© 2002 by Oxford University Press
Journal of the National Cancer Institute, Vol. 94, No. 14, 1080-1091,
July 17, 2002
© 2002 Oxford University Press
ARTICLE |
Coexpression of Glucose Transporter 1 and Matrix Metalloproteinase-2 in Human Cancers
Affiliations of authors: S. Ito, Department of Physiological Chemistry and Metabolism, Graduate School of Medicine, University of Tokyo, Japan, and Third Department of Internal Medicine, Yokohama City University School of Medicine, Japan; T. Fukusato, Department of Pathology, Faculty of Medicine, Gunma University, Maebashi, Japan; T. Nemoto, Y. Seyama, S. Kubota, Department of Physiological Chemistry and Metabolism, Graduate School of Medicine, University of Tokyo; H. Sekihara, Third Department of Internal Medicine, Yokohama City University School of Medicine.
Correspondence to: Shunichiro Kubota, M.D., Department of Physiological Chemistry and Metabolism, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113–0033, Japan (e-mail: kubota{at}bio.m.u-tokyo.ac.jp).
Background: Cancer cells express higher levels of glucose transporter proteins (Gluts) than do normal cells. Glut-1 overexpression is associated with invasiveness. Because matrix metalloproteinase-2 (MMP-2) is also overexpressed in cancer cells and is associated with invasiveness, we tested the hypothesis that Glut-1 may regulate MMP-2 expression. Methods: We transiently transfected Glut-1 complementary DNA (cDNA) or Glut-1 antisense oligonucleotides in the human rhabdomyosarcoma cell line RD and analyzed MMP-2 mRNA expression and cell invasiveness. Empty vector and sense oligonucleotides were used for controls. We analyzed MMP-2 promoter activity in transfectants with a luciferase reporter assay and with p53 and Ets-1 gel mobility shift assays. Eight human cancer cell lines and 80 human cancer specimens were analyzed for coexpression of Glut-1 and MMP-2 by western blot and immunohistochemical analyses, respectively. Results: Overexpression of Glut-1 in RD cells increased MMP-2 expression 4.3-fold (95% confidence interval [CI] = 3.7-fold to 4.9-fold) and invasiveness 3.2-fold (95% CI = 2.6-fold to 3.8-fold) relative to control transfected cells. Conversely, suppression of Glut-1 expression by antisense oligonucleotides decreased MMP-2 expression by 71.5% (95% CI = 71.1% to 71.9%) and invasiveness by 53.0% (95% CI = 47.5% to 58.5%). Glut-1-mediated MMP-2 expression involved the binding of the transcription factor p53 but not Ets-1. All eight human cancer cell lines coexpressed Glut-1 and MMP-2 by western blotting, and 45 of 80 human tumor tissues coexpressed Glut-1 and MMP-2 by immunohistochemistry. Conclusions: MMP-2 expression and cell invasiveness are tightly associated with Glut-1 expression in human cancer cell lines. Because suppression of Glut-1 decreased MMP-2 expression and cancer cell invasion, Glut-1 could be a target for therapy of various cancers that overexpress Glut-1.
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