Constitutive Epidermal Expression of Osteopontin in Osteopontin-Null Mice Restores Ultraviolet B-Induced Cutaneous Squamous Cell Carcinomas to Wild-Type Levels.

Abstract

Studies of osteopontin (OPN)-null mice have supported the role of OPN as a critical factor in the promotion of skin tumorigenesis. OPN is a highly inducible integrin- and CD44-interacting acidic glycoprotein with pleiotropic functions. In various cancers, elevated levels of OPN from cancer and inflammatory cells are secreted into the microenvironment and the bloodstream. To determine whether OPN expressed by keratinocytes without contribution from activated resident and infiltrating inflammatory cells promotes cutaneous tumorigenesis, transgenic mice with constitutive epidermal expression of OPN in an OPN-null background (tg(K14-OPN)) were generated. In photocarcinogenesis studies, tumor multiplicity and the incidence of cutaneous squamous cell carcinoma (cSCC) were similar in the tg(K14-OPN) and wild-type (WT) mice. The incidence of cSCC was significantly higher in the WT than in OPN-null mice. This incidence did not reach significance in tg(K14-OPN) and OPN-null mice, likely due to fewer mice. Tg(K14-OPN) mice exhibited reduced keratinocyte apoptosis but not enhanced epidermal hyperplasia after ultraviolet B (UVB) exposure compared to OPN-null mice. Additionally, tg(K14-OPN) and OPN-null mice irradiated with long-term low dose UVB had significantly lower numbers of mutated p53 keratinocytes than WT mice. RNA-sequencing data from the epidermis of acute UVB-irradiated tg(K14-OPN) versus OPN-null mice compared to UVB-irradiated WT versus OPN-null mice suggests the importance of inflammation, Wnt, integrin and gonadotropin-releasing hormone receptor signaling in cutaneous tumorigenesis and implicates UVB irradiation and its induction of OPN in driving those pathways. In summary, the constitutive epidermal expression of OPN in OPN-null mice facilitates the development of cSCC comparable to WT mice.