title: Glo1 genetic amplification as a potential therapeutic target in hepatocellular carcinoma.
abstract: Glyoxalase 1 (Glo1) gene aberrations is associated with tumorigenesis and progression in numerous cancers. In this study, we explored the role of Glo1 genetic amplification and expression in Chinese patients with hepatocellular carcinoma (HCC), and Glo1 genetic amplification as potential therapeutic target for HCC. We used fluorescence in situ hybridization (FISH) analysis and qRT-PCR to examine Glo1 genetic aberrations and Glo1 mRNA expression in paired tumor samples obtained from HCC patients. Glo1 genetic amplification was identified in a subset of HCC patient (6%, 3/50), and up-regulation of Glo1 expression was found in 48% (24/50) of tumor tissues compared with adjacent non-tumorous tissues. Statistic analysis showed that Glo1-upregulation significantly correlated with high serum level of alpha-fetoprotein (AFP). Interfering Glo1 expression with shRNA knocking-down led to significant inhibition of cell growth and induced apoptosis in primarily cultured HCC cells carrying genetic amplified Glo1 gene, while no inhibitory effects on cell proliferation were observed in HCC cells with normal copies of Glo1 gene. Glo1 knockdown also inhibited tumor growth and induced apoptosis in xenograft tumors established from primarily cultured HCC cells with Glo1 gene amplification. In addition, Glo1 knocking-down with shRNA interfering caused cellular accumulation of methylglyoxal, a Glo1 cytotoxic substrate. Our data suggested Glo1 pathway activation is required for cell proliferation and cell survival of HCC cells carrying Glo1 genetic amplification. Intervention of Glo1 activation could be a potential therapeutic option for patients with HCC carrying Glo1 gene amplification.
authors: Department of Oncology, Hangzhou First People's Hospital Hangzhou, Zhejiang, China.
authors: Shirong
authors: S
authors: Zhang
authors: Department of Oncology, Hangzhou First People's Hospital Hangzhou, Zhejiang, China.
authors: Xiaodong
authors: X
authors: Liang
authors: Centre of Molecular Medicine, Zhejiang Academy of Medical Sciences Hangzhou, Zhejiang, China.
authors: Xiaoliang
authors: X
authors: Zheng
authors: Department of Oncology, Hangzhou First People's Hospital Hangzhou, Zhejiang, China.
authors: Haixiu
authors: H
authors: Huang
authors: Department of Pathology and Laboratory Medicine, University of California at Los Angeles Los Angeles, CA, USA.
authors: Xufeng
authors: X
authors: Chen
authors: Centre of Molecular Medicine, Zhejiang Academy of Medical Sciences Hangzhou, Zhejiang, China.
authors: Kan
authors: K
authors: Wu
authors: Centre of Molecular Medicine, Zhejiang Academy of Medical Sciences Hangzhou, Zhejiang, China.
authors: Bing
authors: B
authors: Wang
authors: Department of Oncology, Hangzhou First People's Hospital Hangzhou, Zhejiang, China.
authors: Shenglin
authors: S
authors: Ma
mesh_terms: D000818:Animals; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000201:enzymology / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002681:China; D005260:Female; D005784:Gene Amplification; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007791:Lactoylglutathione Lyase / Q000235:genetics* / Q000378:metabolism; D008113:Liver Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D011765:Pyruvaldehyde / Q000378:metabolism; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden; D014407:Tumor Cells, Cultured; D000509:alpha-Fetoproteins / Q000032:analysis
chemical_list: C097353:AFP protein, human; D014408:Biomarkers, Tumor; D012333:RNA, Messenger; D000509:alpha-Fetoproteins; D011765:Pyruvaldehyde; D007791:Lactoylglutathione Lyase
keywords: Glyoxalase 1; apoptosis; cell proliferation; genetic amplification; hepatocellular carcinoma