Abstract
Among astrocyte tumors, glioblastoma (GBM) is the most malignant glioma, highly aggressive and invasive, with extremely poor prognosis. Previous research has reported that microRNAs (miRNAs) participate in the progression of many cancers. Thus, this study aimed to explore the role and the underlying mechanisms of microRNA (miR)-489-3p in GBM progression. The expression of miR-489-3p and brain-derived neurotrophic factor (BDNF) mRNA was measured by quantitative real-time polymerase chain reaction. Western blot analysis was used to detect BDNF protein and the PI3K/AKT pathway-related protein. Cell proliferation, apoptosis, migration, and invasion were analyzed using CKK-8 assay, flow cytometry, and transwell assay, respectively. The interaction between BDNF and miR-489-3p was explored by luciferase reporter assay and RNA immunoprecipitation (RIP) assay. MiR-489-3p was down-regulated and BDNF was up-regulated in GBM tissues and cells. MiR-489-3p re-expression or BDNF knockdown inhibited GBM cell proliferation, migration, and invasion, and promoted apoptosis. BDNF was a target of miR-489-3p, and BDNF up-regulation reversed the effects of miR-489-3p on GBM cells. The protein levels of p-AKT and p-PI3K were notably reduced in GBM cells by overexpression of miR-489-3p, but were rescued following BDNF up-regulation. Therefore, miR-489-3p inhibited proliferation, migration, and invasion, and induced apoptosis, by targeting the BDNF-mediated PI3K/AKT pathway in GBM, providing new strategies for clinical treatment of GBM.
Highlights
Glioblastoma (GBM), accounting for more than 80% of all tumors in the brain, is the most malignant glioma among astrocyte tumors [1]
We found that miR-489-3p was downregulated in GBM tissues and cells. miR-489-3p targeted brain-derived neurotrophic factor (BDNF) and regulated GBM cell proliferation, migration, invasion, and apoptosis, suppressing the BDNF-mediated PI3K/AKT signaling pathway
The data showed that the protein level of BDNF was significantly elevated in GBM tissue compared with the normal group (Figure 1a and b, P < 0.0001), and the mRNA of BDNF in LN229 and U251 cells was highly expressed compared with the NHAs cells (Figure 1c, P = 0.014; P = 0.0039)
Summary
Glioblastoma (GBM), accounting for more than 80% of all tumors in the brain, is the most malignant glioma among astrocyte tumors [1]. MicroRNAs (miRNAs) are a class of endogenous, non-coding, single-stranded small RNAs of approximately 21–23 nucleotides in length. Due to their capacity to achieve post-transcriptional silencing of tumor suppressors or oncogenes, miRNAs are regarded as important regulators of gene expression, both in pathological and physiological conditions [5]. Many miRNA molecules were identified in different GBM samples [6,7], most of them are highly expressed while a few are down-regulated compared with normal tissues; all of them display oncogenic or antioncogenic features though the regulation of crucial biological processes, such as proliferation, metastasis, apoptosis, DNA repair, and so on [8,9,10]
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