title: Hypoxia induces adhesion molecules on cancer cells: A missing link between Warburg effect and induction of selectin-ligand carbohydrates.
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.
authors.affiliation: Department Molecular Pathology, Aichi Cancer Center, Nagoya 464-8681, Japan.
authors.forename: Tetsufumi
authors.initials: T
authors.lastname: Koike
authors.forename: Naoko
authors.initials: N
authors.lastname: Kimura
authors.forename: Keiko
authors.initials: K
authors.lastname: Miyazaki
authors.forename: Tomonori
authors.initials: T
authors.lastname: Yabuta
authors.forename: Kensuke
authors.initials: K
authors.lastname: Kumamoto
authors.forename: Seiichi
authors.initials: S
authors.lastname: Takenoshita
authors.forename: Jian
authors.initials: J
authors.lastname: Chen
authors.forename: Masanobu
authors.initials: M
authors.lastname: Kobayashi
authors.forename: Masuo
authors.initials: M
authors.lastname: Hosokawa
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Taniguchi
authors.forename: Tetsuhito
authors.initials: T
authors.lastname: Kojima
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Ishida
authors.forename: Masao
authors.initials: M
authors.lastname: Kawakita
authors.forename: Harumi
authors.initials: H
authors.lastname: Yamamoto
authors.forename: Hiromu
authors.initials: H
authors.lastname: Takematsu
authors.forename: Akemi
authors.initials: A
authors.lastname: Suzuki
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Kozutsumi
authors.forename: Reiji
authors.initials: R
authors.lastname: Kannagi
authors.forename: Reiji
authors.initials: R
authors.lastname: Kanangi
mesh_terms: D015295:Antigens, Tumor-Associated, Carbohydrate / Q000235:genetics / Q000378:metabolism; D050260:Carbohydrate Metabolism; D002241:Carbohydrates / Q000235:genetics*; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000096:biosynthesis / Q000235:genetics*; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D006801:Humans; D000860:Hypoxia / Q000235:genetics* / Q000503:physiopathology*; D039482:Integrin alpha5 / Q000235:genetics; D007983:Lewis Blood Group Antigens; D008024:Ligands; D008156:Luciferases / Q000032:analysis / Q000235:genetics; D008562:Membrane Glycoproteins / Q000235:genetics; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D009844:Oligosaccharides / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D011509:Proteoglycans / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D019087:Selectins / Q000378:metabolism*; D000080506:Sialyl Lewis X Antigen; D053671:Syndecan-4; D014158:Transcription, Genetic / Q000235:genetics
chemical_list: C410209:2-6 sialyl Le(a) antigen; D015295:Antigens, Tumor-Associated, Carbohydrate; D002241:Carbohydrates; D015815:Cell Adhesion Molecules; D039482:Integrin alpha5; D007983:Lewis Blood Group Antigens; D008024:Ligands; D008562:Membrane Glycoproteins; D009844:Oligosaccharides; D011509:Proteoglycans; D012333:RNA, Messenger; C508304:SDC4 protein, human; D019087:Selectins; D000080506:Sialyl Lewis X Antigen; D053671:Syndecan-4; D008156:Luciferases