Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
The National Key Clinical Specialty, Engineering Technology Research Center of Education Ministry of China, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Guangzhou, China.
J Cell Physiol. 2019 Jun;234(6):9144-9155. doi: 10.1002/jcp.27591. Epub 2018 Oct 20.
The prognosis for human glioma, a malignant tumor of the central nervous system, is poor due to its rapid growth, genetic heterogeneity, and inadequate understanding of its underlying molecular mechanisms. Circular RNAs composed of exonic sequences, represent an understudied form of noncoding RNAs (ncRNAs) that was discovered more than a decade ago, function as microRNA sponges. We aimed to assess the relationship between circ-U2AF1 (CircRNA ID: hsa_circ_0061868) and hsa-mir-7-5p and examine their effects on proliferation, apoptosis, and the metastatic phenotype of glioma cells regulated by neuro-oncological ventral antigen 2 (NOVA2). We found that the expression levels of circ-U2AF1 and NOVA2 were upregulated, while hsa-miR-7-5p was downregulated in human glioma tissues and glioma cell lines. Our data and bioinformatic analysis indicated the association of these molecules with glioma grade, a positive correlation between circ-U2AF1 and NOVA2 expression levels and a negative correlation of hsa-miR-7-5p with both circ-U2AF1 and NOVA2, respectively. In addition, silencing of circ-U2AF1 expression resulted in increased hsa-miR-7-5p expression and decreased NOVA2 expression both in vitro and in vivo. Luciferase assay confirmed hsa-miR-7-5p as a direct target of circ-U2AF1 and NOVA2 as a direct target of hsa-miR-7-5p. Functionally, silencing of circ-U2AF1 inhibits glioma development by repressing NOVA2 via upregulating hsa-miR-7-5p both in vitro and in vivo. Thus, we assumed that circ-U2AF1 promotes glioma malignancy via derepressing NOVA2 by sponging hsa-miR-7-5p. Taken together, we suggest that circ-U2AF1 can be a prognostic biomarker and the circ-U2AF1/hsa-miR-7-5p/NOVA2 regulatory pathway may be a novel therapeutic target for treating gliomas.
人神经胶质瘤的预后较差，这是由于其快速生长、遗传异质性以及对其潜在分子机制的认识不足所致。由外显子序列组成的环状 RNA 是一种研究较少的非编码 RNA（ncRNA）形式，它是十多年前发现的，作为 microRNA 海绵发挥作用。我们旨在评估 circ-U2AF1（circRNA ID：hsa_circ_0061868）和 hsa-mir-7-5p 之间的关系，并研究它们对神经肿瘤学腹侧抗原 2（NOVA2）调节的神经胶质瘤细胞增殖、凋亡和转移表型的影响。我们发现，circ-U2AF1 和 NOVA2 的表达水平在人神经胶质瘤组织和神经胶质瘤细胞系中上调，而 hsa-miR-7-5p 的表达水平下调。我们的数据和生物信息学分析表明，这些分子与神经胶质瘤的分级有关，circ-U2AF1 和 NOVA2 的表达水平呈正相关，hsa-miR-7-5p 分别与 circ-U2AF1 和 NOVA2 呈负相关。此外，在体外和体内，沉默 circ-U2AF1 的表达导致 hsa-miR-7-5p 的表达增加和 NOVA2 的表达减少。荧光素酶报告基因实验证实 hsa-miR-7-5p 是 circ-U2AF1 的直接靶基因，NOVA2 是 hsa-miR-7-5p 的直接靶基因。功能上，沉默 circ-U2AF1 通过上调 hsa-miR-7-5p 抑制 NOVA2 的表达，从而抑制神经胶质瘤的发展，无论是在体外还是体内。因此，我们假设 circ-U2AF1 通过海绵吸附 hsa-miR-7-5p 来抑制 NOVA2 的表达，从而促进神经胶质瘤的恶性转化。综上所述，我们认为 circ-U2AF1 可作为一种预后生物标志物，circ-U2AF1/hsa-miR-7-5p/NOVA2 调控途径可能成为治疗神经胶质瘤的新的治疗靶点。
