信号转导和转录激活因子4（STAT4）表达降低提示肝细胞癌预后不良且细胞增殖增强。
Decreased STAT4 indicates poor prognosis and enhanced cell proliferation in hepatocellular carcinoma.
作者信息
Wang Gang, Chen Jia-Hui, Qiang Yong, Wang Dong-Zhi, Chen Zhong
机构信息
Gang Wang, Yong Qiang, Dong-Zhi Wang, Zhong Chen, Department of General Surgery, Medical School of Nantong University, Nantong 226000, Jiangsu Province, China.
出版信息
World J Gastroenterol. 2015 Apr 7;21(13):3983-93. doi: 10.3748/wjg.v21.i13.3983.
AIM
To investigate the role of signal transduction and activation of transcription 4 (STAT4) in the development and progression of human hepatocellular carcinoma (HCC).
METHODS
Recent genetic investigations have identified that a genetic variant of STAT4 is associated with hepatitis B virus (HBV)-related HCC. The level of STAT4 in 90 HCC patients was examined via Western blot and immunohistochemical analyses. The correlation between STAT4 expression and the clinicopathological characteristics of the patients was analyzed. The level of STAT4 expression in the HCC liver tissues was significantly lower than that in the non-HCC liver tissues and correlated with tumor size, histological grade of HCC and serum hepatitis B surface antigen level in HCC patients. The data were statistically analyzed using SPSS. Furthermore, siRNA oligos targeting STAT4 were employed to investigate the influence of STAT4 RNA interference on HCC cell physiology. Based on Cell Counting Kit-8 and flow cytometric assays, we found that depletion of STAT4 expression significantly enhanced the proliferation of L02 cells.
RESULTS
STAT4 protein expression was significantly lower in HCC tissues than in normal liver tissues. Immunohistochemistry followed by statistical analysis revealed that the expression of STAT4 negatively correlated with Ki67 expression (r = 0.851; P < 0.05) and positively correlated with maximal tumor size (P < 0.05), HBV (P = 0.012) and histological grade (P < 0.05). Kaplan-Meier analysis revealed significant differences in the survival curves between HCC patients expressing low and high levels of STAT4 and Ki67 (P < 0.05). Based on a multivariate Cox proportional hazard model, STAT4 expression was an independent prognostic indicator for HCC patients who underwent curative resection. In vitro, following the release of L02 cell lines from serum starvation, the expression of STAT4 was downregulated, and transfection of L02 cells with siRNA targeting STAT4 inhibited cell proliferation.
CONCLUSION
Our data indicate that STAT4 may inhibit HCC development by modulating HCC cell proliferation.
目的
探讨信号转导与转录激活因子4（STAT4）在人类肝细胞癌（HCC）发生发展过程中的作用。
方法
近期的基因研究发现，STAT4的一个基因变异与乙型肝炎病毒（HBV）相关的HCC有关。通过蛋白质免疫印迹法和免疫组织化学分析检测了90例HCC患者中STAT4的水平。分析了STAT4表达与患者临床病理特征之间的相关性。HCC肝组织中STAT4的表达水平显著低于非HCC肝组织，且与肿瘤大小、HCC的组织学分级以及HCC患者血清乙肝表面抗原水平相关。使用SPSS对数据进行统计学分析。此外，采用靶向STAT4的小干扰RNA（siRNA）寡核苷酸来研究STAT4 RNA干扰对HCC细胞生理学的影响。基于细胞计数试剂盒8法和流式细胞术检测，我们发现STAT4表达的缺失显著增强了L02细胞的增殖。
结果
HCC组织中STAT4蛋白表达明显低于正常肝组织。免疫组织化学及统计学分析显示，STAT4的表达与Ki67表达呈负相关（r = 0.851；P < 0.05），与最大肿瘤大小（P < 0.05）、HBV（P = 0.012）及组织学分级（P < 0.05）呈正相关。Kaplan-Meier分析显示，STAT4和Ki67表达水平低和高的HCC患者生存曲线存在显著差异（P < 0.05）。基于多变量Cox比例风险模型，STAT4表达是接受根治性切除的HCC患者独立的预后指标。在体外，血清饥饿解除后L02细胞系中STAT4的表达下调，用靶向STAT4的siRNA转染L02细胞可抑制细胞增殖。
结论
我们的数据表明，STAT4可能通过调节HCC细胞增殖来抑制HCC的发展。
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