title: Integrated genomic and functional analyses reveal glyoxalase I as a novel metabolic oncogene in human gastric cancer.
abstract: Chromosomal abnormalities are good guideposts when hunting for cancer-related genes. We analyzed copy number alterations of 163 primary gastric cancers using array-based comparative genomic hybridization and simultaneously performed a genome-wide integrated analysis of copy number and gene expression using microarray data for 58 tumors. We showed that chromosome 6p21 amplification frequently occurred secondary to ERBB2 amplification, was associated with poorer prognosis and caused overexpression of half of the genes mapped. A comprehensive small interfering RNA knockdown of 58 genes overexpressed in tumors identified 32 genes that reduced gastric cancer cell growth. Enforced expression of 16 of these genes promoted cell growth in vitro, and six genes showing more than two-fold activity conferred tumor-forming ability in vivo. Among these six candidates, GLO1, encoding a detoxifying enzyme glyoxalase I (GLO1), exhibited the strongest tumor-forming activity. Coexpression of other genes with GLO1 enhanced growth-stimulating activity. A GLO1 inhibitor, S-p-bromobenzyl glutathione cyclopentyl diester, inhibited the growth of two-thirds of 24 gastric cancer cell lines examined. The efficacy was found to be associated with the mRNA expression ratio of GLO1 to GLO2, encoding glyoxalase II (GLO2), another constituent of the glyoxalase system. GLO1 downregulation affected cell growth through inactivating central carbon metabolism and reduced the transcriptional activities of nuclear factor kappa B and activator protein-1. Our study demonstrates that GLO1 is a novel metabolic oncogene of the 6p21 amplicon, which promotes tumor growth and aberrant transcriptional signals via regulating cellular metabolic activities for energy production and could be a potential therapeutic target in gastric cancer.
authors.affiliation: Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: F
authors.initials: F
authors.lastname: Hosoda
authors.affiliation: Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Arai
authors.affiliation: Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Okada
authors.affiliation: Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Shimizu
authors.affiliation: Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Miyamoto
authors.affiliation: Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Kitagawa
authors.affiliation: Division of Gastric Surgery, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Katai
authors.affiliation: Division of Clinical Laboratory, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Taniguchi
authors.affiliation: Division of Translational Research, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center, Chiba, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Yanagihara
authors.affiliation: 1] Department of Molecular Cytogenetics, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan [2] Department of Human Genetics and Public Health, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
authors.forename: I
authors.initials: I
authors.lastname: Imoto
authors.affiliation: Department of Molecular Cytogenetics, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: J
authors.initials: J
authors.lastname: Inazawa
authors.affiliation: Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Ohki
authors.affiliation: Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Shibata
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics*; D055028:Comparative Genomic Hybridization; D005784:Gene Amplification; D018628:Gene Dosage; D023281:Genomics / Q000379:methods*; D005978:Glutathione / Q000031:analogs & derivatives / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007791:Lactoylglutathione Lyase / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000235:genetics; D041681:NIH 3T3 Cells; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018808:Transcription Factor AP-1 / Q000235:genetics
chemical_list: D005978:Glutathione; D007791:Lactoylglutathione Lyase; D016328:NF-kappa B; D018719:Erb-b2 Receptor Tyrosine Kinases; D018808:Transcription Factor AP-1; C099177:S-4-bromobenzylglutathione cyclopentyl diester; C508053:ERBB2 protein, human