miR-135a-5p Functions as a Glioma Proliferation Suppressor by Targeting Tumor Necrosis Factor Receptor-Associated Factor 5 and Predicts Patients' Prognosis
miR-135a-5p Functions as a Glioma Proliferation Suppressor by Targeting Tumor Necrosis Factor Receptor-Associated Factor 5 and Predicts Patients' Prognosis
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miR-135a-5p 通过靶向肿瘤坏死因子受体相关因子 5 发挥神经胶质瘤增殖抑制剂的作用并预测患者的预后
DOI：
10.1016/j.ajpath.2018.08.019
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发表时间：
2019-01-01
影响因子：
6
通讯作者：
Yu, Shizhu
中科院分区：
文献类型：
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作者：
Luo, Wenjun;Sun, Cuiyun;Yu, Shizhu
已有报道称，miR-135a-5p在一些颅外肿瘤中具有肿瘤抑制作用。然而，它在胶质瘤发生中的确切作用以及与患者预后的相关性在很大程度上还不清楚。我们检测了120例人脑胶质瘤组织和20例非肿瘤脑组织中miR-135a-5p和肿瘤坏死因子受体相关因子5(TRAF5)的水平，发现miR-135a-5p的表达水平随着胶质瘤分级的升高而降低，而TRAF5的表达水平则随着胶质瘤分级的升高而升高。它们的标记指数呈负相关，与Ki-67指数呈强负相关(miR-135a-5p)和正相关(TRAF5)。Cox回归分析表明，两者的表达水平均是独立的生存预测因素，而Kaplan-Meier分析显示，无论病理、分子和临床特征是否相似，按胶质瘤患者的表达水平进行分组能较好地反映患者的预后。随后的体内外研究表明，miR-135a-5p通过靶向TRAF5，进而阻断AKT的磷酸化以及c-Myc和细胞周期蛋白D1的表达，诱导胶质瘤细胞G1期停滞，抑制细胞增殖。这些效应可以被TRAF5的过度表达逆转，并被特异性的TRAF5沉默所模拟。这项研究强调了miR-135a-5p和TRAF5在胶质瘤发生和发展中的重要性，并暗示了它们在恶性胶质瘤中的潜在预后和治疗价值。
miR-135a-5p has been reported as a tumor suppressor in several extracranial tumors. However, its exact roles in gliomagenesis and relevance to the patients' prognoses are largely unknown. Herein, we detected the miR-135a-5p and tumor necrosis factor receptor associated factor 5 (TRAF5) levels in 120 human glioma specimens and 20 nontumoral brain tissues; we found the miR-135a-5p level decreased, whereas the TRAF5 level increased, with the elevation of glioma grade. Their labeling indexes were inversely correlated with each other and showed strong negative (miR-135a-5p) and positive (TRAF5) correlation with the Ki-67 index. Cox regression demonstrated that both of their expression levels were independent survival predictors, whereas Kaplan-Meier analysis showed that subgrouping the glioma patients according to their levels could perfectly reflect the patients' prognoses regardless of the similarities in pathologic, molecular, and clinical features. In the following in vitro and in vivo studies, it was demonstrated that miR-135a-5p induced G1 arrest and inhibited the proliferation of glioma cells by targeting TRAF5 and subsequently blocking AKT phosphorylation as well as c-Myc and cyclin D1 expression. These effects could be reversed by TRAF5 overexpression and simulated by specific TRAF5 silencing. This study highlights the importance of miR-135a-5p and TRAF5 in gliomagenesis and progression and implies their potential prognostic and therapeutic values in malignant glioma.