ZNF452 facilitates tumor proliferation and invasion via activating AKT-GSK3β signaling pathway and predicts poor prognosis of non-small cell lung cancer patients.
ZNF452 facilitates tumor proliferation and invasion via activating AKT-GSK3β signaling pathway and predicts poor prognosis of non-small cell lung cancer patients.
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ZNF452通过激活AKT-GSK3beta信号通路促进肿瘤增殖和侵袭，并预测非小细胞肺癌患者的不良预后。
DOI：
10.18632/oncotarget.16408
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发表时间：
2017-06-13
期刊：
影响因子：
--
通讯作者：
Wang E
中科院分区：
文献类型：
--
作者：
Zhang X;Zhou H;Zhang Y;Cai L;Jiang G;Li A;Miao Y;Li Q;Qiu X;Wang E
ZNF452是锌指蛋白家族成员，包含一个分离的SCAN （SRE-ZBP、CTfin51、AW-1和18号cDNA）锌指结构域。尽管已知SCAN n端结构域在参与细胞存活和分化的基因的转录调控中发挥作用，但ZNF452没有精确的细胞功能。在本研究中，我们发现无论是内源性还是外源性ZNF452在NSCLC细胞的细胞质中都存在过表达，并且在NSCLC样本中ZNF452的阳性比例（50.8%,93/183）显著高于正常肺组织（22.4%,13/58，P<0.001）。ZNF452过表达与TNM晚期（P=0.033）、淋巴结转移阳性（P=0.002）相关，预示NSCLC患者总生存期较差（P<0.001）。ZNF452通过上调CyclinD1、CyclinE1、p-Rb或Snail的表达，下调Zo-1的表达，促进肿瘤生长、集落形成、G1-S期阻滞、迁移和侵袭。在裸鼠异种移植物中，过表达ZNF452也促进了肿瘤的增殖和转移。随后，我们发现ZNF452通过激活其下游AKT-GSK3β信号通路促进肿瘤增殖和侵袭。AKT抑制剂可显著抑制AKT和GSK3β的磷酸化，从而抵消CyclinD1、CyclinE1或Snail的表达增加，恢复ZNF452过表达引起的Zo-1的表达下降以及肿瘤增殖和侵袭的上调。综上所述，本研究提示ZNF452可能是AKT-GSK3β信号通路的上游调控因子，促进NSCLC的增殖和侵袭。
ZNF452 is a zinc-finger protein family member which contains an isolated SCAN (SRE-ZBP, CTfin51, AW-1 and Number 18 cDNA) zinc-finger domain. Despite the SCAN N-terminus domain is known to play a role in transcriptional regulation of genes involved in cell survival and differentiation, there are no precise cellular functions that have been assigned to ZNF452. In the present study, we found that either endogenous or exogenous ZNF452 was overexpressed in the cytoplasm of NSCLC cells and positive ratio of ZNF452 in NSCLC samples (50.8%, 93/183) was significantly higher than that in normal lung tissues (22.4%, 13/58, P<0.001). ZNF452 overexpression was correlated with advanced TNM stage (P=0.033), positive lymph node metastasis (P=0.002) and predicted poor overall survival of NSCLC patients (P<0.001). ZNF452 facilitated tumor growth, colony formation, G1-S phase arrest, migration and invasion through upregulating the levels of CyclinD1, CyclinE1, p-Rb, or Snail, and downregulating the expression of Zo-1. In nude mice xenografts, overexpressing ZNF452 also promoted tumor proliferation and metastasis. Subsequently, we found that the effect of ZNF452 on facilitating tumor proliferation and invasion was through activating its downstream AKT-GSK3β signaling pathway. Treatment of AKT inhibitor markedly prevented the phosphorylation of AKT and GSK3β which subsequently counteracted increasing expression of CyclinD1, CyclinE1 or Snail and restored the decreasing expression of Zo-1, as well as the upregulation of tumor proliferation and invasion, caused by ZNF452 overexpression. Taken together, the present study indicated that ZNF452 may be an upstream regulator of AKT-GSK3β signaling pathway and facilitates proliferation and invasion of NSCLC.
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影响因子：
8
作者：
Jen J;Lin LL;Chen HT;Liao SY;Lo FY;Tang YA;Su WC;Salgia R;Hsu CL;Huang HC;Juan HF;Wang YC
通讯作者：
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影响因子：
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作者：
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通讯作者：
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影响因子：
4.8
作者：
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通讯作者：
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影响因子：
1.9
作者：
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通讯作者：
Goldstraw, Peter
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影响因子：
11.2
作者：
Li, Rong;Wei, Jie;Wang, Ping
通讯作者：
Wang, Ping