MicroRNA-377 inhibited proliferation and invasion of human glioblastoma cells by directly targeting specificity protein 1.
MicroRNA-377 inhibited proliferation and invasion of human glioblastoma cells by directly targeting specificity protein 1.
复制标题
DOI：
10.1093/neuonc/nou111
复制
发表时间：
2014-11
期刊：
影响因子：
15.9
通讯作者：
Rui Zhang;Hui Luo;Shuai Wang;Wanghao Chen;Zhengxin Chen;Hong-Wei Wang;Yuanyuan Chen;Jingmin Yang;Xiaotian Zhang;Wenting Wu;Shuyong Zhang;Shuying Shen;Q. Dong;Yaxuan Zhang;T. Jiang;D. Lu;Shiguang Zhao;Y. You;Ning Liu;Huibo Wang
中科院分区：
文献类型：
--
作者：
Rui Zhang;Hui Luo;Shuai Wang;Wanghao Chen;Zhengxin Chen;Hong-Wei Wang;Yuanyuan Chen;Jingmin Yang;Xiaotian Zhang;Wenting Wu;Shuyong Zhang;Shuying Shen;Q. Dong;Yaxuan Zhang;T. Jiang;D. Lu;Shiguang Zhao;Y. You;Ning Liu;Huibo Wang
背景越来越多的证据表明微小RNA（miRNA）与多形性胶质母细胞瘤（GBM）的发生和发展密切相关。在这里，我们艾德了一种新的肿瘤抑制性miRNA，miR-377，并研究了它对GBM的作用和治疗效果。方法对GBM患者标本和邻近非肿瘤脑组织进行miRNA筛查。实时荧光定量PCR检测miR-377的表达。研究了miR-377对GBM细胞增殖、细胞周期进展、侵袭和原位致瘤性的影响。在皮下GBM模型中探索了miR-377模拟物的治疗效果。采用Western blot和荧光素酶报告基因分析鉴定miR-377的直接和功能靶点。结果MiR-377在人GBM组织和细胞系中表达显著下调。miR-377的过表达显著抑制了培养物和原位异种移植肿瘤模型中的细胞生长，阻断了G1/S转换，并抑制了GBM细胞中的细胞侵袭。重要的是，miR-377的引入可以强烈抑制皮下GBM模型中的肿瘤生长。随后的研究表明，特异性蛋白1（Sp1）是GBM细胞中miR-377的直接和功能性靶点。Sp1的沉默重现了miR-377的抗增殖和抗侵袭作用，而恢复Sp1表达则拮抗了miR-377的肿瘤抑制功能。最后，对人GBM组织中miR-377和Sp1水平的分析显示，miR-377与Sp1表达呈负相关。结论miR-377/Sp1信号通路可能参与GBM的发生发展，并可能成为GBM治疗的靶点。
BACKGROUND Increasing evidence has indicated that microRNAs (miRNAs) are strongly implicated in the initiation and progression of glioblastoma multiforme (GBM). Here, we identified a novel tumor suppressive miRNA, miR-377, and investigated its role and therapeutic effect for GBM. METHODS MiRNA global screening was performed on GBM patient samples and adjacent nontumor brain tissues. The expression of miR-377 was detected by real-time reverse-transcription PCR. The effects of miR-377 on GBM cell proliferation, cell cycle progression, invasion, and orthotopic tumorigenicity were investigated The therapeutic effect of miR-377 mimic was explored in a subcutaneous GBM model. Western blot and luciferase reporter assay were used to identify the direct and functional target of miR-377. RESULTS MiR-377 was markedly downregulated in human GBM tissues and cell lines. Overexpression of miR-377 dramatically inhibited cell growth both in culture and in orthotopic xenograft tumor models, blocked G1/S transition, and suppressed cell invasion in GBM cells. Importantly, introduction of miR-377 could strongly inhibit tumor growth in a subcutaneous GBM model. Subsequent investigation revealed that specificity protein 1 (Sp1) was a direct and functional target of miR-377 in GBM cells. Silencing of Sp1 recapitulated the antiproliferative and anti-invasive effects of miR-377, whereas restoring the Sp1 expression antagonized the tumor-suppressive function of miR-377. Finally, analysis of miR-377 and Sp1 levels in human GBM tissues revealed that miR-377 is inversely correlated with Sp1 expression. CONCLUSION These findings reveal that miR-377/Sp1 signaling that may be required for GBM development and may consequently serve as a therapeutic target for the treatment of GBM.