Hypoxia induces adhesion molecules on cancer cells: A missing link between Warburg effect and induction of selectin-ligand carbohydrates.
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.
Koike
Tetsufumi
T
Department Molecular Pathology, Aichi Cancer Center, Nagoya 464-8681, Japan.
Kimura
Naoko
N
Miyazaki
Keiko
K
Yabuta
Tomonori
T
Kumamoto
Kensuke
K
Takenoshita
Seiichi
S
Chen
Jian
J
Kobayashi
Masanobu
M
Hosokawa
Masuo
M
Taniguchi
Akiyoshi
A
Kojima
Tetsuhito
T
Ishida
Nobuhiro
N
Kawakita
Masao
M
Yamamoto
Harumi
H
Takematsu
Hiromu
H
Suzuki
Akemi
A
Kozutsumi
Yasunori
Y
Kannagi
Reiji
R
Kanangi
Reiji
R
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
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