The IGF-1/IGF-1R signaling axis in the skin: a new role for the dermis in aging-associated skin cancer.
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.
Lewis
D A
DA
Department of Dermatology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Travers
J B
JB
Somani
A-K
AK
Spandau
D F
DF
D000328:Adult; D000367:Age Factors; D000368:Aged; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D002478:Cells, Cultured; D020405:Dermis / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D006801:Humans; D007150:Immunohistochemistry; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D008297:Male; D034622:RNA Interference; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D012867:Skin / Q000166:cytology / Q000378:metabolism* / Q000528:radiation effects; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D014466:Ultraviolet Rays; D055815:Young Adult
D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1