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Constitutive upregulation of hypoxia-inducible factor-1α mRNA occurring in highly metastatic lung carcinoma cells leads to vascular endothelial growth factor overexpression upon hypoxic exposure

Abstract

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-1α (HIF-1α) mRNA, but not HIF-1β mRNA, was found to be constitutively upregulated in A11 cells compared to P29 cells. Accordingly, the level of HIF-1α protein in response to hypoxia was higher in A11 cells than in P29 cells. Upregulation of HIF-1α 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-1α mRNA upregulation compared to the low-metastatic cells, thereby leading to extensive neoangiogenesis.

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Acknowledgements

We thank Dr S Sakiyama for his critical reading of the manuscript. This work was supported in part by Grants-in-Aid for Cancer Research for a New 10-Year Strategy for Cancer Control, and Research (H14-nano-007) on Advanced Medical Technology, from the Ministry of Health, Labour and Welfare of Japan and the Swiss National Science Foundation.

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Correspondence to Keizo Takenaga.

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Koshikawa, N., Iyozumi, A., Gassmann, M. et al. Constitutive upregulation of hypoxia-inducible factor-1α mRNA occurring in highly metastatic lung carcinoma cells leads to vascular endothelial growth factor overexpression upon hypoxic exposure. Oncogene 22, 6717–6724 (2003). https://doi.org/10.1038/sj.onc.1206765

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