Insulin-like growth factor II induced by hypoxia may contribute to angiogenesis of human hepatocellular carcinoma.
Insulin-like growth factor II (IGF-II) is highly expressed during hepatocarcinogenesis (P. Schirmacher et al., Cancer Res., 52: 2549-2556, 1992; B. C. Park et al., J. Hepatol., 22: 286-294, 1995). However, the mechanism of its enhanced expression is largely unknown. In this study, we show that IGF-II mRNA levels are increased within six h of exposing human hepatoma cell cultures to hypoxia, suggesting that hypoxia may be a strong stimulus for the induction of IGF-II expression in the process of hepatocarcinogenesis. This finding and the fact that hepatocellular carcinoma (HCC) is a typical hypervascular tumor (M. Mise et al., Hepatology, 23: 455-464, 1996) imply that IGF-II may play an important role in the development of neovascularization of HCC. Here we demonstrate that IGF-II substantially increases vascular endothelial growth factor (VEGF) mRNA and protein levels in a time-dependent manner in human hepatoma cells. The induction of VEGF by IGF-II was additively increased by hypoxia. Moreover, the direct angiogenic activity of IGF-II was observed in the quantitative chick chorioallantoic membrane assay (M. Nguyen et al., Microvasc. Res., 47: 31-40, 1994). These data suggest that IGF-II may be a hypoxia-inducible angiogenic factor in HCC.
Kim
K W
KW
Department of Molecular Biology, Pusan National University, Korea. kimkw@hyowon.cc.pusan.ac.kr
Bae
S K
SK
Lee
O H
OH
Bae
M H
MH
Lee
M J
MJ
Park
B C
BC
D000818:Animals; D015152:Blotting, Northern; D006528:Carcinoma, Hepatocellular / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D015687:Cell Hypoxia / Q000502:physiology; D002642:Chick Embryo; D002823:Chorion / Q000098:blood supply / Q000187:drug effects; D016228:Endothelial Growth Factors / Q000235:genetics / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007124:Immunoenzyme Techniques; D007335:Insulin-Like Growth Factor II / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D008222:Lymphokines / Q000235:genetics / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D008222:Lymphokines; D012333:RNA, Messenger; D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D007335:Insulin-Like Growth Factor II