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 (a and h), plays a key role in this process, activating proangiogenic factors such as vascular endothelial growth factor (VEGF). The HIF a 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-1a and HIF-2a were expressed in KS biopsies in all tumoral stages. HIF-1a immunopositivity increased through the tumor development with highest expression in the late nodular stages. In KSIMM cells, IGF-I induced accumulation of both HIF a 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 a 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 aIR3 antibody or with picropodophyllin, a specific IGF-IR tyrosine kinase inhibitor, diminishes the basal and IGF-I^dependent induction of both HIF a 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.

Validation of the type 1 insulin-like growth factor receptor as a therapeutic target in renal cancer

“…1D). This finding is consistent with reports that expression of HIF-2α by breast cancer cells was unaffected by PI3K inhibition (21), although in other cell types, HIF-2α was reported to be IGF-inducible (22,23).…”

Effects of oxygen tension and IGF-I on HIF-1α protein expression in mouse blastocysts

“…The α-subunit is hydroxylated at conserved prolyl and asparaginyl residues and targeted for degradation by the von Hippel-Lindau (VHL) ubiquitin E3 ligase complex under normal oxygen conditions. In response to low levels of oxygen, HIF-1α becomes activated and dimerizes with a constitutively expressed HIF-1β, and the complex binds to cis-acting hypoxia response elements in the promoter of target genes, which eventually regulates many cellular activities involved in oxygen homeostasis [3,4,11,[29][30][31]. Consistent with this, Harvey [7,32] suggested that HIFs may be involved in molecular mechanisms which respond to changes in oxygen status during embryo development by expressing genes of HIF-1α, -2α, and -1β subunits in mouse and bovine blastocysts.…”

“…In vascular smooth muscle cells, HIF-1α protein levels are strongly increased under normoxic conditions when cells are stimulated with angiotensin II (Ang II), thrombin, and platelet derived growth factor (PDGF) [10]. Similarly, IGF-I can induce HIF-1α protein synthesis and function in several cell lines under normoxic conditions [3,11]. This occurs independently of oxygen tension, but by regulatory mechanisms that involve mitogen-activated protein kinase and phosphatidylinositol 3-kinase/Akt signaling pathways [12,13].…”

Dauricine inhibits insulin-like growth factor-I-induced hypoxia inducible factor 1α protein accumulation and vascular endothelial growth factor expression in human breast cancer cells

“…We wondered whether the tube formation was induced by IGF-I directly or by other genes. Previous studies have demonstrated that IGF-I can enhance the expression of VEGF [5][6][7][8] , which plays a central role in the process of angiogenesis. Our results also showed that IGF-I induced VEGF expression and transcriptional activation (Figure 3).…”

“…Accumulating evidence has demonstrated that IGF-I could significantly increase HIF-1α-mediated VEGF expression [5][6][7][8] . We also found that IGF-I enhanced VEGF protein secretion ( Figure 3A) and mRNA expression ( Figure 3B).…”