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  • gallic acid Among the down regulated genes were several of i


    Among the down-regulated genes were several of interest. Coronin2a (Coro2a), a component of the nuclear receptor co-repressor complexes, contributes to de-repression of inflammatory response genes (Huang et al., 2011). Mill1, an MHC family member expressed in hair follicles, represses wound healing (Rabinovich et al., 2008); the reduction in Mill1 expression may thus contribute to the robust wound healing response to the toxicity of DMBA in the transgenic mice. SMOC2 is known to stimulate the attachment of keratinocytes to matrices (Maier et al., 2008); reduction in SMOC2 would likely contribute to cell migration and a dysplastic/hyperplastic epidermis. STEAP4 is an oxidoreductase that mediates apoptosis and glucose metabolism (Gomes et al., 2012), although its function in skin has not been clearly elucidated. Overall, the genes upregulated by over-expression and activation of the EP4 receptor are primarily those that are associated with increased proliferation and inflammation and thus likely contribute to the robust regenerative response of the epidermis of DMBA-treated BK5.EP4 mice. This response is reminiscent of the protein kinase C epsilon transgenic mice in which complete epidermal necrosis occurs after TPA treatment, followed by regeneration beginning from the hair follicles. It was proposed that prolonged hyperplasia of the hair follicle results in an expansion of initiated gallic acid leading to subsequent development of SCCs (Li et al., 2005). Similarly, apoptotic cell death has been shown to promote wound healing and tissue regeneration via a pathway referred to as the “phoenix rising” pathway (Li et al., 2010). In the case of the BK5.EP4 mice, this pathway is facilitated by the upregulation of pro-inflammatory and proliferation-related genes. In summary, the EP4 receptor for PGE2 confers endogenous tumor promoting and even greater tumor progression activity in murine skin. This receptor causes the upregulation of a number of genes involved in the proliferative and inflammatory aspects of tumor development and thus is a reasonable target for the prevention and therapeutic treatment of skin cancer.
    Conflict of interests
    Acknowledgments We are grateful to Shawna Johnson and Laura Denton for help in formatting this manuscript. We acknowledge the Histology and Tissue Processing Facility Core, the Molecular Biology Facility Core, and the Next Generation Sequencing Core at Science Park in Smithville, Texas. This study also made use of the Research Animal Support Facilities, and the Genetically Engineered Mouse Facility, supported by the National Institutes of Health grants CA100140, P30 CA16672-30 DHHS ⁄ NCI Cancer Center Support Grant (CCSG) and CPRIT Core Facility Support Grant RP120348.
    Introduction Prostaglandin E2 (PGE2) is a bioactive lipid derived from plasma membrane phospholipids, through enzymatic metabolism of arachidonic acid by cyclooxygenases -1 and -2 (COX -1,-2) and prostaglandin synthase [1]. PGE2 mediates biosynthetic pathways that regulate biological functions such as sleep, fever, inflammation, and pain [2]. PGE2 also plays a critical role in the proper development of the nervous system. It induces differentiation of neuronal cells [3] and plays a regulatory role in membrane excitability and synaptic transmission in neurons [4]. PGE2 can also increase dendritic length and alter neuronal firing activity in the brain [5]. PGE2 exerts it physiological function through its four cell surface G protein-coupled receptors (GPCRs) designated EP (E-Prostanoid) 1-4, with different affinities [1], [6], [7]. Activation of EP1 receptor is associated with an increase of intracellular calcium [Ca2+]i, mediated by phospholipase C and inositol 1,4,5-triphosphate (IP3) [7], [8]. EP2 and EP4 are coupled to the stimulatory Gs protein and cause an increase in cAMP through activation of adenylate cyclase [9], which in turn activates protein kinase A (PKA) and mediates phosphorylation of cAMP response element binding the protein (CREB) transcription factor [10]. Activation of a specific EP3 isoform, can both decrease and increase cyclic AMP (cAMP) and IP3. It is also shown that the EP4 receptor signaling can operate via Gi proteins- phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) pathways [11], [12].