Expression profiles of cortisol-inactivating enzyme, 11-hydroxysteroid dehydrogenase-2, in human epidermal tumors and its role in keratinocyte proliferation

The enzyme 11-hydroxysteroid dehydrogenase (11-HSD) catalyzes the interconversion between hormonally active cortisol and inactive cortisone within cells. There are two isozymes: 11-HSD1 activates cortisol from cortisone and 11-HSD2 inactivates cortisol to cortisone. 11-HSD1 was recently discovered in skin, and we subsequently found that the enzyme negatively regulates keratinocyte proliferation. We verified 11-HSD1 and 11-HSD2 expression in benign and malignant skin tumors and investigated the role of 11-HSD in skin tumor pathogenesis. Randomly selected formalin-fixed sections of skin lesions of seborrheic keratosis (SK), squamous cell carcinoma (SCC), and basal cell carcinoma (BCC) were stained with 11-HSD1 and 11-HSD2 antibodies, and 11-HSD expression was also evaluated in murine epidermis in which hyperproliferation was induced by 12-O-tetradecanoylphorbol-13 acetate (TPA). We observed that 11-HSD1 expression was decreased in all SK, SCC, and BCC lesions compared with unaffected skin. Conversely, 11-HSD2 expression was increased in SK and BCC but not in SCC. Overexpression of 11-HSD2 in keratinocytes increased cell proliferation. In the murine model, 11-HSD1 expression was decreased in TPA-treated hyperproliferative skin. Our findings suggest that 11-HSD1 expression is decreased in keratinocyte proliferative conditions, and 11-HSD2 expression is increased in basal cell proliferating conditions, such as BCC and SK. Assessing 11-HSD1 and 11-HSD2 expression could be a useful tool for diagnosing and characterizing skin tumors.