Am. J. Respir. Cell Mol. Biol., Volume 26, Number 2, February, 2002 246-253

Stimulation of Vascular Endothelial Growth Factor Gene Transcription by all trans Retinoic Acid through Sp1 and Sp3 Sites in Human Bronchioloalveolar Carcinoma Cells

Toshitaka Maeno, Toru Tanaka, Yoshichika Sando, Tatsuo Suga, Yuri Maeno, Junichi Nakagawa, Tatsuya Hosono, Mahito Sato, Hideo Akiyama, Shoji Kishi, Ryozo Nagai, and Masahiko Kurabayashi

Second Department of Internal Medicine and Department of Ophthalmology, Gunma University School of Medicine, Gunma, Japan; and Department of Cardiovascular Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan

In this study, we examined the effects of all trans-retinoic acid (at-RA) on the vascular endothelial growth factor (VEGF) expression in human bronchioloalveolar carcinoma NCI-H322 cells to evaluate the potential of at-RA to affect tumor progression. Northern blot and enzyme-linked immunosorbent assay analyses indicate that VEGF production is significantly increased by 1 µM of at-RA. A series of 5'-deletion and site-directed mutation analyses indicated that G+C-rich sequence located at 81 and 52 was required for at-RA- and retinoic acid receptor -mediated induction of VEGF promoter. Electrophoretic mobility shift and supershift assays showed that major constituents of nuclear factors binding to G+C-rich sequences are Sp1 and Sp3. Pretreatment with cycloheximide, a protein synthesis inhibitor, prevented the at-RA-mediated induction of VEGF mRNA expression. Likewise, at-RA-mediated VEGF expression was completely blocked in the presence of genistein, an inhibitor for tyrosine kinases. These results suggest that an increase in transcription of the VEGF promoter by at-RA is mediated through Sp1 site, and both new protein synthesis and tyrosine kinase activation are necessary for this induction. Because VEGF can promote neovascularization in cancer cells, an induction of VEGF by at-RA may preclude the therapeutic application of at-RA to cancer patients.

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