title: Activation of MEK1/2-ERK1/2 signaling during NNK-induced lung carcinogenesis in female A/J mice.
abstract: The extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway is activated by several growth factors and mitogens, and upregulation has been noted in many human cancers, including examples in the lung. In this study, to study the association of ERK1/2 activation with mutation of Kras encoding an upstream activator of ERK1/2 in lung premalignant lesions, we immunohistochemically examined expression of phosphorylated forms of ERK1/2 (pERK1/2) and MAP/ERK kinase 1/2 (pMEK1/2) proteins and correlation between ERK activation and mutation of Kras encoding an upstream activator of ERK1/2, in a mouse lung carcinogenesis model. Female 7-week-old A/J mice were administered a single dose of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), then maintained without additional treatment until sacrifice at week 52. Histopathologically, adenocarcinomas, adenomas and hyperplasias were observed in the lung. pMEK1/2 was expressed mostly in the cell cytoplasm in all three. In contrast, pERK1/2-positive cells were also relatively rare in any histological types as compared with level of pMEK1/2 expression. However, pERK1/2-positive cells in adenocarcinoma were still markedly more common than in hyperplasias and adenomas (~5-fold, ~4-fold; P < 0.01). Activating mutations of Kras gene at codons 12, 13 and 61 were detected in the majority of adenomas and adenocarcinomas, but without any significant relation to pERK1/2 expression. These results suggest that activation of ERK1/2 plays a key role in malignant transformation during lung carcinogenesis featuring Kras mutaion. Activation of ERK1/2 in lung premalignant lesions was little regardless of the mutation of Kras, and ERK1/2 activation in NNK-induced mouse lung carcinogenesis may be regulated not only by Kras mutation but also other signaling pathway or regulatory factor.
authors: Departments of Pathology and Host-Defense, Onco-Pathology, Faculty of Medicine, Kagawa University, Kagawa, Japan.
authors: Keiko
authors: K
authors: Yamakawa
authors: Departments of Pathology and Host-Defense, Onco-Pathology, Faculty of Medicine, Kagawa University, Kagawa, Japan.
authors: Masanao
authors: M
authors: Yokohira
authors: Departments of Pathology and Host-Defense, Onco-Pathology, Faculty of Medicine, Kagawa University, Kagawa, Japan.
authors: Yuko
authors: Y
authors: Nakano
authors: Departments of Pathology and Host-Defense, Onco-Pathology, Faculty of Medicine, Kagawa University, Kagawa, Japan.
authors: Sosuke
authors: S
authors: Kishi
authors: Departments of Pathology and Host-Defense, Onco-Pathology, Faculty of Medicine, Kagawa University, Kagawa, Japan.|Toxicology Laboratory, TAIHO Pharmaceutical Co., Ltd., Tokushima, Japan.
authors: Shohei
authors: S
authors: Kanie
authors: Departments of Pathology and Host-Defense, Onco-Pathology, Faculty of Medicine, Kagawa University, Kagawa, Japan.
authors: Katsumi
authors: K
authors: Imaida
mesh_terms: D000230:Adenocarcinoma / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics; D000077192:Adenocarcinoma of Lung; D000236:Adenoma / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics; D000818:Animals; D002471:Cell Transformation, Neoplastic; D004789:Enzyme Activation / Q000235:genetics; D005260:Female; D008175:Lung Neoplasms / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics; D048728:MAP Kinase Kinase Kinase 1 / Q000378:metabolism; D048730:MAP Kinase Kinase Kinase 2 / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000235:genetics / Q000502:physiology*; D008805:Mice, Inbred A; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009154:Mutation; D009602:Nitrosamines; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics
chemical_list: D009602:Nitrosamines; D018809:Proliferating Cell Nuclear Antigen; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; C535148:Mapk1 protein, mouse; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048728:MAP Kinase Kinase Kinase 1; D048730:MAP Kinase Kinase Kinase 2; C482619:Map3k2 protein, mouse; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)
keywords: ERK1/2; Kras mutation; MEK1/2; lung carcinogenesis; nonsmall lung cancer