Ku80 functions as a tumor suppressor in hepatocellular carcinoma by inducing S-phase arrest through a p53-dependent pathway
Ku80 functions as a tumor suppressor in hepatocellular carcinoma by inducing S-phase arrest through a p53-dependent pathway
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Ku80 通过 p53 依赖性途径诱导 S 期阻滞，在肝细胞癌中发挥肿瘤抑制因子的作用
DOI：
10.1093/carcin/bgr319
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发表时间：
2012-03-01
期刊：
影响因子：
4.7
通讯作者：
Chen, Xiao-ping
中科院分区：
文献类型：
--
作者：
Wei, Shuang;Xiong, Min;Chen, Xiao-ping
Ku 80是一种称为DNA依赖性蛋白激酶的蛋白质复合物的组成部分，它参与DNA双链断裂修复和多种其他功能。以往的研究表明，Ku 80单倍不足和聚腺苷二磷酸核糖聚合酶基因敲除转基因小鼠发生肝细胞癌（HCC）的频率很高。Ku 80在人类HCC中的作用从未被研究过。采用免疫组化和westernblot方法检测Ku 80在肝癌及癌旁肝组织中的表达。将Ku 80转染到Ku 80缺陷型肝癌细胞系SMMC 7721中，观察Ku 80表达细胞和载体转染细胞的体内外生长特性。采用细胞周期分析和RNA干扰技术研究Ku 80表达对细胞生长的调控机制。Ku 80在肝癌组织中表达较癌旁肝组织明显下调。Ku 80表达下调与B型肝炎病毒DNA载量升高及肝硬化严重程度显著相关。Ku 80在SMMC 7721细胞中的过表达在体外和体内均显著抑制细胞增殖。Ku 80过表达导致细胞周期S期阻滞，并与p53和p21（CIP 1/WAF 1）的上调相关，并且通过RNA干扰抑制p53或p21（CIP 1/WAF 1）表达克服了Ku 80表达细胞的生长抑制和S期阻滞。Ku 80通过p53依赖性途径诱导S期阻滞，从而发挥抑癌作用。
Ku80 is a component of the protein complex called DNA-dependent protein kinase, which is involved in DNA double-strand break repair and multiple other functions. Previous studies revealed that Ku80 haplo-insufficient and poly (adenosine diphosphate-ribose) polymerase-null transgenic mice developed hepatocellular carcinoma (HCC) at a high frequency. The role of Ku80 has never been investigated in human HCC. Ku80 expressions in HCC and adjacent liver tissue were investigated by using immunohistochemical staining and western blot. Ku80 was transfected into a Ku80-deficient HCC cell line SMMC7721 cells, and the growth features of the Ku80-expressing cells and vector-transfected cells were studied both in vitro and in vivo. Cell cycle analysis and RNA interference were employed to investigate the mechanisms underlying the growth regulation associated with Ku80 expression. Ku80 was found frequently downregulated in HCC compared with adjacent liver tissue. Ku80 downregulation was significantly correlated with elevated hepatitis B virus-DNA load and severity of liver cirrhosis. Overexpression of Ku80 in SMMC7721 cells significantly suppressed cell proliferation in vitro and in vivo. Ku80 overexpression caused S-phase cell cycle arrest and was associated with upregulation of p53 and p21(CIP1/WAF1), and the inhibition of p53 or p21(CIP1/WAF1) expression by RNA interference overcame the growth suppression and S-phase arrest in the Ku80-expressing cells. A novel mechanism was revealed that Ku80 functions as a tumor suppressor in HCC by inducing S-phase arrest through a p53-dependent pathway.