Selective Ablation of Glucocorticoid Receptor in Mouse Keratinocytes Increases Susceptibility to Skin Tumorigenesis

Abstract

We recently demonstrated that mice lacking the epidermal glucocorticoid (GC) receptor (GR) (GR epidermal knockout (GR(EKO)) mice) have developmental defects and sensitivity to epidermal challenge in adulthood. We examined the susceptibility of GR(EKO) mice to skin chemical carcinogenesis. GR(EKO) mice treated with a low dose of 12-dimethylbenz(a) anthracene (DMBA) followed by phorbol 12-myristate 13-acetate (PMA) promotion exhibited earlier papilloma formation with higher incidence and multiplicity relative to control littermates (CO). Augmented proliferation and inflammation and defective differentiation of GR(EKO) keratinocytes contributed to the phenotype, likely through increased AKT and STAT3 (signal transducer and activator of transcription 3) activities. GR(EKO) tumors exhibited signs of early malignization, including delocalized expression of laminin A, dermal invasion of keratin 5 (K5)-positive cells, K13 expression, and focal loss of E-cadherin. Cultured GR(EKO) keratinocytes were spindle like, with loss of E-cadherin and upregulation of smooth muscle actin (SMA) and Snail, suggesting partial epithelial-mesenchymal transition. A high DMBA dose followed by PMA promotion generated sebaceous adenomas and melanocytic foci in GR(EKO) and CO. Importantly, the number, growth kinetics, and extent of both tumor types increased in GR(EKO) mice, suggesting that in addition to regulating tumorigenesis from epidermal lineages, GR in keratinocytes is important for cross-talk with other skin cells. Altogether, our data reinforce the importance of GR in the pathogenesis of skin cancer.

Glucocorticoid receptor and Klf4 co-regulate anti-inflammatory genes in keratinocytes

“…We used a GR deficient cell line derived from adult GR EKO epidermis to unequivocally determine the dependence of Dex-induced changes in gene expression on this TF ( Fig. 3C; Latorre et al, 2013). In GR EKO cells, neither Tsc22d3 nor Zfp36 was induced by Dex, showing that the presence of GR is necessary for this process (Fig.…”

Animal Models of Altered Glucocorticoid Signaling

“…This phenotype is recapitulated in keratinocyte specifi c GR KO mice generated using cre lox technology and keratin14-cre mice [ 30 ]. These epidermal GR KO mice also have increased susceptibility to chemical induced skin tumors [ 31 ]. Overexpression of GR in transgenic mice driven by the keratin5 promoter results in abnormal skin including hypoplasia and impaired hyperplastic response to topical TPA [ 32 ].…”

Glucocorticoid Receptor Signaling in Skin Barrier Function

“…In fact, the analyses of mouse models with epidermal-specific GR overexpression or inactivation demonstrated that GR exerts tumor suppressor actions during skin carcinogenesis [80,84]. GR EKO mice subjected to the classical two-stage protocol-consisting in a single low-dose application of the mutagen 12-dimethylbenz(a) anthracene (DMBA) followed by repeated PMA treatments-exhibited earlier papilloma formation with higher incidence and multiplicity, as well as increased tumor size relative to controls [83]. Also, papillomas in GR EKO mice displayed signs of early malignization, including delocalized expression of laminin A, dermal K5-positive cells, abnormal expression of K13, and focal loss of E-cadherin.…”