CPSF4 activates telomerase reverse transcriptase and predicts poor prognosis in human lung adenocarcinomas
CPSF4 activates telomerase reverse transcriptase and predicts poor prognosis in human lung adenocarcinomas
复制标题
CPSF4激活端粒酶逆转录酶并预测人肺腺癌的不良预后
DOI：
10.1016/j.molonc.2014.02.001
复制
发表时间：
2014-05-01
影响因子：
6.6
通讯作者：
Deng, Wuguo
中科院分区：
文献类型：
--
作者：
Chen, Wangbing;Qin, Lijun;Deng, Wuguo
人端粒酶逆转录酶（human telomerase reverse transcriptase，hTERT）的高表达和激活与癌细胞的无限增殖有关。然而，在癌变过程中hTERT调控的切除机制还不清楚。在这项研究中，我们发现切割和多聚腺苷酸化特异性因子4（CPSF 4）作为一种新的肿瘤特异性hTERT启动子调节蛋白在肺癌细胞中，并确定CPSF 4在调节肺hTERT和肺癌生长的作用。CPSF 4的异位过表达上调了hTERT启动子驱动的报告基因的表达，激活了肺癌细胞和正常肺细胞内源性hTERT mRNA和蛋白的表达以及端粒酶活性。相反，通过siRNA敲低CPSF 4具有相反的效果。CPSF 4敲除还显著抑制体外肺癌细胞和体内异种移植小鼠模型中的肿瘤细胞生长，并且这种抑制作用部分通过降低hTERT的表达来介导。与正常肺细胞相比，肺腺癌细胞中CPSF 4和hTERT蛋白均呈高表达。肺腺癌的组织芯片免疫组化分析也揭示了CPSF 4和hTERT蛋白表达之间的强正相关。此外，Kaplan-Meier分析显示，高水平CPSF 4和hTERT表达的患者的总生存期显著短于低水平CPSF 4和hTERT表达的患者。总之，这些结果表明，CPSF 4在调节hTERT表达和肺肿瘤发生中起着关键作用，并可能是肺腺癌的一个新的预后因子。(C)2014年欧洲生物化学学会联合会。Elsevier B. V.出版，保留所有权利。
The elevated expression and activation of human telomerase reverse transcriptase (hTERT) is associated with the unlimited proliferation of cancer cells. However, the excise mechanism of hTERT regulation during carcinogenesis is not well understood. In this study, we discovered cleavage and polyadenylation specific factor 4 (CPSF4) as a novel tumor-specific hTERT promoter-regulating protein in lung cancer cells and identified the roles of CPSF4 in regulating lung hTERT and lung cancer growth. The ectopic overexpression of CPSF4 upregulated the hTERT promoter-driven report gene expression and activated the endogenous hTERT mRNA and protein expression and the telomerase activity in lung cancer cells and normal lung cells. In contrast, the knockdown of CPSF4 by siRNA had the opposite effects. CPSF4 knockdown also significantly inhibited tumor cell growth in lung cancer cells in vitro and in a xenograft mouse model in vivo, and this inhibitory effect was partially mediated by decreasing the expression of hTERT. High expression of both CPSF4 and hTERT proteins were detected in lung adenocarcinoma cells by comparison with the normal lung cells. Tissue microarray immunohistochemical analysis of lung adenocarcinomas also revealed a strong positive correlation between the expression of CPSF4 and hTERT proteins. Moreover, Kaplan-Meier analysis showed that patients with high levels of CPSF4 and hTERT expression had a significantly shorter overall survival than those with low CPSF4 and hTERT expression levels. Collectively, these results demonstrate that CPSF4 plays a critical role in the regulation of hTERT expression and lung tumorigenesis and may be a new prognosis factor in lung adenocarcinomas. (C) 2014 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.