Differential impacts of insulin-like growth factor-binding protein-3 (IGFBP-3) in epithelial IGF-induced lung cancer development

Woo Young Kim, Mi Jung Kim, Hojin Moon, Ping Yuan, Jin Soo Kim, Jong Kyu Woo, Guangcheng Zhang, Young Ah Suh, Lei Feng, Carmen Behrens, Carolyn S. Van Pelt, Hyunseok Kang, J. Jack Lee, Waun Ki Hong, Ignacio I. Wistuba, Ho Young Lee

Research output: Contribution to journalArticle

Abstract

The IGF axis has been implicated in the risk of various cancers. We previously reported a potential role of tissue-derived IGF in lung tumor formation and progression. However, the role of IGF-binding protein (IGFBP)-3, a major IGFBP, on the activity of tissue-driven IGF in lung cancer development is largely unknown. Here,weshow that IGF-I, but not IGF-II, protein levels in non-small-cell lung cancer (NSCLC) were significantly higher than those in normal and hyperplastic bronchial epithelium. We found that IGF-I and IGFBP-3 levels in NSCLC tissue specimens were significantly correlated with phosphorylated IGF-IR (pIGF-IR) expression. We investigated the impact of IGFBP-3 expression on the activity of tissue-driven IGF-I in lung cancer development using mice carrying lung-specific human IGF-I transgene (Tg), a germline-null mutation of IGFBP-3, or both. Compared with wild-type (BP3 +/+) mice, mice carrying heterozygous (BP3 +/-) or homozygous (BP3 -/-) deletion of IGFBP-3 alleles exhibited decreases in circulating IGFBP-3 and IGF-I. Unexpectedly, IGF Tg mice with 50% of physiological IGFBP-3 (BP3 +/-; IGF Tg) showed higher levels of pIGF-IR/IR and a greater degree of spontaneous or tobacco carcinogen [4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone]-induced lung tumor development and progression than did the IGF Tg mice with normal (BP3 +/+; IGF Tg) or homozygous deletion of IGFBP-3 (BP3 -/-; IGF Tg). These data show that IGF-I is overexpressed in NSCLC, leading to activation of IGF-IR, and that IGFBP-3, depending on its expression level, either inhibits or potentiates IGF-I actions in lung carcinogenesis.

Original languageEnglish (US)
Pages (from-to)2164-2173
Number of pages10
JournalEndocrinology
Volume152
Issue number6
DOIs
StatePublished - Jun 1 2011

ASJC Scopus subject areas

  • Endocrinology

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  • Cite this

    Kim, W. Y., Kim, M. J., Moon, H., Yuan, P., Kim, J. S., Woo, J. K., Zhang, G., Suh, Y. A., Feng, L., Behrens, C., Van Pelt, C. S., Kang, H., Lee, J. J., Hong, W. K., Wistuba, I. I., & Lee, H. Y. (2011). Differential impacts of insulin-like growth factor-binding protein-3 (IGFBP-3) in epithelial IGF-induced lung cancer development. Endocrinology, 152(6), 2164-2173. https://doi.org/10.1210/en.2010-0693