Constitutive upregulation of hypoxia-inducible factor-1alpha mRNA occurring in highly metastatic lung carcinoma cells leads to vascular endothelial growth factor overexpression upon hypoxic exposure.
Neoangiogenesis is crucial for tumor growth and metastasis and is regulated by various angiogenic factors including vascular endothelial growth factor (VEGF). However, little is known whether highly metastatic cells express higher level of VEGF in response to various stimuli, thereby increasing neoangiogenesis compared to low-metastatic cells. Here we report that hypoxia markedly induced the expression of VEGF mRNA in the cell lines with high-metastatic potential (A11 and D6 cells) compared to the cell lines with low-metastatic potential (P29 and P34 cells) established from Lewis lung carcinoma. A11 cells exhibited higher VEGF gene-promoter activity, produced a larger amount of VEGF and showed higher activity to induce neoangiogenesis than P29 cells. Although the degradation rate of VEGF mRNA under hypoxic conditions was similar in both cell lines, hypoxia-inducible factor-1alpha (HIF-1alpha) mRNA, but not HIF-1beta mRNA, was found to be constitutively upregulated in A11 cells compared to P29 cells. Accordingly, the level of HIF-1alpha protein in response to hypoxia was higher in A11 cells than in P29 cells. Upregulation of HIF-1alpha mRNA was also observed in D6 cells but not in P34 cells. Thus, the high-metastatic cells produced a larger amount of VEGF under hypoxic conditions through constitutive HIF-1alpha mRNA upregulation compared to the low-metastatic cells, thereby leading to extensive neoangiogenesis.
Koshikawa
Nobuko
N
Division of Pathology, Chiba Cancer Center Research Institute, 666-2 Nitona, Chuoh-ku, Chiba 260-8717, Japan.
Iyozumi
Ayako
A
Gassmann
Max
M
Takenaga
Keizo
K
D000818:Animals; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D015152:Blotting, Northern; D002467:Cell Nucleus / Q000378:metabolism; D004268:DNA-Binding Proteins; D004591:Electrophoresis, Polyacrylamide Gel; D016228:Endothelial Growth Factors / Q000378:metabolism*; D005260:Female; D017930:Genes, Reporter; D000860:Hypoxia / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D015151:Immunoblotting; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D008156:Luciferases / Q000378:metabolism; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology*; D008222:Lymphokines / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic; D010957:Plasmids / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism*; D018336:Receptors, Aryl Hydrocarbon; D011994:Recombinant Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014157:Transcription Factors / Q000096:biosynthesis* / Q000378:metabolism; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
C497397:Arnt protein, mouse; D004268:DNA-Binding Proteins; D016228:Endothelial Growth Factors; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D011994:Recombinant Proteins; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D012313:RNA; D008156:Luciferases