Document Detail

Hypoxia induces adhesion molecules on cancer cells: A missing link between Warburg effect and induction of selectin-ligand carbohydrates.
MedLine Citation:
PMID:  15141079     Owner:  NLM     Status:  MEDLINE    
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.
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 Kannagi; Reiji Kanangi
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2004-05-12
Journal Detail:
Title:  Proceedings of the National Academy of Sciences of the United States of America     Volume:  101     ISSN:  0027-8424     ISO Abbreviation:  Proc. Natl. Acad. Sci. U.S.A.     Publication Date:  2004 May 
Date Detail:
Created Date:  2004-05-26     Completed Date:  2004-07-09     Revised Date:  2009-11-18    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  United States    
Other Details:
Languages:  eng     Pagination:  8132-7     Citation Subset:  IM    
Department Molecular Pathology, Aichi Cancer Center, Nagoya 464-8681, Japan.
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MeSH Terms
Anoxia / genetics*,  physiopathology*
Antigens, Tumor-Associated, Carbohydrate / genetics,  metabolism
Carbohydrate Metabolism*
Carbohydrates / genetics*
Cell Adhesion
Cell Adhesion Molecules / biosynthesis,  genetics*
Cell Culture Techniques
Cell Line, Tumor
Gene Expression Regulation, Neoplastic*
Genes, Reporter
Integrin alpha5 / genetics
Luciferases / analysis,  genetics
Membrane Glycoproteins / genetics
Neoplasms / genetics,  metabolism*,  pathology*
Oligosaccharides / genetics,  metabolism
Promoter Regions, Genetic / genetics
Proteoglycans / genetics
RNA, Messenger / genetics,  metabolism
Selectins / metabolism*
Transcription, Genetic / genetics
Reg. No./Substance:
0/2-6 sialyl Le(a) antigen; 0/5-acetylneuraminyl-(2-3)-galactosyl-(1-4)-(fucopyranosyl-(1-3))-N-acetylglucosamine; 0/Antigens, Tumor-Associated, Carbohydrate; 0/Carbohydrates; 0/Cell Adhesion Molecules; 0/Integrin alpha5; 0/Ligands; 0/Membrane Glycoproteins; 0/Oligosaccharides; 0/Proteoglycans; 0/RNA, Messenger; 0/SDC4 protein, human; 0/Selectins; 0/Syndecan-4; EC 1.13.12.-/Luciferases
Erratum In:
Proc Natl Acad Sci U S A. 2004 Jul 13;101(28):10494
Note: Kanangi R [corrected to Kannagi R]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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