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Hypoxic Culture Induces Expression of Sialin, a Sialic Acid Transporter, and Cancer-Associated Gangliosides Containing Non–Human Sialic Acid on Human Cancer Cells

¹ Department of Molecular Pathology, Aichi Cancer Center; ² Department of Bioengineering Sciences, Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya; ³ CREST, Japan Science and Technology Agency, Kawaguchi; ⁴ Supra-Biomolecular System Research Group, RIKEN Frontier Research System, Saitama; ⁵ School of Pharmaceutical Sciences, Kitasato University, Tokyo, Japan; and ⁶ Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan

Requests for reprints: Reiji Kannagi, Department of Molecular Pathology, Research Institute, Aichi Cancer Center, 1-1 Kanokoden, Chikusaku, Nagoya 464-8681, Japan. Phone/Fax: 81-52-764-2973; E-mail: rkannagi{at}aichi-cc.jp.

Tumor hypoxia figures heavily in malignant progression by altering the intracellular glucose metabolism and inducing angiogenic factor production, thus, selecting and expanding more aggressive cancer cell clones. Little is known, however, regarding hypoxia-induced antigenic changes in cancers. We investigated the expression of N-glycolyl sialic acid (NeuGc)-G_M2, a cancer-associated ganglioside containing non–human sialic acid, NeuGc, in human cancers. Cancer tissues prepared from patients with colon cancers frequently expressed NeuGc-G_M2, whereas it was virtually absent in nonmalignant colonic epithelia. Studies on cultured cancer cells indicated that the non–human sialic acid was incorporated from culture medium. Hypoxic culture markedly induced mRNA for a sialic acid transporter, sialin, and this accompanied enhanced incorporation of NeuGc as well as N-acetyl sialic acid. Transfection of cells with sialin gene conferred accelerated sialic acid transport and induced cell surface expression of NeuGc-G_M2. We propose that the preferential expression of NeuGc-G_M2 in cancers is closely associated with tumor hypoxia. Hypoxic culture of tumor cells induces expression of the sialic acid transporter, and enhances the incorporation of non–human sialic acid from the external milieu. A consequence of this is the acquisition of cancer-associated cell surface gangliosides, typically G_M2, containing non–human sialic acid (NeuGc), which is not endogenously synthesized through CMP-N-acetyl sialic acid hydroxylase because humans lack the gene for the synthetic enzyme. As hypoxia is associated with diminished response to radiotherapy and chemotherapy, NeuGc-G_M2 is a potential therapeutic target for hypoxic cancer cells. (Cancer Res 2006; 66(6): 2937-45)

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