title: Role of the BrafV637E mutation in hepatocarcinogenesis induced by treatment with diethylnitrosamine in neonatal B6C3F1 mice.
abstract: The BrafV637E mutation is frequently reported in mouse hepatic tumors, depending on the mouse strain, and corresponds to the human BrafV600E mutation. In this study, we detected the BrafV637E mutation by whole-exome analysis in 4/4 hepatic tumors induced by neonatal treatment with diethylnitrosamine (DEN) in male B6C3F1 mice. We also detected the BrafV637E mutation in 54/63 (85.7%) hepatic lesions, including microscopic foci and grossly visible tumors, by PCR-direct sequencing. Although the mutation was detected in 5/7 (71.4%) hepatic tumors induced by neonatal DEN treatment followed by repeated CCl4administration, it was not detected in 24 tumors induced by CCl4treatment without DEN or in eight spontaneous lesions in B6C3F1 mice, suggesting that the mutation is induced by the genotoxic action of DEN. The DEN-induced tumors exhibited hyperphosphorylation of ERK1 and Akt, suggesting that the BrafV637E mutation might activate the MAPK and Akt pathways. Moreover, the DEN-induced tumors overexpressed mRNAs for the oncogene-induced senescence (OIS) markers such as p15Ink4band p19Arfas well as pro-survival/pro-proliferative cytokines/chemokines such as complement C5/C5a, ICAM-1, IL-1 receptor antagonist and CXCL9, suggesting that the BrafV637E mutation influences the expression of genes involved in either OIS or cellular growth/survival. Liver-specific expression of mutated Braf under control of the albumin enhancer/promoter resulted in an enlarged liver that consisted entirely of small basophilic hepatocytes resembling DEN-induced preneoplastic hepatocytes with ERK1/Akt hyperphosphorylation and C5/C5a overexpression. These results indicate that the BrafV637E mutation induces hepatocytic changes in DEN-induced hepatic tumors. © 2016 The Authors. Molecular Carcinogenesis published by Wiley Periodicals, Inc.
authors.affiliation: Department of Pathology, Asahikawa Medical University, Asahikawa, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Yamamoto
authors.affiliation: Department of Forensic Medicine, Asahikawa Medical University, Asahikawa, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Tanaka
authors.affiliation: Department of Pathology, Asahikawa Medical University, Asahikawa, Japan.
authors.forename: Bing
authors.initials: B
authors.lastname: Xin
authors.affiliation: Department of Pathology, Asahikawa Medical University, Asahikawa, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Nishikawa
authors.affiliation: Department of Clinical Medicine, Surgery Area, Japanese Red Cross Hokkaido College of Nursing, Kitami, Japan.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Yamazaki
authors.affiliation: Department of Forensic Medicine, Asahikawa Medical University, Asahikawa, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Shimizu
authors.affiliation: Department of Pathology, Asahikawa Medical University, Asahikawa, Japan.
authors.forename: Katsuhiro
authors.initials: K
authors.lastname: Ogawa
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000139:chemically induced / Q000235:genetics / Q000473:pathology; D002453:Cell Cycle; D016207:Cytokines / Q000032:analysis; D004052:Diethylnitrosamine; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008113:Liver Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology*; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017354:Point Mutation; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*
chemical_list: D016207:Cytokines; D004052:Diethylnitrosamine; D048493:Proto-Oncogene Proteins B-raf
keywords: BrafV600E transgenic mice; cytokines/chemokines; hepatic tumors; intracellular signaling; whole-exome analysis