Liu Jing, Xu Jinling, Li Huining, Sun Cuiyun, Yu Lin, Li Yanyan, Shi Cuijuan, Zhou Xuexia, Bian Xiuwu, Ping Yifang, Wen Yanjun, Zhao Shujun, Xu Hui, Ren Linlin, An Tongling, Wang Qian, Yu Shizhu
Department of Neuropathology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin 300052, China.
Tianjin Key Laboratory of Injuries, Variations and Regeneration of the Nervous System, Tianjin 300052, China.
Oncotarget. 2015 Oct 6;6(30):29129-42. doi: 10.18632/oncotarget.4895.
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.
miR-146b-5p的下调在多种人类癌症的肿瘤发生中起作用。然而，miR-146b-5p与胶质瘤的预后、增殖和凋亡之间的相关性仍不清楚。在本研究中，我们证明在147例人类胶质瘤标本中，miR-146b-5p的表达与肿瘤分级和Ki-67指数呈负相关，但与患者生存率呈正相关。此外，根据我们标本中miR-146b-5p的表达，将I-IV级胶质瘤患者分为两个预后不同的亚组。Cox回归分析表明，miR-146b-5p是患者生存的独立预测因子。miR-146b-5p的过表达显著抑制胶质瘤细胞增殖并诱导凋亡。机制上，我们验证了TRAF6是miR-146b-5p的直接功能靶点，发现miR-146b-5p过表达显著降低了TRAF6关键下游效应分子磷酸化的TAK1和IκBα。此外，TRAF6的表达与胶质瘤分级和Ki-67指数呈正相关，但与miR-146b-5p的表达呈负相关，并预测胶质瘤患者预后不良。在胶质母细胞瘤细胞系中，沉默TRAF6可模拟miR-146b-5p的抗肿瘤作用。我们的研究结果表明miR-146b-5p是胶质瘤的肿瘤抑制因子和新的预后生物标志物，并提示miR-146b-5p和TRAF6是恶性胶质瘤潜在的治疗靶点。
