| RRC ID |
44983
|
| 著者 |
Hosoda F, Arai Y, Okada N, Shimizu H, Miyamoto M, Kitagawa N, Katai H, Taniguchi H, Yanagihara K, Imoto I, Inazawa J, Ohki M, Shibata T.
|
| タイトル |
Integrated genomic and functional analyses reveal glyoxalase I as a novel metabolic oncogene in human gastric cancer.
|
| ジャーナル |
Oncogene
|
| 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.
|
| 巻・号 |
34(9)
|
| ページ |
1196-206
|
| 公開日 |
2015-2-26
|
| DOI |
10.1038/onc.2014.57
|
| PII |
onc201457
|
| PMID |
24662817
|
| MeSH |
Animals
Cell Line, Tumor
Chromosomes, Human, Pair 6 / genetics*
Comparative Genomic Hybridization
Gene Amplification
Gene Dosage
Genomics / methods*
Glutathione / analogs & derivatives
Glutathione / metabolism
HEK293 Cells
Humans
Lactoylglutathione Lyase / genetics*
Lactoylglutathione Lyase / metabolism
Mice
NF-kappa B / genetics
NIH 3T3 Cells
Receptor, ErbB-2 / genetics*
Signal Transduction
Stomach Neoplasms / genetics*
Stomach Neoplasms / metabolism
Stomach Neoplasms / pathology
Transcription Factor AP-1 / genetics
|
| IF |
7.971
|
| 引用数 |
31
|
|
WOS 分野
|
GENETICS & HEREDITY
ONCOLOGY
BIOCHEMISTRY & MOLECULAR BIOLOGY
CELL BIOLOGY
|
| リソース情報 |
| ヒト・動物細胞 |
293(RCB1637)
NIH3T3 |
