Growth regulation via insulin-like growth factor binding protein-4 and -2 in association with mutant K-ras in lung epithelia.
Gain-of-function point mutations in K-ras affect early events in pulmonary bronchioloalveolar carcinoma. We investigated altered mRNA expression on K-Ras activation in human peripheral lung epithelial cells (HPL1A) using oligonucleotide microarrays. Mutated K-Ras stably expressed in HPL1A accelerated cell growth and induced the expression of insulin-like growth factor (IGF)-binding protein (IGFBP)-4 and IGFBP-2, which modulate cell growth via IGF. Other lung epithelial cell lines (NHBE and HPL1D) revealed the same phenomena as HPL1A by mutated K-ras transgene. Lung cancer cell growth was also accelerated by mutated K-ras gene transduction, whereas IGFBP-4/2 induction was weaker compared with mutated K-Ras-expressing lung epithelial cells. To understand the differences in IGFBP-4/2 inducibility via K-Ras-activated signaling between nonneoplastic lung epithelia and lung carcinoma, we addressed the mechanisms of IGFBP-4/2 transcriptional activation. Our results revealed that Egr-1, which is induced on activation of Ras-mitogen-activated protein kinase signaling, is crucial for transactivation of IGFBP-4/2. Furthermore, IGFBP-4 and IGFBP-2 promoters were often hypermethylated in lung carcinoma, yielding low basal expression/weak induction of IGFBP-4/2. These findings suggest that continuous K-Ras activation accelerates cell growth and evokes a feedback system through IGFBP-4/2 to prevent excessive growth. Moreover, this growth regulation is disrupted in lung cancers because of promoter hypermethylation of IGFBP-4/2 genes.
Sato
Hanako
H
Department of Pathobiology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanagawa, Japan.
Yazawa
Takuya
T
Suzuki
Takehisa
T
Shimoyamada
Hiroaki
H
Okudela
Koji
K
Ikeda
Masaichi
M
Hamada
Kenji
K
Yamada-Okabe
Hisafumi
H
Yao
Masayuki
M
Kubota
Yoshinobu
Y
Takahashi
Takashi
T
Kamma
Hiroshi
H
Kitamura
Hitoshi
H
D000230:Adenocarcinoma / Q000473:pathology; D048708:Cell Growth Processes; D019175:DNA Methylation; D051766:Early Growth Response Protein 1 / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology* / Q000473:pathology; D015870:Gene Expression; D005786:Gene Expression Regulation; D011905:Genes, ras / Q000235:genetics*; D006801:Humans; D018971:Insulin-Like Growth Factor Binding Protein 2 / Q000378:metabolism*; D018974:Insulin-Like Growth Factor Binding Protein 4 / Q000378:metabolism*; D008168:Lung / Q000166:cytology* / Q000473:pathology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation; D017354:Point Mutation / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017384:Sequence Deletion; D014162:Transfection; D014407:Tumor Cells, Cultured
D051766:Early Growth Response Protein 1; D018971:Insulin-Like Growth Factor Binding Protein 2; D018974:Insulin-Like Growth Factor Binding Protein 4; D012333:RNA, Messenger; D020928:Mitogen-Activated Protein Kinases