miR-146b-5p functions as a tumor suppressor by targeting TRAF6 and predicts the prognosis of human gliomas

// Jing Liu 1, 2, 3, * , Jinling Xu 1, 2, 3, * , Huining Li 1, 2, 3, * , Cuiyun Sun 1, 2, 3 , Lin Yu 4 , Yanyan Li 1, 2, 3 , Cuijuan Shi 1, 2, 3 , Xuexia Zhou 1, 2, 3 , Xiuwu Bian 5 , Yifang Ping 5 , Yanjun Wen 1, 2, 3 , Shujun Zhao 1, 2, 6 , Hui Xu 1, 2, 3 , Linlin Ren 1, 2, 3 , Tongling An 1, 2, 3 , Qian Wang 1, 2, 3 , Shizhu Yu 1, 2, 3 1 Department of Neuropathology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin 300052, China 2 Tianjin Key Laboratory of Injuries, Variations and Regeneration of the Nervous System, Tianjin 300052, China 3 Key Laboratory of Post-trauma Neuro-repair and Regeneration in Central Nervous System, Ministry of Education, Tianjin 300052, China 4 Department of Biochemistry, Basic Medical College of Tianjin Medical University, Tianjin 300070, China 5 Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, China 6 Laboratory of Hormone and Development, Ministry of Health, Institute of Endocrinology, Tianjin Medical University, Tianjin 300070, China * These authors have contributed equally to this work Correspondence to: Shizhu Yu, e-mail: tjyushizhu@yahoo.com Qian Wang, e-mail: wangqiantni@163.com Keywords: gliomas, miR-146b-5p, TRAF6, proliferation, apoptosis, prognosis Received: May 20, 2015 Accepted: July 24, 2015 Published: August 06, 2015 ABSTRACT 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.