SP1-mediated upregulation of lncRNA SNHG4 functions as a ceRNA for miR-377 to facilitate prostate cancer progression through regulation of ZIC5
SP1-mediated upregulation of lncRNA SNHG4 functions as a ceRNA for miR-377 to facilitate prostate cancer progression through regulation of ZIC5
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DOI：
10.1002/jcp.29285
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发表时间：
2019-10-14
影响因子：
5.6
通讯作者：
Wang, Peng
中科院分区：
文献类型：
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作者：
Wang, Zhi-Yong;Duan, Yu;Wang, Peng
背景/目的长非编码RNA(LncRNAs)已被证明在人类肿瘤发生中起着不同的作用。以往的研究发现，LncRNA小核仁RNA宿主基因4(SNHG4)在一些肿瘤中表达异常。然而，SNHG4在前列腺癌(Pca)中的表达、临床意义及作用机制尚不清楚。方法采用实时定量聚合酶链式反应(qRT-PCR)检测SNHG4在组织标本和PCa细胞中的表达。细胞计数试剂盒-8，5-乙炔-2‘-脱氧尿苷、克隆形成、伤口愈合和跨孔侵袭实验分别用于评估细胞增殖、集落形成能力、迁移和侵袭能力。流式细胞仪检测细胞凋亡率。染色质免疫沉淀法检测SP1与SNHG4启动子的结合。通过荧光素酶报告实验、qRT-PCR和蛋白质印迹分析，探讨和证实了SNHG4、miR-377和ZIC5之间的相互作用。结果SNHG4在PCa中高表达，其表达受转录因子SP1的诱导。SNHG4的高水平与PCa患者的肿瘤分期、淋巴结转移和总生存期降低显著相关。SNHG4基因敲除可抑制PCa细胞的生长、迁移和侵袭。此外，miR-377是SNHG4的靶基因，ZIC5是miR-377在PCa中的靶基因。SNHG4通过调控miR-377促进ZIC5介导的生长和转移。结论SNHG4在PCa中形成调控网络，发挥促肿瘤作用，可能成为PCa治疗的新靶点和预后标志物。
Background/Aims Long noncoding RNAs (lncRNAs) have been demonstrated to serve distinct roles in human tumorigenesis. Previous studies have found that lncRNA small nucleolar RNA host gene 4 (SNHG4) was dysregulated in several tumors. However, the expression, clinical significances, and action mechanisms of SNHG4 in prostate cancer (PCa) are still unclear. Methods Quantitative real-time polymerase chain reaction (qRT-PCR) was utilized to detect SNHG4 expression in tissue samples and PCa cells. Cell counting kit-8, 5-ethynyl-2 '-deoxyuridine, clonogenic formation, wound-healing, and transwell invasion assays were, respectively, used to evaluate cell proliferation, colony formation ability, migration, and invasion. Flow cytometric analysis was applied to assess cell apoptosis. Chromatin immunoprecipitation assays were conducted to determine the binding between SP1 and SNHG4 promoter. Luciferase reporter assay, qRT-PCR, and western blot analysis were carried out to explore and confirm the interaction among SNHG4, miR-377, and ZIC5. Results SNHG4 was highly expressed in PCa and its upregulation was induced by transcription factor SP1. The high levels of SNHG4 were distinctly associated with tumor stage, lymph node metastasis, and reduced overall survival of patients with PCa. SNHG4 knockdown inhibited the growth, migration, and invasion of PCa cells. In addition, miR-377 was a target of SNHG4 and ZIC5 was a target gene of miR-377 in PCa. SNHG4 promoted ZIC5-mediated growth and metastasis through modulating miR-377. Conclusion Our findings illuminate how SNHG4 formed a regulatory network to display a tumor-promotive effect in PCa and revealed that SNHG4 may be a novel therapeutic target and prognostic marker for patients with PCa.