Role of the BrafV637E mutation in hepatocarcinogenesis induced by treatment with diethylnitrosamine in neonatal B6C3F1 mice.
Role of the BrafV637E mutation in hepatocarcinogenesis induced by treatment with diethylnitrosamine in neonatal B6C3F1 mice.
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DOI：
10.1002/mc.22510
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发表时间：
2017-02
影响因子：
4.6
通讯作者：
Ogawa, Katsuhiro
中科院分区：
文献类型：
--
作者：
Yamamoto, Masahiro;Tanaka, Hiroki;Xin, Bing;Nishikawa, Yuji;Yamazaki, Kosuke;Shimizu, Keiko;Ogawa, Katsuhiro
关键词：
BrafV 637 E突变在小鼠肝肿瘤中经常报告，这取决于小鼠品系，并且对应于人BrafV 600 E突变。在这项研究中，我们通过全外显子组分析检测了4/4雄性B6 C3 F1小鼠新生儿二乙基亚硝胺（DEN）治疗诱导的肝肿瘤中的BrafV 637 E突变。我们还通过PCR直接测序在54/63（85.7%）例肝脏病变中检测到BrafV 637 E突变，包括显微镜下病灶和肉眼可见的肿瘤。虽然在5/7（71.4%）的肝肿瘤中检测到突变的新生儿DEN治疗后，重复CCl 4管理，它没有检测到在24个肿瘤CCl 4治疗诱导无DEN或在8个自发病变B6 C3 F1小鼠，这表明突变是由DEN的遗传毒性作用。DEN诱导的肿瘤表现出ERK 1和Akt的过度磷酸化，表明BrafV 637 E突变可能激活MAPK和Akt通路。此外，DEN诱导的肿瘤过表达癌基因诱导的衰老（OIS）标志物（如p15 Ink 4 b和p19 Arf）以及促生存/促增殖细胞因子/趋化因子（如补体C5/C5 a、ICAM-1、IL-1受体拮抗剂和CXCL 9）的mRNA，表明BrafV 637 E突变影响参与OIS或细胞生长/存活的基因表达。在白蛋白增强子/启动子的控制下，突变的Braf的肝脏特异性表达导致肝脏扩大，完全由小的嗜碱性肝细胞组成，类似于DEN诱导的肿瘤前肝细胞，具有ERK 1/Akt过度磷酸化和C5/C5 a过表达。这些结果表明，BrafV 637 E突变在DEN诱导的肝肿瘤中诱导肝细胞变化。© 2016作者。由Wiley Periodicals，Inc.出版的《分子致癌作用》
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 CCl4 administration, it was not detected in 24 tumors induced by CCl4 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 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 p15Ink4b and p19Arf 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 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.
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