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The  Braf V637E mutation is frequently reported in mouse hepatic tumors, depending on the mouse strain, and corresponds to the human  Braf V600E mutation. In this study, we detected the  Braf V637E 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  Braf V637E 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 CCl 4  administration, it was not detected in 24 tumors induced by CCl 4  treatment 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  Braf V637E mutation might activate the MAPK and Akt pathways. Moreover, the DEN‐induced tumors overexpressed mRNAs for the oncogene‐induced senescence (OIS) markers such as p15 Ink4b  and p19 Arf  as well as pro‐survival/pro‐proliferative cytokines/chemokines such as complement C5/C5a, ICAM‐1, IL‐1 receptor antagonist and CXCL9, suggesting that the  Braf V637E 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  Braf V637E mutation induces hepatocytic changes in DEN‐induced hepatic tumors. © 2016 The Authors.  Molecular Carcinogenesis  published by Wiley Periodicals, Inc.

Role of the Braf V637E mutation in hepatocarcinogenesis induced by treatment with diethylnitrosamine in neonatal B6C3F1 mice