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Mol Oncol. 2016 Oct;10(8):1245-54. doi: 10.1016/j.molonc.2016.06.002. Epub 2016 Jun 16.

Insulin-like growth factor-1 receptor regulates repair of ultraviolet B-induced DNA damage in human keratinocytes in vivo.

Author information

1
Department of Dermatology, Indiana University School of Medicine, Indianapolis, IN, United States.
2
Department of Biochemistry & Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, United States.
3
Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, United States; Richard L. Roudebush V.A. Medical Center, Indiana University School of Medicine, Indianapolis, IN, United States.
4
Department of Dermatology, Indiana University School of Medicine, Indianapolis, IN, United States; Richard L. Roudebush V.A. Medical Center, Indiana University School of Medicine, Indianapolis, IN, United States.
5
Department of Dermatology, Indiana University School of Medicine, Indianapolis, IN, United States; Department of Biochemistry & Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, United States. Electronic address: dspanda@iupui.edu.

Abstract

The activation status of the insulin-like growth factor-1 receptor (IGF-1R) regulates the cellular response of keratinocytes to ultraviolet B (UVB) exposure, both in vitro and in vivo. Geriatric skin is deficient in IGF-1 expression resulting in an aberrant IGF-1R-dependent UVB response which contributes to the development of aging-associated squamous cell carcinoma. Furthermore, our lab and others have reported that geriatric keratinocytes repair UVB-induced DNA damage less efficiently than young adult keratinocytes. Here, we show that IGF-1R activation influences DNA damage repair in UVB-irradiated keratinocytes. Specifically, in the absence of IGF-1R activation, the rate of DNA damage repair following UVB-irradiation was significantly slowed (using immortalized human keratinocytes) or inhibited (using primary human keratinocytes). Furthermore, inhibition of IGF-1R activity in human skin, using either ex vivo explant cultures or in vivo xenograft models, suppressed DNA damage repair. Primary keratinocytes with an inactivated IGF-1R also exhibited lower steady-state levels of nucleotide excision repair mRNAs. These results suggest that deficient UVB-induced DNA repair in geriatric keratinocytes is due in part to silenced IGF-1R activation in geriatric skin and provide a mechanism for how the IGF-1 pathway plays a role in the initiation of squamous cell carcinoma in geriatric patients.

KEYWORDS:

IGF-1R; Keratinocyte; NER; UVB; Xenograft

PMID:
27373487
PMCID:
PMC5026895
DOI:
10.1016/j.molonc.2016.06.002
[Indexed for MEDLINE]
Free PMC Article

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