Nuclear receptor peroxisome proliferator activated receptor (PPAR) β/δ in skin wound healing and cancer.

Abstract

We review the functions of peroxisome proliferator activated receptor (PPAR) β/δ in skin wound healing and cancer. In particular, we highlight the roles of PPARβ/δ in inhibiting keratinocyte apoptosis at wound edges via activation of the PI3K/PKBα/Akt1 pathway and its role during re-epithelialization in regulating keratinocyte adhesion and migration. In fibroblasts, PPARβ/δ controls IL-1 signalling and thereby contributes to the homeostatic control of keratinocyte proliferation. We discuss its therapeutic potential for treating diabetic wounds and inflammatory skin diseases such as psoriasis and acne vulgaris. PPARβ/δ is classified as a tumour growth modifier; it is activated by chronic low-grade inflammation, which promotes the production of lipids that, in turn, enhance PPARβ/δ transcription activity. Our earlier work unveiled a cascade of events triggered by PPARβ/δ that involve the oncogene Src, which promotes ultraviolet-induced skin cancer in mice via enhanced EGFR/Erk1/2 signalling and the expression of epithelial-to-mesenchymal transition (EMT) markers. Interestingly, PPARβ/δ expression is correlated with the expression of SRC and EMT markers in human skin squamous cell carcinoma. Furthermore, there is a positive interaction between PPARβ/δ, SRC, and TGFβ1 at the transcriptional level in various human epithelial cancers. Taken together, these observations suggest the need for evaluating PPARβ/δ modulators that attenuate or increase its activity, depending on the therapeutic target.