Decreased Selenium-Binding Protein 1 Enhances Glutathione Peroxidase 1 Activity and Downregulates HIF-1α to Promote Hepatocellular Carcinoma Invasiveness
Decreased Selenium-Binding Protein 1 Enhances Glutathione Peroxidase 1 Activity and Downregulates HIF-1α to Promote Hepatocellular Carcinoma Invasiveness
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DOI：
10.1158/1078-0432.ccr-12-0183
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发表时间：
2012-06-01
影响因子：
11.5
通讯作者：
Fan, Jia
中科院分区：
文献类型：
--
作者：
Huang, Cheng;Ding, Guangyu;Fan, Jia
目的：研究硒结合蛋白1 （SBP1）在肝细胞癌（HCC）侵袭中的作用及其潜在的临床意义。实验设计：采用Western blotting检测SBP1在逐步转移的HCC细胞系中的表达。利用siRNA研究SBP1在HCC中的作用。免疫荧光分析检测SBP1与谷胱甘肽过氧化物酶1 （GPX1）的相互作用。19例新鲜肿瘤组织和323例石蜡包埋样本分别用于验证体外结果和检测SBP1的预后意义。结果：抑制SBP1仅在氧化应激下才能有效增加细胞活力，促进细胞增殖，抑制细胞凋亡；在不改变GPX1表达的情况下，显著增强GPX1活性，下调缺氧诱导因子-1 α (HIF-1 α)表达。SBP1和GPX1在氧化应激下形成核体并进行共定位。在新分离的临床HCC组织中，SBP1的降低与GPX1活性的增加有关，并与血管侵袭相关。肿瘤组织微阵列显示SBP1是总生存和疾病复发的独立危险因素；SBP1表达较低的患者总生存期较短，疾病复发率较高(P
Purpose: We aimed to characterize the role of selenium-binding protein 1 (SBP1) in hepatocellular carcinoma (HCC) invasiveness and underlying clinical significance.Experimental Design: SBP1 expression was measured in stepwise metastatic HCC cell lines by Western blotting. The role of SBP1 in HCC was investigated using siRNA. Immunofluorescence analyses were used to detect the interaction between SBP1 and glutathione peroxidase 1 (GPX1). Nineteen fresh tumor tissues and 323 paraffin-embedded samples were used to validate in vitro findings and to detect the prognostic significance of SBP1, respectively.Results: Inhibition of SBP1 effectively increased cell motility, promoted cell proliferation, and inhibited apoptosis only under oxidative stress; it also greatly enhanced GPX1 activity without altering GPX1 expression and downregulated hypoxia-inducible factor-1 alpha (HIF-1 alpha) expression. SBP1 and GPX1 formed nuclear bodies and colocalized under oxidative stress. In freshly isolated clinical HCC tissues, decreased SBP1 was linked with increased GPX1 activity and correlated with vascular invasion. Tumor tissue microarrays indicated that SBP1 was an independent risk factor for overall survival and disease recurrence; patients with lower SBP1 expression experienced shorter overall survival periods and higher rates of disease recurrence (P