Induction of ErbB2 by ultraviolet A irradiation: Potential role in malignant transformation of keratinocytes

Ultraviolet (UV) A (320-400 nm), which constitutes more than 90% of UV radiation in the sunlight that reaches the earth's surface, is considered a major cause of human skin photo-aging and skin cancer. Exposure of keratinocytes to UVA has previously been reported to lead to the activation of a variety of epidermal growth factor receptors (EGFR), including ErbB2, and ErbB2 activation is involved in skin tumor development. Here, we demonstrate that ErbB2 expression is enhanced by low-energy UVA (300-3000 mJ/cm²) irradiation in the skin tissues of both hairless mice and HaCaT keratinocytes. Luciferase reporter-gene activity using the 756-bp flanking region of the human erbB2 gene was increased by UVA irradiation. UVA irradiation also selectively increased the levels of activator protein (AP)-2α, but not AP-2β and AP-2γ. The increase in the reporter gene activity of HaCaT cells exposed to UVA was abolished by mutation of the two AP-2 binding sites in the promoter region of the erbB2 gene. Inhibition of cAMP-dependent protein kinase caused complete blockage of ErbB2 induction and AP-2α activation by UVA irradiation. Finally, we reveal that pre-exposure of HaCaT cells to UVA potentiates EGF-inducible anchorage-independent growth of the keratinocytes, which is significantly suppressed by ErbB2 inhibition. These results support the hypothesis that UVA enhances the expression of ErbB2 via cAMP- and protein kinase-dependent AP-2α activation in keratinocytes, which may serve as a key mechanistic basis for the malignant transformation of keratinocytes exposed to UVA irradiation.