Expression of nuclear survivin in normal skin and squamous cell carcinoma: a possible role in tumor invasion

Background: Survivin is detected in few adult normal cells and it is highly expressed in cancer. Nuclear survivin facilitates cell cycle entry, while the mitochondrial pool protects cells from apoptosis. Survivin is overexpressed in keratinocyte stem cells (KSC) and protects them from apoptosis. Methods: As KSC are at the origin of squamous cell carcinoma (SCC), we evaluated survivin expression in normal and cancerous skin in vivo by immunohistochemistry and western blotting. HaCaT cells overexpressing survivin and wound-healing assay are used. Anova and Student-T tests are used for statistical analysis. Results: Survivin is localized both in the cytoplasm and in the nucleus of normal adult and young keratinocytes. Nuclear survivin is detected in one every 10/11 basal keratinocytes. When present in suprabasal cells, nuclear survivin is co-expressed with K10, but not with K15 or p75-neurotrophin-receptor (p75NTR), a transit amplifying cell marker. Nuclear, but not cytoplasmic survivin expression dramatically increases in actinic keratosis and in SCC in situ, as compared to normal epidermis, and it is highest in poorly differentiated SCC. In SCC tumors, nuclear survivin-positive cells are mainly K10/p75NTR-negative and K15-positive. In poorly differentiated tumors, survivin mostly localizes in the deep infiltrating areas. When overexpressed in keratinocytes, survivin increases cell migration. Conclusion: High survivin expression and the subcellular localization of survivin correlate with keratinocyte differentiation and are associated with undifferentiated and more invasive SCC phenotype.