Selective ablation of glucocorticoid receptor in mouse keratinocytes increases susceptibility to skin tumorigenesis.

9 páginas, 5 figuras. En material suplementario 5 figuras.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.This work was supported by grant SAF2011-28115 of the Ministerio de Economía y Competitividad from the Spanish government. VL holds a fellowship from the MICINN (BES-2009-021944).Peer reviewe