Chen Bin, Shen Shunli, Wu Jian, Hua Yunpeng, Kuang Ming, Li Shaoqiang, Peng Baogang
Department of Hepatic Surgery, The First Affiliated Hospital, Sun Yat-sen University Guangzhou, China.
Int J Clin Exp Pathol. 2015 Oct 1;8(10):13725-38. eCollection 2015.
An evolutionarily conserved gene, the CDGSH iron sulfur domain 2 (CISD2), functions to control mammalian life span and regulates human cells proliferation. However, the role of CISD2 in HCC remains unclear. This study was aimed at investigating the expression pattern and clinicopathological significance of CISD2 in patients with HCC.
The mRNA and protein expression levels of CISD2 were analyzed in six HCC lines and eight paired hepatic cancer tumors by real-time PCR, Western blotting and immunohistochemical staining. Statistical analysis was used to evaluate the clinicopathological significance of CISD2 expression. Short hairpin RNA interfering approach was employed to suppress endogenous CISD2 expression in hepatic cancer cells to determine its role in proliferation.
CISD2 expression in liver cancer cell lines and tissues was significantly up-regulated at both the RNA and protein levels compared with that in normal cells and adjacent non-tumorous liver tissues (ANT). CISD2 was an independent prognostic factor for poor prognosis. It was correlated with tumor size (P=0.001), number of tumors (P=0.003), surgical margin (P=0.006), hepatitis B surface antigen (HBsAg) infection (P=0.002) and recurrence (P<0.001) of liver cancer. Multivariate analysis suggested that CISD2 expression was an independent prognostic indicator for the survival of patients with HCC. HCC patients with high CISD2 expression displayed a shorter overall survival and a higher recurrence rate than those with low CISD2 expression (P<0.05, respectively). Additionally, stable down-expression of CISD2 in hepatoma cells suppressed cell proliferation in vitro. Similarly, an in vivo assay showed that CISD2 down-regulation in hepatoma cells inhibited remarkably tumorigenic potential in tumor size and weight.
CISD2 protein may serve as a candidate prognostic marker and a novel therapeutic target for HCC and play an important role in promoting proliferation and enhanced progression of HCC.
CDGSH铁硫结构域2（CISD2）是一种进化上保守的基因，其功能是控制哺乳动物寿命并调节人类细胞增殖。然而，CISD2在肝癌中的作用仍不清楚。本研究旨在探讨CISD2在肝癌患者中的表达模式及其临床病理意义。
采用实时PCR、蛋白质印迹法和免疫组织化学染色，分析6种肝癌细胞系和8对肝癌组织中CISD2的mRNA和蛋白质表达水平。采用统计学分析评估CISD2表达的临床病理意义。采用短发夹RNA干扰方法抑制肝癌细胞内源性CISD2表达，以确定其在增殖中的作用。
与正常细胞和癌旁非肿瘤肝组织（ANT）相比，肝癌细胞系和组织中CISD2在RNA和蛋白质水平均显著上调。CISD2是预后不良的独立预后因素。它与肿瘤大小（P = 0.001）、肿瘤数量（P = 0.003）、手术切缘（P = 0.006）、乙型肝炎表面抗原（HBsAg）感染（P = 0.002）及肝癌复发（P < 0.001）相关。多因素分析表明，CISD2表达是肝癌患者生存的独立预后指标。CISD2高表达的肝癌患者总生存期短于低表达患者，复发率高于低表达患者（P均< 0.05）。此外，肝癌细胞中CISD2的稳定下调抑制了体外细胞增殖。同样，体内实验表明，肝癌细胞中CISD2的下调显著抑制了肿瘤大小和重量方面的致瘤潜能。
CISD2蛋白可能作为肝癌的候选预后标志物和新型治疗靶点，在促进肝癌增殖和进展中起重要作用。
