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

Tetsufumi Koike, 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 Kanangi

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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 α5-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 cotransfection 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.

Original languageEnglish
Pages (from-to)8132-8137
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume101
Issue number21
DOIs
Publication statusPublished - 21-05-2004

All Science Journal Classification (ASJC) codes

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    Koike, T., Kimura, N., Miyazaki, K., Yabuta, T., Kumamoto, K., Takenoshita, S., Chen, J., Kobayashi, M., Hosokawa, M., Taniguchi, A., Kojima, T., Ishida, N., Kawakita, M., Yamamoto, H., Takematsu, H., Suzuki, A., Kozutsumi, Y., & Kanangi, R. (2004). Hypoxia induces adhesion molecules on cancer cells: A missing link between Warburg effect and induction of selectin-ligand carbohydrates. Proceedings of the National Academy of Sciences of the United States of America, 101(21), 8132-8137. https://doi.org/10.1073/pnas.0402088101