Department of Radiation Oncology, Tianjin Huanhu Hospital, Tianjin 300060, China.
J Transl Med. 2012 Jun 8;10:119. doi: 10.1186/1479-5876-10-119.
MiR-221 and miR-222 (miR-221/222), upregulated in gliomas, can regulate glioma cell cycle progression and apoptosis, respectively. However, the association of miR-221/222 with glioma cell invasion and survival remains unknown.
Invasion capability of miR-221/222 was detected by mutiple analyses, including diffusion tensor imaging (DTI), transwell, wound healing and nude mouse tumor xenograft model assay. Further, the target of miR-221/222 was determined by luciferase reporter, western blot and gene rescue assay. The association of miR-221/222 with outcome was examined in fifty glioma patients.
MiR-221/222 expression was significantly increased in high-grade gliomas compared with low-grade gliomas, and positively correlated with the degree of glioma infiltration. Over-expression of miR-221/222 increased cell invasion, whereas knockdown of miR-221/222 decreased cell invasion via modulating the levels of the target, TIMP3. Introduction of a TIMP3 cDNA lacking 3' UTR abrogated miR-221/222-induced cell invasion. In addition, knockdown of miR-221/222 increased TIMP3 expression and considerably inhibited tumor growth in a xenograft model. Finally, the increased level of miR-221/222 expression in high-grade gliomas confers poorer overall survival.
The present data indicate that miR-221 and miR-222 directly regulate cell invasion by targeting TIMP3 and act as prognostic factors for glioma patients.
miR-221 和 miR-222（miR-221/222）在神经胶质瘤中上调，分别可以调节神经胶质瘤细胞周期进程和细胞凋亡。然而，miR-221/222 与神经胶质瘤细胞侵袭和存活的关联尚不清楚。
通过多种分析，包括扩散张量成像（DTI）、Transwell、划痕愈合和裸鼠肿瘤异种移植模型检测 miR-221/222 的侵袭能力。进一步通过荧光素酶报告、Western blot 和基因拯救实验确定 miR-221/222 的靶标。在 50 例神经胶质瘤患者中检测 miR-221/222 与预后的相关性。
与低级别神经胶质瘤相比，高级别神经胶质瘤中 miR-221/222 的表达显著增加，并且与神经胶质瘤浸润程度呈正相关。miR-221/222 的过表达增加了细胞侵袭，而通过调节靶标 TIMP3 的水平，miR-221/222 的敲低降低了细胞侵袭。引入缺乏 3'UTR 的 TIMP3 cDNA 可消除 miR-221/222 诱导的细胞侵袭。此外，miR-221/222 的敲低增加了 TIMP3 的表达，并在异种移植模型中显著抑制肿瘤生长。最后，高级别神经胶质瘤中 miR-221/222 表达水平的增加提示总体生存较差。
本研究数据表明，miR-221 和 miR-222 通过靶向 TIMP3 直接调节细胞侵袭，并作为神经胶质瘤患者的预后因素。
Zotero 插件
