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

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.

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Acknowledgements

We are grateful to Dr Raymond Konger for his valuable suggestions. The recombinant human IGF-1 was generously provided by Tercica, Inc. This work was supported by grants from the National Institutes of Health (R01ES11155 and R21CA131901 to DFS; R01HL062996 and U19A1070448 to JBT) and VA Merit Award (JBT).

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Correspondence to D F Spandau.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Lewis, D., Travers, J., Somani, AK. et al. The IGF-1/IGF-1R signaling axis in the skin: a new role for the dermis in aging-associated skin cancer. Oncogene 29, 1475–1485 (2010). https://doi.org/10.1038/onc.2009.440

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