The human papillomavirus (HPV) 16 E6 oncoprotein leads to an increase in gene expression of the angiogenic switch molecule FGF-BP in non-immortalized human keratinocytes

Fibroblast growth factor binding protein (FGF-BP) is a secreted protein that binds FGF-1 and FGF-2 and is involved in mobilization and activation of FGFs from the extracellular matrix. FGF-BP overexpression as well as ribozyme-mediated reduction of endogenous FGF-BP revealed that FGF-BP can be rate-limiting for tumor growth and angiogenesis. Recent studies showed that FGF-BP expression is up-regulated during early phases of tumorigenesis, indicating that the role of FGF-BP in angiogenesis is a critical early step in the development and progression of tumors. Human papillomavirus type 16 (HPV 16) is highly associated with the development of anogenital cancers. Here we demonstrate that the stable expression of the E6 oncogene of HPV 16 leads to an activation of the FGF-BP promoter in primary human foreskin keratinocytes (one of the natural host cells of these viruses). This is associated with an increase in the steady state levels of FGF-BP mRNA and FGF-BP protein in cells stably expressing E6. Transient E6 expression revealed that the observed activation of the FGF-BP promoter by the viral oncogene is an early process which is independent from immortalization/transformation events in the cells.