Abstract
BackgroundMiR-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.MethodsInvasion 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.ResultsMiR-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.ConclusionsThe present data indicate that miR-221 and miR-222 directly regulate cell invasion by targeting TIMP3 and act as prognostic factors for glioma patients.
Highlights
MiR-221 and miR-222, upregulated in gliomas, can regulate glioma cell cycle progression and apoptosis, respectively
Correlation of miR-221/222 expression levels and glioma invasion To evaluate tumor invasion in patients, we employed MR diffusion tensor imaging (DTI), which is an MRI technique that can indirectly evaluate the integrity of the white matter by measuring water diffusion and its directionality
Similar trends were observed in the expression of proteins relevant to invasion (TIMP3, MMP2 and MMP9) (Figure 4C). These results indicate that TIMP3 is a major target of miR-221 and miR-222 in regulating glioma cell invasion
Summary
MiR-221 and miR-222 (miR-221/222), upregulated in gliomas, can regulate glioma cell cycle progression and apoptosis, respectively. The association of miR-221/222 with glioma cell invasion and survival remains unknown. The hallmark of GBM is the widespread diffuse invasion of tumor cells into brain tissues. Growing evidence has indicated important roles for miRNAs in tumor invasion. MiR-21 is an important oncogenic miRNA that promotes cell invasion by regulating multiple genes, including PTEN, RECK and MARCKS in several kinds of cancers, such as glioma, ovarian epithelial carcinoma and prostate cancer [5,6,7]. MiR-146a inhibits the invasive capacity with concomitant down-regulation of EGFR and the NF-kappaB regulatory kinase, interleukin 1 receptorassociated kinase 1 (IRAK-1) [8]. Over-expression of miR-146b inhibits glioma cell invasion by targeting matrix metalloproteinases (MMPs) [10]. There is little direct evidence to show the mechanism by which miR-221/222 controls glioma invasion
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