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. 2004 May 25;101(21):8132-7.
doi: 10.1073/pnas.0402088101. Epub 2004 May 12.

Hypoxia induces adhesion molecules on cancer cells: A missing link between Warburg effect and induction of selectin-ligand carbohydrates

Tetsufumi Koike  1 , Naoko Kimura, Keiko Miyazaki, Tomonori Yabuta, Kensuke Kumamoto, Seiichi Takenoshita, Jian Chen, Masanobu Kobayashi, Masuo Hosokawa, Akiyoshi Taniguchi, Tetsuhito Kojima, Nobuhiro Ishida, Masao Kawakita, Harumi Yamamoto, Hiromu Takematsu, Akemi Suzuki, Yasunori Kozutsumi, Reiji Kannagi
Affiliations

Hypoxia induces adhesion molecules on cancer cells: A missing link between Warburg effect and induction of selectin-ligand carbohydrates

Tetsufumi Koike et al. Proc Natl Acad Sci U S A. .

Erratum in

  • Proc Natl Acad Sci U S A. 2004 Jul 13;101(28):10494. Kanangi R [corrected to Kannagi R]

Abstract

Cancer cells undergo distinct metabolic changes to cope with their hypoxic environment. These changes are achieved at least partly by the action of transcriptional factors called hypoxia-inducible factors (HIFs). We investigated gene expression in cultured human colon cancer cells induced by hypoxic conditions with special reference to cell-adhesion molecules and carbohydrate determinants having cell-adhesive activity by using DNA-microarray and RT-PCR techniques. Hypoxic culture of colon cancer cells induced a marked increase in expression of selectin ligands, the sialyl Lewis x and sialyl Lewis a determinants at the cell surface, which led to a definite increase in cancer cell adhesion to endothelial E-selectin. The transcription of genes for fucosyltransferase VII (FUT7), sialyltransferase ST3Gal-I (ST3O), and UDP-galactose transporter-1 (UGT1), which are all known to be involved in the synthesis of the carbohydrate ligands for E-selectin, was significantly induced in cancer cells by hypoxic culture. In addition, a remarkable induction was detected in the genes for syndecan-4 (SDC4) and alpha5-integrin (ITGA5), the cell-adhesion molecules involved in the enhanced adhesion of cancer cells to fibronectin. The transcriptional induction by hypoxia was reproduced in the luciferase-reporter assays for these genes, which were significantly suppressed by the co-transfection of a dominant-negative form of HIF. These results indicate that the metabolic shifts of cancer cells partly mediated by HIFs significantly enhance their adhesion to vascular endothelial cells, through both selectin- and integrin-mediated pathways, and suggest that this enhancement further facilitates hematogenous metastasis of cancers and tumor angiogenesis.

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Figures

Fig. 1.
Fig. 1.
Hypoxia-induced sialyl Lewis x (sialyl Lex) and sialyl Lewis a (sialyl Lea) expression and E-selectin-mediated adhesion of colon cancer cells. (A) A human colon cancer cell line, SW480, was cultured under 1% O2 for 7 days (hypoxia) and subsequently under 20% O2 for additional 7 days (reoxygenation) and analyzed for sialyl Lewis x/a expression by flow cytometry. Results on the SW480 cells transfected with dominant-negative HIF are shown also. (B) SW480 cells were cultured in the presence of 100 μM desferrioxamine for 6 days before analyses of carbohydrate determinants. (C) Hypoxia-induced enhancement of SW480 cell adhesion to 300.19/E-selectin cells. Filled bars, adhesion of 300.19/E-selectin cells; open bars, adhesion of parental 300.19 cells (negative control); N.S., not significant.
Fig. 2.
Fig. 2.
RT-PCR analyses of the genes up-regulated in SW480 cells cultured under hypoxic conditions. Hypoxia-induced up-regulation of carbohydrate-related genes in parental SW480 cells (A) and dominant-negative HIF transfectant cells (B) and hypoxia-induced up-regulation of genes for syndecan-4 and α5-integrin in parental SW480 cells (C) are shown. For other genes, see Fig. 8.
Fig. 3.
Fig. 3.
Hypoxia-induced syndecan-4 and α5-integrin expression and adhesion to fibronectin of colon cancer cells cultured under hypoxic conditions. (A) Signals of syndecan-4 and α5-integrin in the DNA microarray (white arrows). Cy3-dUTP (normoxia: red) or Cy5-dUTP (hypoxia, 1% O2 for 24 h: green) was incorporated into cDNA prepared from a human colon cancer cell line SW480. (B) SW480 cells were cultured under 1% O2 for 7 days and subsequently under 20% O2 for an additional 14 days and analyzed for syndecan-4 and α5-integrin expression by flow cytometry. (C) Hypoxia-induced enhancement of SW480 cell adhesion to immobilized fibronectin. Filled bars, adhesion to immobilized fibronectin; open bars, adhesion to BSA (negative control).
Fig. 4.
Fig. 4.
Effect of hypoxia on FUT7 (A), ST3O (B), UGT1 (C), and SDC4 (D) promoter activity. The reporter construct of each gene was transfected to SW480 cells and cultured for 12, 24, or 48 h under hypoxic (1% O2) or normoxic (20% O2) conditions. (Lower) Effect of cotransfection of the dominant-negative form of HIF (DN-HIF). The same amount of empty vector served as negative control, and nonmutated HIF-1 and HIF-2 constructs in the same vector served as positive controls.
Fig. 5.
Fig. 5.
Real-time RT-PCR analyses of expression of genes for fucosyltransferase VII (FUT7), sialyltransferase ST3Gal-I (ST3O), UDP-galactose transporter-1 (UGT1), GLUT1, syndecan-4 (SDC4), and α5-integrin (ITGA5) in cancer tissues prepared from the patients with colon cancer. Ca, cancer tissues; N, nonmalignant mucosa prepared from the same patient. A paired t test was performed to ascertain statistical significance between the amount in cancer tissue and in nonmalignant mucosa.
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References

    1. Hakomori, S. (2002) Proc. Natl. Acad. Sci. USA 99, 10231–10233. - PMC - PubMed
    1. Hakomori, S. (1996) Cancer Res. 56, 5309–5318. - PubMed
    1. Kannagi, R. (2004) Glycoconj. J. 20, 353–364. - PubMed
    1. Kannagi, R. (2002) Curr. Opin. Struct. Biol. 12, 599–608. - PubMed
    1. Kannagi, R. (1997) Glycoconj. J. 14, 577–584. - PubMed

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