High level of miR-221/222 confers increased cell invasion and poor prognosis in glioma.
BACKGROUND
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Department of Radiation Oncology, Tianjin Huanhu Hospital, Tianjin 300060, China.
Chunzhi
C
Zhang
Junxia
J
Zhang
Jianwei
J
Hao
Zhendong
Z
Shi
Yingyi
Y
Wang
Lei
L
Han
Shizhu
S
Yu
Yongping
Y
You
Tao
T
Jiang
Jinhuan
J
Wang
Meili
M
Liu
Peiyu
P
Pu
Chunsheng
C
Kang
D000818:Animals; D001483:Base Sequence; D001932:Brain Neoplasms / Q000235:genetics* / Q000473:pathology*; D045744:Cell Line, Tumor; D056324:Diffusion Tensor Imaging; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000235:genetics* / Q000473:pathology*; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D060787:Neoplasm Grading; D009361:Neoplasm Invasiveness; D011379:Prognosis; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
D035683:MicroRNAs; D019717:Tissue Inhibitor of Metalloproteinase-3; C525709:MIR221, human; C525710:MIR222, human; C088390:TIMP3 protein, human