Zhi Feng, Wang Qiang, Deng Danni, Shao Naiyuan, Wang Rong, Xue Lian, Wang Suinuan, Xia Xiwei, Yang Yilin
Modern Medical Research Center, Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, China.
Department of Neurosurgery, Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, China.
PLoS One. 2014 Oct 9;9(10):e109124. doi: 10.1371/journal.pone.0109124. eCollection 2014.
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.
微小RNA（miRNA）是一类小的非编码RNA，通过靶向mRNA来调控众多基因的表达。在各种人类恶性肿瘤中观察到许多异常的miRNA表达模式，某些miRNA可作为癌基因或肿瘤抑制因子。星形细胞瘤是最常见的神经上皮性癌症，占人类恶性脑肿瘤的大多数。在我们之前的研究中，我们发现星形细胞瘤中miR-181b-5p的下调与预后不良相关。本研究的目的是探讨miR-181b-5p的功能作用及其可能的靶基因。miR-181b-5p在星形细胞瘤标本中显著下调，其表达降低与临床分期呈负相关。miR-181b-5p的异位表达在体外抑制星形细胞瘤癌细胞的增殖、迁移和侵袭，并诱导其凋亡。NOVA1（神经肿瘤腹侧抗原1）基因被进一步鉴定为miR-181b-5p的一个新的直接靶点。具体而言，miR-181b-5p直接与NOVA1的3'非翻译区（UTR）结合并抑制其表达。在临床标本中，NOVA1过表达，其蛋白水平与miR-181b-5p表达呈负相关。此外，NOVA1水平的变化与生存结果不良显著相关。与恢复miR-181b-5p表达类似，下调NOVA1可抑制细胞生长、迁移和侵袭。NOVA1的过表达逆转了miR-181b-5p的抑制作用。我们的结果表明，miR-181b-5p是星形细胞瘤中的一种肿瘤抑制因子，通过靶向NOVA1抑制肿瘤进展。这些发现表明，miR-181b-5p可能作为星形细胞瘤的一个新的治疗靶点。
