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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References
Chuang T-Y, Lewis DA, Spandau DF . (2005). Decreased incidence of nonmelanoma skin cancer in patients with type 2 diabetes mellitus using insulin: a pilot study. Br J Dermatol 153: 552–557.
Cotton J, Spandau DF . (1997). Ultraviolet B dose influences the induction of apoptosis and p53 in human keratinocytes. Radiat Res 147: 148–155.
Dimri GP, Lee X, Basile G, Acosta M, Scott G, Roskelley C et al. (1995). A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc Natl Acad Sci USA 92: 9363–9367.
Donovan EA, Kummar S . (2008). Role of the insulin-like growth factor-1R system in colorectal carcinogenesis. Crit Rev Oncol-Hematol 66: 91–98.
Dziadziuszko R, Camidge DR, Hirsch FR . (2008). The insulin-like growth factor in lung cancer. J Thoracic Oncol 3: 815–818.
Ferber A, Chang C, Sells C, Ptasznik A, Cristofalo V et al. (1993). Failure of senescent human fibroblasts to express the insulin-like growth factor-1 gene. J Biol Chem 268: 17883–17888.
Kraemer KH . (1997). Sunlight and skin cancer: another link revealed. Proc Natl Acad Sci USA 94: 11–14.
Krtolica A, Parrinello S, Lockett S, Desprez P-Y, Campisi J . (2001). Senescent fibroblasts promote epithelial cell growth and tumorigenesis: a link between cancer and aging. Proc Natl Acad Sci USA 98: 12072–12077.
Kuhn C, Kumar M, Hurwitz SA, Cotton J, Spandau DF . (1999). Activation of the insulin-like growth factor-1 receptor promotes the survival of human keratinocytes following ultraviolet B irradiation. Intl J Cancer 80: 431–438.
Lann D, LeRoith D . (2008). The role of endocrine insulin-like growth factor-1 and insulin in breast cancer. J Mammary Gland Biol Neoplasia 13: 371–379.
Lewis DA, Hurwitz SA, Spandau DF . (2003a). UVB-induced apoptosis in normal human keratinocytes: role of the erbB receptor family. Exp Cell Res 284: 316–327.
Lewis DA, Zweig B, Hurwitz SA, Spandau DF . (2003b). Inhibition of erbB receptor family members protects HaCaT keratinocytes from UVB-induced apoptosis. J Invest Dermatol 120: 483–488.
Lewis DA, Spandau DF . (2007). UVB-induced activation of NF- κB is regulated by the IGF-1R and dependent on p38 MAPK. J Invest Dermatol 128: 1022–1029.
Lewis DA, Travers JB, Spandau DF . (2008a). A new paradigm for the role of aging in the development of skin cancer. J Invest Dermatol 129: 787–791.
Lewis DA, Yi Q, Travers JB, Spandau DF . (2008b). UVB-induced senescence in human keratinocytes requires a functional IGF-1R and p53. Mol Biol Cell 19: 1346–1353.
Parrinello S, Coppe J-P, Krtolica A, Campisi J . (2005). Stromal-epithelial interactions in aging and cancer: senescent fibroblasts alter epithelial cell differentiation. J Cell Science 118: 485–496.
Pollak M . (2008). Insulin insulin-like growth factor signaling in neoplasia. Nature Rev Cancer 8: 915–928.
Shelton DN, Chang E, Whittier PS, Choi D, Funk WD . (1999). Microarray analysis of replicative senescence. Curr Biol 9: 939–945.
Tavakkol A, Elder JT, Griffiths CEM, Cooper KD, Talwar H, Fisher GJ et al. (1992). Expression of growth hormone receptor, insulin-like growth factor 1 (IGF-1) and IGF-1 receptor mRNA and proteins in human skin. J Invest Dermatol 99: 343–349.
Whiteman DC, Whiteman CA, Green AC . (2001). Childhood sun exposure as a risk factor for melanoma: a systematic review of epidemiologic studies. Cancer Causes Control 12: 69–82.
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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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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DOI: https://doi.org/10.1038/onc.2009.440
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