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

Endocrinology. 2011 Jun;152(6):2164-73. doi: 10.1210/en.2010-0693. Epub 2011 Mar 29.


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, we show 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Carcinoma, Non-Small-Cell Lung / genetics
  • Carcinoma, Non-Small-Cell Lung / metabolism*
  • Carcinoma, Non-Small-Cell Lung / pathology*
  • Down-Regulation
  • Epithelial Cells / cytology
  • Epithelial Cells / metabolism*
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Insulin-Like Growth Factor Binding Protein 3 / genetics
  • Insulin-Like Growth Factor Binding Protein 3 / metabolism*
  • Insulin-Like Growth Factor I / genetics
  • Insulin-Like Growth Factor I / metabolism*
  • Insulin-Like Growth Factor II / genetics
  • Insulin-Like Growth Factor II / metabolism
  • Lung / cytology
  • Lung / metabolism
  • Lung / pathology
  • Lung Neoplasms / genetics
  • Lung Neoplasms / metabolism*
  • Lung Neoplasms / pathology*
  • Male
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Neoplastic Processes
  • Receptor, IGF Type 1 / genetics
  • Receptor, IGF Type 1 / metabolism
  • Transcriptional Activation
  • Up-Regulation


  • Insulin-Like Growth Factor Binding Protein 3
  • Insulin-Like Growth Factor I
  • Insulin-Like Growth Factor II
  • Receptor, IGF Type 1