Centromere protein U expression promotes nonsmall-cell lung cancer cell proliferation through FOXM1 and predicts poor survival
Centromere protein U expression promotes nonsmall-cell lung cancer cell proliferation through FOXM1 and predicts poor survival
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DOI：
10.2147/cmar.s182852
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发表时间：
2018-01-01
影响因子：
3.3
通讯作者：
Wu, Wei
中科院分区：
文献类型：
--
作者：
Wang, Xinxin;Chen, Diangang;Wu, Wei
目的：着丝粒蛋白U(CENPU)在多种类型的人类肿瘤组织中异常高表达，参与肿瘤的进展，但其在肺癌中的表达模式和生物学功能尚不清楚。本研究旨在探讨CENPU在肺癌中的临床意义和生物学功能。材料和方法：采用肿瘤基因组图谱(TCGA)数据分析、实时定量聚合酶链式反应(RT-PCR)和Western blotting方法检测CENPU和FOXM1在非小细胞肺癌(NSCLC)组织中的表达。生存数据来自Kaplan-Meier绘图仪或PROGgene V2预后数据库。应用5-乙炔-2‘-脱氧尿嘧啶核苷(EDU)、细胞计数试剂盒(CCK-8)和细胞周期分析检测CENPU在肺癌细胞增殖中的作用，并通过生物信息学分析和体外siRNA或质粒转染实验验证其作用机制。结果：CENPU在NSCLC组织中异常高表达。CENPU的高表达预示着NSCLC患者总生存期(OS)和无复发生存期(RFS)的下降。通过siRNA抑制CENPU的表达可显著抑制肺癌细胞的增殖和延缓细胞周期进程。生物信息学分析表明，转录因子FOXM1与CENPU呈正相关。进一步的体外实验表明，FOXM1可能是CENPU的下游转录因子，因为CENPU的敲除导致FOXM1表达降低，FOXM1的过表达显着逆转了CENPU敲除对细胞增殖的抑制。此外，FOXM1在非小细胞肺癌中高表达。结论：CENPU在非小细胞肺癌组织中高表达，可通过转录因子FOXM1促进肺癌细胞增殖，有望成为治疗肺癌的潜在靶点。
Purpose: Centromere protein U (CENPU) abnormally exhibits high expression in various types of human tumor tissues and participates in tumor progression; however, its expression pattern and biological function in lung cancer have not yet been elucidated. In the present study, we explored the clinical significance and biological function of CENPU in lung cancer.Materials and methods: The Cancer Genome Atlas (TCGA) data analyses, quantitative real-time PCR (RT-PCR), and Western blotting were performed to quantify CENPU and FOXM1 expression in non-small-cell lung cancer (NSCLC) samples. Survival data were obtained from Kaplan-Meier plotter or PROGgene V2 prognostic database. The function of CENPU in lung cancer cell proliferation was determined using 5-ethynyl-2'-deoxyuridine (EdU), Cell Counting Kit-8 (CCK-8), and cell cycle assays, and the underlying mechanism was determined through bioinformatic analyses and validated by in vitro siRNA or plasmid transfection experiments.Results: CENPU was abnormally overexpressed in NSCLC samples compared with matched paired normal tissues. Higher expression of CENPU predicted worse overall survival (OS) and relapse-free survival (RFS) in NSCLC patients. Knockdown of CENPU expression by siRNA significantly inhibited proliferation and delayed cell cycle progression of lung cancer cells. To figure out the mechanism, bioinformatic analyses were performed and the results showed that the transcription factor, FOXM1, positively correlated with CENPU. Further in vitro experiments indicated that FOXM1 was the possible downstream transcription factor of CENPU as the knockdown of CENPU led to lower expression of FOXM1 and the overexpression of FOXM1 significantly reversed the inhibition of proliferation caused by CENPU knockdown. Furthermore, FOXM1 was highly expressed in NSCLC. The knockdown of FOXM1 also attenuated proliferation and induced G1 arrest in lung cancer cells.Conclusion: CENPU was highly expressed in NSCLC tissues, wherein it promoted lung cancer cell proliferation via the transcription factor, FOXM1, which could be a potential target for therapeutic strategies.