Zhang Shirong, Liang Xiaodong, Zheng Xiaoliang, Huang Haixiu, Chen Xufeng, Wu Kan, Wang Bing, Ma Shenglin
Department of Oncology, Hangzhou First People's Hospital Hangzhou, Zhejiang, China.
Centre of Molecular Medicine, Zhejiang Academy of Medical Sciences Hangzhou, Zhejiang, China.
Int J Clin Exp Pathol. 2014 Apr 15;7(5):2079-90. eCollection 2014.
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.
乙二醛酶1（Glo1）基因畸变与多种癌症的发生和进展相关。在本研究中，我们探讨了Glo1基因扩增和表达在中国肝细胞癌（HCC）患者中的作用，以及Glo1基因扩增作为HCC潜在治疗靶点的可能性。我们使用荧光原位杂交（FISH）分析和qRT-PCR检测从HCC患者获取的配对肿瘤样本中的Glo1基因畸变和Glo1 mRNA表达。在一部分HCC患者（6%，3/50）中检测到Glo1基因扩增，与相邻非肿瘤组织相比，48%（24/50）的肿瘤组织中发现Glo1表达上调。统计分析表明，Glo1上调与高血清甲胎蛋白（AFP）水平显著相关。用shRNA敲低干扰Glo1表达导致携带基因扩增Glo1基因的原代培养HCC细胞的细胞生长受到显著抑制并诱导凋亡，而在Glo1基因拷贝正常的HCC细胞中未观察到对细胞增殖的抑制作用。Glo1敲低还抑制了由携带Glo1基因扩增的原代培养HCC细胞建立的异种移植肿瘤的生长并诱导其凋亡。此外，用shRNA干扰敲低Glo1会导致甲基乙二醛（一种Glo1细胞毒性底物）在细胞内蓄积。我们的数据表明，携带Glo1基因扩增的HCC细胞的细胞增殖和细胞存活需要Glo1途径激活。干预Glo1激活可能是携带Glo1基因扩增的HCC患者的一种潜在治疗选择。
