Upregulation of miR-181s reverses mesenchymal transition by targeting KPNA4 in glioblastoma.
Upregulation of miR-181s reverses mesenchymal transition by targeting KPNA4 in glioblastoma.
复制标题
miR-181s 的上调通过靶向胶质母细胞瘤中的 KPNA4 来逆转间质转化。
DOI：
10.1038/srep13072
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发表时间：
2015-08-18
影响因子：
4.6
通讯作者：
Jiang C
中科院分区：
文献类型：
--
作者：
Wang H;Tao T;Yan W;Feng Y;Wang Y;Cai J;You Y;Jiang T;Jiang C
这项工作的目标是探索影响多形性胶质母细胞瘤 (GBM) 表型转变和恶性进展的最有效 miRNA。我们根据 mRNA 亚型注释了 491 个 TCGA 样本的 miRNA 表达谱，发现与其他三种亚型相比，间充质肿瘤的 miR-181 家族表达显着降低，而原神经亚型则具有极高的 miR-181 家族表达。 miR-181 家族高表达的患者总生存期较长 (p = 0.0031)。我们还证实，NF-κB 靶向基因和 EMT（上皮间质转化）途径与 miR-181 家族表达呈负相关，并且整个 miR-181 家族抑制神经胶质瘤细胞侵袭和增殖；其中，miR-181b 是最有效的抑制剂。此外，miR-181b 被验证可以通过靶向 KPNA4 来抑制 EMT，并且在 TCGA 和 CGGA 数据集以及另一个独立队列中与生存结果相关。 KPNA4 表达恢复后，miR-181b 的 EMT 抑制作用消失。我们还鉴定了 miR-181b 的体外和体内抗肿瘤活性。我们的结果表明，miR-181 家族的表达与 TCGA 亚型和患者的总生存期密切相关，表明 miR-181b（一种肿瘤抑制 miRNA）可能成为治疗神经胶质瘤的新候选药物。
The goal of this work was to explore the most effective miRNAs affecting glioblastoma multiforme (GBM) phenotype transition and malignant progression. We annotated 491 TCGA samples’ miRNA expression profiles according to their mRNA-based subtypes and found that the mesenchymal tumors had significantly decreased miR-181 family expression compared with the other three subtypes while the proneural subtype harbored extremely high miR-181 family expression. Patients with high miR-181 family expression had longer overall survival (p = 0.0031). We also confirmed that NF-κB-targeting genes and the EMT (epithelial-mesenchymal transition) pathway were inversely correlated with miR-181 family expression and that the entire miR-181 family inhibited glioma cell invasion and proliferation; of these, miR-181b was the most effective suppressor. Furthermore, miR-181b was validated to suppress EMT by targeting KPNA4 and was associated with survival outcome in the TCGA and CGGA datasets and in another independent cohort. The EMT-inhibitory effect of miR-181b was lost after KPNA4 expression was restored. We also identified the antitumorigenic activity of miR-181b in vitro and in vivo. Our results showed that miR-181 family expression was closely correlated with TCGA subtypes and patients’ overall survival, indicating that miR-181b, a tumor-suppressive miRNA, could be a novel therapeutic candidate for treating gliomas.