MicroRNA-485 inhibits malignant biological behaviour of glioblastoma cells by directly targeting PAK4
MicroRNA-485 inhibits malignant biological behaviour of glioblastoma cells by directly targeting PAK4
复制标题
DOI：
10.3892/ijo.2017.4122
复制
发表时间：
2017-11-01
影响因子：
5.2
通讯作者：
You, Chao
中科院分区：
文献类型：
--
作者：
Mao, Ke;Lei, Ding;You, Chao
胶质母细胞瘤（GBM）是成人胶质瘤中最常见的组织学亚型，其特征在于快速生长、细胞异质性、血管生成、广泛侵袭、缺氧和坏死。微小RNA（miRNA）失调是人类癌症（包括GBM）的共同特征。先前的研究表明，miRNAs是一种新型的调节分子在各种人类癌症。因此，miRNAs有望成为GBM临床诊断、治疗和预后的新的候选基因和筛选工具。最近越来越多的证据表明，miRNA-485（miR-485）参与了几种类型的人类癌症的发生和发展。然而，miR-485在GBM中的表达水平、确切作用和潜在机制尚不清楚。在这项研究中，miR-485在GBM组织标本和细胞系中均下调。miR-485过表达抑制GBM细胞增殖、集落形成、迁移和侵袭;增加体外凋亡;并减少体内肿瘤生长。此外，p21激活激酶4（PAK 4）被证明是GBM中miR-485的直接和功能性靶点。此外，PAK 4在GBM组织中上调，并与miR-485表达呈负相关。此外，PAK 4敲低在GBM细胞中表现出与miR-485过表达相似的效果。PAK 4的增强表达挽救了GBM细胞中miR-485的肿瘤抑制功能。miR-485抑制GBM中AKT和ERK信号通路的激活。这些结果表明，miR-485通过至少部分地直接靶向PAK 4并调节AKT和ERK信号通路而在GBM中充当肿瘤抑制剂。因此，miR-485可能是治疗GBM患者的潜在靶点。
Glioblastoma (GBM), which is characterised by rapid growth, cellular heterogeneity, angiogenesis, extensive invasion, hypoxia and necrosis, is the most common histological subtype of glioma in adults. MicroRNA (miRNA) dysregulation is a common feature of human cancers, including GBM. Previous studies have suggested that miRNAs are a novel class of regulatory molecules in various human cancers. Therefore, miRNAs may be investigated as a novel candidate and screening tool in the clinical diagnosis, therapy and prognosis of GBM. Recent accumulating evidence has demonstrated that miRNA-485 (miR-485) is involved in the development and progression of several types of human cancers. However, the expression level, exact role and underlying mechanisms of miR-485 in GBM remain unclear. In this study, miR-485 was downregulated in both GBM tissue specimens and cell lines. miR-485 overexpression inhibited GBM cell proliferation, colony formation, migration and invasion; increased apoptosis in vitro; and reduced tumour growth in vivo. In addition, p21-activated kinase 4 (PAK4) was demonstrated to be a direct and functional target of miR-485 in GBM. Furthermore, PAK4 was upregulated in GBM tissues and negatively correlated with miR-485 expression. Moreover, PAK4 knockdown exhibited a similar effect to miR-485 overexpression in GBM cells. Enforced expression of PAK4 rescued miR-485 tumour-suppressor functions in GBM cells. miR-485 inhibited the activation of the AKT and ERK signalling pathways in GBM. These results indicate that miR-485 acts as a tumour suppressor in GBM by, at least partially, directly targeting PAK4 and regulating the AKT and ERK signalling pathways. Thus, miR-485 may be a potential target for the treatment of patients with GBM.