miR-29s function as tumor suppressors in gliomas by targeting TRAF4 and predict patient prognosis.
miR-29s function as tumor suppressors in gliomas by targeting TRAF4 and predict patient prognosis.
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miR-29s 通过靶向 TRAF4 作为神经胶质瘤的肿瘤抑制因子并预测患者预后
DOI：
10.1038/s41419-018-1092-x
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发表时间：
2018-10-22
影响因子：
9
通讯作者：
Yu S
中科院分区：
文献类型：
--
作者：
Shi C;Rao C;Sun C;Yu L;Zhou X;Hua D;Wang R;Luo W;Jiang Z;Zhou J;Wang Q;Yu S
肿瘤细胞的强大增殖和凋亡抑制是高级别胶质瘤患者高死亡率和低预后的原因。据报道，miR-29a/b/c在几种人类肿瘤类型中是重要的抑制基因。然而，它们在胶质瘤发生中的确切作用以及它们与患者预后的相关性仍不清楚。本研究以187例人脑胶质瘤标本和20例非肿瘤脑组织为研究对象，发现miR-29a/b/c的表达随胶质瘤分级和Ki-67指数的升高而递减。而miR-29a/b/c的功能靶点TRAF4的表达与miR-29a/b/c呈负相关。Kaplan-Meier分析显示，即使在相同的肿瘤分级和相同的IDH基因状态下，miR-29a/b/c和TRAF4的表达水平也与患者的生存密切相关。功能研究证实miR-29a/b/c通过直接靶向TRAF4诱导胶质瘤细胞凋亡和抑制细胞增殖。对其作用机制的研究表明，miR-29a/b/c通过TRAF4/akt/mdm2途径促进肿瘤细胞的凋亡，其作用依赖于p53，而miR-29a/b/c通过阻断AKT和GSK-3β的磷酸化，抑制细胞周期蛋白D1和c-Myc的表达，诱导细胞周期停滞于G1期，抑制肿瘤细胞增殖。此外，TRAF4基因的敲除很好地模拟了miR-29a/b/c的抗胶质瘤作用。这些发现丰富了我们对胶质瘤发生的理解，突出了miR-29a/b/c和TRAF4的预后价值，并暗示了它们在恶性胶质瘤中的潜在治疗作用。
Robust proliferation and apoptosis inhibition of tumor cells are responsible for the high mortality and poor outcome of patients with high-grade gliomas. miR-29a/b/c have been reported to be important suppressors in several human tumor types. However, their exact roles in gliomagenesis and their relevance to patient prognosis remain unclear. In this study, using 187 human glioma specimens and 20 nontumoral brain tissues, we demonstrated that the expression of miR-29a/b/c decreased progressively as the grade of glioma and the Ki-67 index increased. However, the expression of TRAF4, the functional target of miR-29a/b/c, exhibited the inverse trend, and its level was inversely correlated with the levels of miR-29a/b/c. A Kaplan–Meier analysis demonstrated that the miR-29a/b/c and TRAF4 levels were closely associated with patient survival even in patients with the same tumor grade and identical IDH gene status. A functional study verified that miR-29a/b/c induced apoptosis and suppressed the proliferation of glioma cells by directly targeting TRAF4. An investigation of the mechanism revealed that miR-29a/b/c promoted apoptosis through the TRAF4/AKT/MDM2 pathway in a p53-dependent manner, while miR-29a/b/c induced G1 arrest and inhibited tumor cell proliferation by blocking the phosphorylation of AKT and GSK-3β, and the expression of cyclin D1 and c-Myc. Furthermore, TRAF4-knockdown perfectly simulated the anti-glioma effects of miR-29a/b/c. These findings enrich our understanding of gliomagenesis, highlight the prognostic value of miR-29a/b/c and TRAF4, and imply their potential therapeutic roles in malignant gliomas.
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影响因子：
3.9
作者：
Leroy, Bernard;Girard, Luc;Hollestelle, Antoinette;Minna, John D.;Gazdar, Adi F.;Soussi, Thierry
通讯作者：
Soussi, Thierry
影响因子：
56.9
作者：
Lagos-Quintana, M;Rauhut, R;Tuschl, T
通讯作者：
Tuschl, T
影响因子：
168.9
作者：
Ricard, Damien;Idbaih, Ahmed;Delattre, Jean-Yves
通讯作者：
Delattre, Jean-Yves
DOI：
10.1165/rcmb.2010-0323oc
发表时间：
2011-08-01
影响因子：
6.4
作者：
Cushing, Leah;Kuang, Ping Ping;Lue, Jining
通讯作者：
Lue, Jining
miR-146b-5p通过靶向MMP16抑制胶质瘤迁移和侵袭
影响因子：
9.7
作者：
Li, Yanyan;Wang, Ying;Kong, Yanling
通讯作者：
Kong, Yanling