Hypoxia-inducible factor-1-independent regulation of vascular endothelial growth factor by hypoxia in colon cancer.
The induction of vascular endothelial growth factor (VEGF) is an essential feature of tumor angiogenesis, and the hypoxia-inducible factor-1 (HIF-1) transcription factor is known to be a key mediator of this process. In colon cancer, the frequently mutated K-ras oncogene also can regulate VEGF expression, but the role that K-ras may play in hypoxia is unknown. Hypoxia induced VEGF promoter activity, mRNA, and protein levels in colon cancer cells. Although HIF-1alpha was induced by hypoxia, VEGF reporter constructs with selectively mutated hypoxia-response elements remained responsive to hypoxia. In addition, "knockdown" of HIF-1alpha by RNA interference only minimally inhibited the hypoxic induction of VEGF. A region of the VEGF promoter between -420 and -90 bp mediated this HIF-independent induction by hypoxia. The introduction of K-ras(Val12) augmented the hypoxic induction of VEGF, and this was observed in wild-type and HIF-1alpha knockdown colon cancer cells. Thus, VEGF may be induced by hypoxia through HIF-dependent and HIF-independent pathways, and K-ras also can induce VEGF in hypoxia independent of HIF-1. These findings suggest the existence of multiple mechanisms regulating the hypoxic induction of VEGF in colon cancer.
Mizukami
Yusuke
Y
Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.
Li
Jingnan
J
Zhang
Xiaobo
X
Zimmer
Michael A
MA
Iliopoulos
Othon
O
Chung
Daniel C
DC
D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000098:blood supply*; D004268:DNA-Binding Proteins / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras; D006801:Humans; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009389:Neovascularization, Pathologic / Q000209:etiology; D009687:Nuclear Proteins / Q000502:physiology*; D011401:Promoter Regions, Genetic; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*
D004268:DNA-Binding Proteins; C497442:HIF1A protein, human; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009687:Nuclear Proteins; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A