Hypoxia-inducible factor-1α- and hypoxia-inducible factor-2α are expressed in Kaposi sarcoma and modulated by insulin-like growth factor-I

Purpose: Neoangiogenesis is essential for tumor development. Hypoxia-inducible factor (HIF), a transcriptional factor composed of two subunits (alpha and beta), plays a key role in this process, activating proangiogenic factors such as vascular endothelial growth factor (VEGF). The HIF alpha subunits are critically regulated by oxygen and are also modulated by growth factors. Kaposi sarcoma (KS) is a highly vascular tumor that releases large amounts of VEGF and for which we have recently described an essential role for the insulin-like growth factor (IGF) system. We therefore investigated the expression of HIF a subunits in biopsies from KS tumors and their modulation by IGF-I in KSIMM, a KS cell line. Results: Both HIF-1 alpha and HIF-2 alpha were expressed in KS biopsies in all tumoral stages. HIF-1 alpha immunopositivity increased through the tumor development with highest expression in the late nodular stages. In KSIMM cells, IGF-I induced accumulation of both HIF alpha subunits. The induction suggests a translation mechanism as documented by cycloheximide chase experiment coupled with constant RNA levels as evaluated by quantitative teal-time PCR. IGF-I - induced HIF alpha accumulation was followed by an increase in HIF function as assessed both by reporter gene assay and by induction of endogenous target gene expression (VEGF-A). Specific blockade of IGF-I receptor with alpha IR3 antibody or with picropoclophyllin, a specific IGF-IR tyrosine kinase inhibitor, diminishes the basal and IGF-I - dependent induction of both HIF alpha congeners. Conclusion: These novel findings show the coupling between the IGF and HIF signaling in KS and suggest a coordinated contribution by these pathways to the characteristic vascular phenotype of this tumor.