P = 1.26 × 10(-10)), transcription (P = 9.70 × 10(-10)), and RNA metabolic process (P = 1.97 × 10(-9)). Bioinformatics analysis showed that the DE-miRNAs were significantly enriched in cancer-associated pathways including neutrophin signaling (P = 6.84 × 10(-5)), pathways in cancer (P = 0.0016), Wnt signaling (P = 0.0027), and MAPK signaling pathway (P = 0.0036). Our results suggest that the DE-miRNAs in BRAF-mutated CRCs in comparison to KRAS-mutated CRCs are implicated in the aggressive phenotype of the BRAF-mutated CRCs. Further experimental validation is required to confirm these results.
authors.affiliation: From the Department of Oncology and Haematology (YWC, HL), Department of Pathology (Y-BK, DL), Department of Surgery (KWS), Ajou University School of Medicine; Department of Pathology (YSS, KY), College of Medicine, and Department of Biomedical Informatics (YSS), Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Republic of Korea.
authors.forename: Yong Won
authors.initials: YW
authors.lastname: Choi
authors.forename: Young Soo
authors.initials: YS
authors.lastname: Song
authors.forename: Hyunwoo
authors.initials: H
authors.lastname: Lee
authors.forename: Kijong
authors.initials: K
authors.lastname: Yi
authors.forename: Young-Bae
authors.initials: YB
authors.lastname: Kim
authors.forename: Kwang Wook
authors.initials: KW
authors.lastname: Suh
authors.forename: Dakeun
authors.initials: D
authors.lastname: Lee
mesh_terms: D000368:Aged; D063646:Carcinogenesis / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D015179:Colorectal Neoplasms / Q000235:genetics / Q000473:pathology; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D011379:Prognosis; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D015398:Signal Transduction; D047368:Tumor Burden
chemical_list: C117307:KRAS protein, human; D035683:MicroRNAs; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras)