The IGF-1/IGF-1R signaling axis in the skin: A new role for the dermis in aging-associated skin cancer

Research output: Contribution to journalArticle

69 Scopus citations

Abstract

The appropriate response of human keratinocytes to ultraviolet-B (UVB) is dependent on the activation status of the insulin-like growth factor 1 (IGF-1) receptor. Keratinocytes grown in conditions in which the IGF-1 receptor is inactive inappropriately replicate in the presence of UVB-induced DNA damage. In human skin, epidermal keratinocytes do not express IGF-1, and hence the IGF-1 receptor on keratinocytes is activated by IGF-1 secreted from dermal fibroblasts. We now show that the IGF-1 produced by human fibroblasts is essential for the appropriate UVB response of keratinocytes. Furthermore, the expression of IGF-1 is silenced in senescent fibroblasts in vitro. Using quantitative reverse transcriptase-PCR and immunohistochemisty, we can show that IGF-1 expression is also silenced in geriatric dermis in vivo. The diminished IGF-1 expression in geriatric skin correlates with an inappropriate UVB response in geriatric volunteers. Finally, the appropriate UVB response is restored in geriatric skin in vivo through pretreatment with exogenous IGF-1. These studies provide further evidence for a role of the IGF-1 receptor (IGF-1R) in suppressing UVB-induced carcinogenesis, suggest that fibroblasts have a critical role in maintaining appropriate activation of the keratinocyte IGF-1R, and imply that reduced expression of IGF-1 in geriatric skin could be an important component in the development of aging-related non-melanoma skin cancer.

Original languageEnglish (US)
Pages (from-to)1475-1485
Number of pages11
JournalOncogene
Volume29
Issue number10
DOIs
StatePublished - Mar 1 2010

Keywords

  • Aging
  • Fibroblasts
  • IGF-1R
  • Keratinocytes
  • Skin cancer
  • UVB

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

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