Hypoxia-inducible factor-1alpha and hypoxia-inducible factor-2alpha are expressed in kaposi sarcoma and modulated by insulin-like growth factor-I.
OBJECTIVE
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 alpha subunits in biopsies from KS tumors and their modulation by IGF-I in KSIMM, a KS cell line.


RESULTS
Both HIF-1alpha and HIF-2alpha were expressed in KS biopsies in all tumoral stages. HIF-1alpha 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 real-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 alphaIR3 antibody or with picropodophyllin, a specific IGF-IR tyrosine kinase inhibitor, diminishes the basal and IGF-I-dependent induction of both HIF alpha congeners.


CONCLUSIONS
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.
Catrina
Sergiu-Bogdan
SB
Department of Molecular Medicine and Surgery, Diabetes Center Karolinska, Stockholm, Sweden. Sergiu-Bogdan.Catrina@ki.se
Botusan
Ileana Ruxandra
IR
Rantanen
Anja
A
Catrina
Anca Irinel
AI
Pyakurel
Pawan
P
Savu
Octavian
O
Axelson
Magnus
M
Biberfeld
Peter
P
Poellinger
Lorenz
L
Brismar
Kerstin
K
D051792:Basic Helix-Loop-Helix Proteins / Q000096:biosynthesis* / Q000187:drug effects / Q000235:genetics; D001707:Biopsy, Needle; D015687:Cell Hypoxia / Q000187:drug effects; D003035:Cobalt / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis* / Q000187:drug effects / Q000235:genetics; D007150:Immunohistochemistry; D007334:Insulin-Like Growth Factor I / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D011034:Podophyllotoxin / Q000031:analogs & derivatives / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012514:Sarcoma, Kaposi / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013329:Structure-Activity Relationship; D013997:Time Factors; D014407:Tumor Cells, Cultured; D000099162:Endothelial PAS Domain-Containing Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D003035:Cobalt; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007334:Insulin-Like Growth Factor I; D011034:Podophyllotoxin; D000099162:Endothelial PAS Domain-Containing Protein 1; C415032:picropodophyllin; C018021:cobaltous chloride