This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Sato, H. Articles by Kitamura, H. Search for Related Content PubMed PubMed Citation Articles by Sato, H. Articles by Kitamura, H.

(American Journal of Pathology. 2006;169:1550-1566.)
© 2006 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2006.051068

Growth Regulation via Insulin-Like Growth Factor Binding Protein-4 and -2 in Association with Mutant K-ras in Lung Epithelia

Hanako Sato^*, Takuya Yazawa^*, Takehisa Suzuki^*, Hiroaki Shimoyamada^*, Koji Okudela, Masaichi Ikeda^*, Kenji Hamada, Hisafumi Yamada-Okabe, Masayuki Yao, Yoshinobu Kubota, Takashi Takahashi^¶, Hiroshi Kamma^|| and Hitoshi Kitamura^*

From the Departments of Pathobiology^* and Urology, Yokohama City University Graduate School of Medicine, Kanagawa; the Department of Pathology 1, Hamamatsu Medical University, Shizuoka; the Pharmaceutical Research Department 4, Kamakura Research Laboratories, Chugai Pharmaceutical Company Limited, Kanagawa; the Department of Molecular Oncology, ^¶ Nagoya University Graduate School of Medicine, Nagoya; and the Department of Pathology,|| Kyorin University School of Medicine, Tokyo, Japan

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.