Abstract
MicroRNAs (miRNAs) are small, short noncoding RNAs that modulate the expression of numerous genes by targeting their mRNA. Numerous abnormal miRNA expression patterns are observed in various human malignancies, and certain miRNAs can act as oncogenes or tumor suppressors. Astrocytoma, the most common neuroepithelial cancer, represents the majority of malignant brain tumors in humans. In our previous studies, we found that the downregulation of miR-181b-5p in astrocytomas is associated with a poor prognosis. The aim of the present study was to investigate the functional role of miR-181b-5p and its possible target genes. miR-181b-5p was significantly downregulated in astrocytoma specimens, and the reduced expression of miR-181b-5p was inversely correlated with the clinical stage. The ectopic expression of miR-181b-5p inhibited proliferation, migration and invasion and induced apoptosis in astrocytoma cancer cells in vitro. The NOVA1 (neuro-oncological ventral antigen 1) gene was further identified as a novel direct target of miR-181b-5p. Specifically, miR-181b-5p bound directly to the 3'-untranslated region (UTR) of NOVA1 and suppressed its expression. In clinical specimens, NOVA1 was overexpressed, and its protein levels were inversely correlated with miR-181b-5p expression. Furthermore, the changing level of NOVA1 was significantly associated with a poor survival outcome. Similar to restoring miR-181b-5p expression, downregulating NOVA1 inhibited cell growth, migration and invasion. Overexpression of NOVA1 reversed the inhibitory effects of miR-181b-5p. Our results indicate that miR-181b-5p is a tumor suppressor in astrocytoma that inhibits tumor progression by targeting NOVA1. These findings suggest that miR-181b-5p may serve as a novel therapeutic target for astrocytoma.
Highlights
Astrocytomas are the most common primary brain tumors in the central nervous system [1]
Our previous studies indicated that miR-181b-5p is downregulated in astrocytoma and that this reduced expression of miR-181b-5p is associated with a poor survival outcome, suggesting that miR181b-5p may act as a tumor suppressor during astrocytoma development and/or progression [7]. miR-181b-5p belongs to the miR-181 family, which includes miR-181a-5p, miR-181b-5p and miR-181c-5p
The results showed that the expression of miR-181b-5p was consistently lower in the astrocytoma tissues compared with the normal adjacent tissues (NATs) samples (Figure 1A)
Summary
Astrocytomas are the most common primary brain tumors in the central nervous system [1]. Efforts to better understand the biological basis of astrocytoma progression may provide important clinically relevant insights into disease management. Accumulating evidence suggests that miRNAs participate in the tumor angiogenesis, invasion and metastasis of human malignancies, acting as oncogenes or tumor suppressors depending on their targets, information that may provide insight into the diagnosis and prognosis of human cancers [5,6]. Our previous studies indicated that miR-181b-5p is downregulated in astrocytoma and that this reduced expression of miR-181b-5p is associated with a poor survival outcome, suggesting that miR181b-5p may act as a tumor suppressor during astrocytoma development and/or progression [7]. As it is well known that miRNAs regulate the expression of multiple target genes and affect a variety of cellular pathways, further research is required to fully understand their contributions to this malignancy
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