MiR-196a exerts its oncogenic effect in glioblastoma multiforme by inhibition of IκBα both in vitro and in vivo.
BACKGROUND
Recent studies have revealed that miR-196a is upregulated in glioblastoma multiforme (GBM) and that it correlates with the clinical outcome of patients with GBM. However, its potential regulatory mechanisms in GBM have never been reported.


METHODS
We used quantitative real-time PCR to assess miR-196a expression levels in 132 GBM specimens in a single institution. Oncogenic capability of miR-196a was detected by apoptosis and proliferation assays in U87MG and T98G cells. Immunohistochemistry was used to determine the expression of IκBα in GBM tissues, and a luciferase reporter assay was carried out to confirm whether IκBα is a direct target of miR-196a. In vivo, xenograft tumors were examined for an antiglioma effect of miR-196a inhibitors.


RESULTS
We present for the first time evidence that miR-196a could directly interact with IκBα 3'-UTR to suppress IκBα expression and subsequently promote activation of NF-κB, consequently promoting proliferation of and suppressing apoptosis in GBM cells both in vitro and in vivo. Our study confirmed that miR-196a was upregulated in GBM specimens and that high levels of miR-196a were significantly correlated with poor outcome in a large cohort of GBM patients. Our data from human tumor xenografts in nude mice treated with miR-196 inhibitors demonstrated that inhibition of miR-196a could ameliorate tumor growth in vivo.


CONCLUSIONS
MiR-196a exerts its oncogenic effect in GBM by inhibiting IκBα both in vitro and in vivo. Our findings provide new insights into the pathogenesis of GBM and indicate that miR-196a may predict clinical outcome of GBM patients and serve as a new therapeutic target for GBM.
Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province 15001, China (G.Y., D.H., X.C., D.Z., W.Z., C.L., X.C., H.L., D.Z., J.K., F.P., Z.L., S.Z.); Institute of Brain Science, Harbin Medical University, Harbin, China (G.Y., D.H., X.C., D.Z., W.Z., C.L., X.C., H.L., D.Z., J.K., F.P., Z.L., S.Z.); Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), Harbin Medical University, Harbin, China (L.W., J.A.); Department of Neurosurgery, New York University Langone Medical Center and School of Medicine, New York, New York (C.S.); Department of Pathology, The First Affiliated Hospital of Harbin Medical University, Harbin, China (J.Q.); Computer, Electrical and Mathematical Sciences and Engineering Division, King Abdullah University of Science and Technology, Thuwal, Saudi Arabia (X.G.); Section of Neurosurgery, Department of Surgery, The University of Chicago, Medical Center and Pritzker School of Medicine, Chicago, Illinois (C.S.).
Guang
G
Yang
Dayong
D
Han
Xin
X
Chen
Daming
D
Zhang
Lu
L
Wang
Chen
C
Shi
Weiguang
W
Zhang
Chenguang
C
Li
Xiaofeng
X
Chen
Huailei
H
Liu
Dongzhi
D
Zhang
Jianhao
J
Kang
Fei
F
Peng
Ziyi
Z
Liu
Jiping
J
Qi
Xin
X
Gao
Jing
J
Ai
Changbin
C
Shi
Shiguang
S
Zhao
D000818:Animals; D017209:Apoptosis; D001932:Brain Neoplasms / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D020672:I-kappa B Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D035683:MicroRNAs / Q000378:metabolism*; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism; D016019:Survival Analysis
D020672:I-kappa B Proteins; C542543:MIRN196 microRNA, human; D035683:MicroRNAs; D016328:NF-kappa B
IκBα; apoptosis; glioblastoma; miR-196a; tumor growth