Abstract
Cholesteatoma is characterized by both the overgrowth of hyperkeratinized squamous epithelium and bone erosion. However, the exact mechanism underlying the hyperproliferative ability of cholesteatoma remains unknown. In this study, we investigated PPAR β/δ expression in human surgical specimens of cholesteatoma and analyzed its functional role as a regulator of epithelial keratinocyte hyperproliferation. We found that the expression of PPAR β/δ was significantly upregulated in cholesteatoma and ligand-activated PPAR β/δ markedly promoted the proliferation of cholesteatoma keratinocytes. Furthermore, we showed that PPAR β/δ activation increased PDK1 expression and decreased PTEN generation, which led to increased phosphorylation of AKT and GSK3β and increased the expression level of Cyclin D1. Overall, our data suggested that the proliferating effect of PPAR β/δ on the cholesteatoma keratinocytes was mediated by the positive regulation of the PDK1/PTEN/AKT/GSK3β/Cyclin D1 pathway. These findings warranted further investigation of PPAR β/δ as a therapeutic target for recurrent or residual cholesteatoma.
Highlights
Cholesteatoma is a benign epidermally derived temporal bone lesion that is locally destructive and frequently recurrent
Di-Poï et al demonstrated this mechanism by elucidating that the proliferative effect of Peroxisome proliferator-activated receptors (PPARs) β/δ was mediated through the direct repression of gene expression of phosphatase and tensin homolog deleted on chromosome ten (PTEN) and increase expression of 3-phosphoinositide-dependent-protein kinase 1 (PDK1), which activated the phosphorylation of protein kinase B (Akt), leading to cell proliferation of keratinocytes [12]
GSK0660 had the reverse effect on the basal phosphorylation of these kinases. These results indicating that ligand-activated PPAR β/δ promotes the proliferation of cholesteatoma keratinocytes via upregulation the PDK1/AKT/PTEN/Glycogen synthase kinase-3β (GSK3β)/Cyclin D1 signaling pathway
Summary
Cholesteatoma is a benign epidermally derived temporal bone lesion that is locally destructive and frequently recurrent. Di-Poï et al demonstrated this mechanism by elucidating that the proliferative effect of PPAR β/δ was mediated through the direct repression of gene expression of phosphatase and tensin homolog deleted on chromosome ten (PTEN) and increase expression of 3-phosphoinositide-dependent-protein kinase 1 (PDK1), which activated the phosphorylation of protein kinase B (Akt), leading to cell proliferation of keratinocytes [12]. These evidences suggest that the role of PPAR β/δ is cell type- and organ-specific. We investigated the expression and distribution of PPAR β/δ in middle ear cholesteatoma, elevated the effects of ligand-activated PPAR β/δ, and explored the mechanisms by which PPAR β/δ mediated the cell proliferation in the cultured cholesteatoma keratinocytes
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