miR-146b-5p functions as a tumor suppressor by targeting TRAF6 and predicts the prognosis of human gliomas
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Jing Liu1,2,3,*, Jinling Xu1,2,3,*, Huining Li1,2,3,*, Cuiyun Sun1,2,3, Lin Yu4, Yanyan Li1,2,3, Cuijuan Shi1,2,3, Xuexia Zhou1,2,3, Xiuwu Bian5, Yifang Ping5, Yanjun Wen1,2,3, Shujun Zhao1,2,6, Hui Xu1,2,3, Linlin Ren1,2,3, Tongling An1,2,3, Qian Wang1,2,3, Shizhu Yu1,2,3
1Department of Neuropathology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin 300052, China
2Tianjin Key Laboratory of Injuries, Variations and Regeneration of the Nervous System, Tianjin 300052, China
3Key Laboratory of Post-trauma Neuro-repair and Regeneration in Central Nervous System, Ministry of Education, Tianjin 300052, China
4Department of Biochemistry, Basic Medical College of Tianjin Medical University, Tianjin 300070, China
5Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, China
6Laboratory of Hormone and Development, Ministry of Health, Institute of Endocrinology, Tianjin Medical University, Tianjin 300070, China
*These authors have contributed equally to this work
Shizhu Yu, e-mail: firstname.lastname@example.org
Qian Wang, e-mail: email@example.com
Keywords: gliomas, miR-146b-5p, TRAF6, proliferation, apoptosis, prognosis
Received: May 20, 2015 Accepted: July 24, 2015 Published: August 06, 2015
Down-regulation of miR-146b-5p contributes to tumorigenesis in several human cancers. However, the relevance of miR-146b-5p to prognosis, proliferation and apoptosis in gliomas remains unknown. In the present study, we demonstrated that miR-146b-5p expression was inversely correlated with grades and Ki-67 index in 147 human glioma specimens, but positively correlated with patients’ survival. Furthermore, two distinct subgroups of patients with grade I-IV gliomas with different prognoses were identified according to miR-146b-5p expression in our specimens. Cox regression showed that miR-146b-5p was an independent predictor for patients’ survival. Overexpression of miR-146b-5p dramatically suppressed glioma cell proliferation and induced apoptosis. Mechanistically, we validated TRAF6 as a direct functional target of miR-146b-5p and found that miR-146b-5p overexpression significantly decreased phosphorylated TAK1 and IκBα, the pivotal downstream effectors of TRAF6. Moreover, TRAF6 expression was positively correlated with glioma grades and Ki-67 index but inversely correlated with miR-146b-5p expression and predicted poor prognosis of glioma patients. In glioblastoma cell lines, silencing of TRAF6 could mimic the anti-tumor effect of miR-146b-5p. Our findings identify miR-146b-5p as a tumor suppressor and novel prognostic biomarker of gliomas, and suggest miR-146b-5p and TRAF6 as potential therapeutic candidates for malignant gliomas.
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