Data from Hypoxia-Inducible Factor-1α and Hypoxia-Inducible Factor-2α Are Expressed in Kaposi Sarcoma and Modulated by Insulin-like Growth Factor-I

Abstract
Purpose: Neoangiogenesis is essential for tumor development. Hypoxia-inducible factor (HIF), a transcriptional factor composed of two subunits (α and β), plays a key role in this process, activating proangiogenic factors such as vascular endothelial growth factor (VEGF). The HIF α 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 α subunits in biopsies from KS tumors and their modulation by IGF-I in KSIMM, a KS cell line.Results: Both HIF-1α and HIF-2α were expressed in KS biopsies in all tumoral stages. HIF-1α immunopositivity increased through the tumor development with highest expression in the late nodular stages. In KSIMM cells, IGF-I induced accumulation of both HIF α subunits. The induction suggests a translation mechanism as documented by cycloheximide chase experiment coupled with constant RNA levels as evaluated by quantitative real-time PCR. IGF-I–induced HIF α 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 αIR3 antibody or with picropodophyllin, a specific IGF-IR tyrosine kinase inhibitor, diminishes the basal and IGF-I–dependent induction of both HIF α 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.

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