Mechanisms of Skin Biology and Carcinogenesis

Abstract

The skin is a vital organ for life; whose primary function is to act as a defensive barrier. Dysfunction in the epidermal barrier of the skin is commonly observed in autosomal recessive congenital ichthyosis (ARCI). The 12R-Lipoxygenase (12R-L) and epidermis-type Lipoxygenase 3 (eLOX-3) pathway plays a key role in the process of epidermal barrier acquisition by affecting lipid metabolism, as well as protein processing. 12R-L KO mice exhibited differential expression of filaggrin, glucosyl ceramide, and ceramide markers, suggesting that they are essential in the proper formation of the epidermis. The skin disorder ARCI, provides perspective into how disruption of the normal skin physiology may contribute to pre-cancerous phenotypes like hyperplasia and dysplasia. The roles of liver kinase B1 (LKB1), adenosine monophosphate-activated protein kinase (AMPK), and human apurinic (apyrimidinic) endonuclease/redox-factor 1 (Ape1/Ref-1) are addressed to highlight some of the molecular pathways associated with ultra violet (UV)-induced skin carcinogenesis. We used UVA-340 as an energy source because it comes closest to mimicking the natural effects of sunlight exposure by containing biologically relevant amounts of UVA and UVB radiation. UVA-340 exerts carcinogenic effects, by reducing AMPK phosphorylation and the activity of its upstream kinase LKB1. Additionally, we demonstrated that UVA-340 stimulates mammalian target of rapamycin (mTOR) activation. Finally, we found that UVA-340 solar simulated light increases the abundance of Ape1/Ref-1 protein in epidermal keratinocytes. The Ape1/Ref-1 protein is involved in activating AP-1 that subsequently activates a transcriptional program associated with cellular proliferation. The natural compound resveratrol was found to inhibit AP-1 DNA binding, although at high concentrations.