CircularRNA_104670 plays a critical role in intervertebral disc degeneration by functioning as a ceRNA.
CircularRNA_104670 plays a critical role in intervertebral disc degeneration by functioning as a ceRNA.
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CircularRNA_104670 作为 ceRNA 在椎间盘退变中发挥关键作用
DOI：
10.1038/s12276-018-0125-y
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发表时间：
2018-08-06
影响因子：
12.8
通讯作者：
Jiang JY
中科院分区：
文献类型：
--
作者：
Song J;Wang HL;Song KH;Ding ZW;Wang HL;Ma XS;Lu FZ;Xia XL;Wang YW;Fei-Zou;Jiang JY
本研究旨在探讨髓核（NP）组织中的环状RNA（circRNA）在椎间盘退变（IDD）中的作用。根据微阵列分析的结果鉴定了 IDD 和正常 NP 组织中差异表达的 circRNA。采用生物信息学技术来预测选定的 circRNA、microRNA (miR) 和 mRNA 的直接相互作用。 CircRNA_104670因其在IDD组织中的大倍数表达而被选为目标circRNA。经过荧光素酶报告基因和EGFP/RFP报告基因检测，我们证实circRNA_104670直接结合miR-17-3p，而MMP-2是miR-17-3p的直接靶标。受试者工作特征（ROC）曲线显示，circRNA_104670和miR-17-3p对IDD具有良好的诊断意义（AUC circRNA_104670 = 0.96；AUC miRNA-17-3p = 0.91）。在 Pfirrmann 分级与 circRNA_104670 (r = 0.63; p = 0.00) 和 miR-17-3p (r = −0.62; p = 0.00) 的表达之间检测到显着相关性。流式细胞术分析和MTT测定表明，使用小干扰RNA（siRNA）干扰circRNA_104670可抑制NP细胞凋亡（p< 0.01），并且通过干扰miR-17-3p可减弱这种抑制作用。干扰 circRNA_104670 可抑制 MMP-2 表达并增加细胞外基质 (ECM) 形成，干扰 miR-17-3p 也可减少细胞外基质 (ECM) 形成。最后，MRI评估显示，与对照小鼠相比，circRNA_104670抑制小鼠的IDD等级较低（p< 0.01），而与circRNA_104670抑制小鼠相比，circRNA_104670和miRNA-17-3p抑制小鼠的IDD等级较高（p< 0.05）。 CircRNA_104670 在 IDD 的 NP 组织中高表达，并在 NP 降解过程中充当 ceRNA。 “RNA海绵”可能会通过吸收通常保护椎间盘细胞周围蛋白质基础设施的调节RNA而引发腰痛。许多人患有由椎间盘退变（IDD）引起的腰痛。中国上海复旦大学邹飞和蒋建元领导的研究小组着手确定可能导致 IDD 的分子机制。他们专注于环状RNA，即与多种疾病相关的非蛋白质编码RNA。研究人员了解到，IDD 与环状 RNA 的表达强烈升高有关，该环状 RNA 充当“RNA 海绵”，与其他 RNA 分子结合并从而使其失活。这种失活最终会导致酶的过量产生，这种酶会破坏支撑椎间盘内细胞的蛋白质基质，从而可能为 IDD 创造条件。
This study was carried out to explore the roles of circular RNAs (circRNAs) in nucleus pulposus (NP) tissues in intervertebral disc degeneration (IDD). Differentially expressed circRNAs in IDD and normal NP tissues were identified based on the results of microarray analysis. Bioinformatics techniques were employed to predict the direct interactions of selected circRNAs, microRNAs (miR), and mRNAs. CircRNA_104670 was selected as the target circRNA due to its large multiplier expression in IDD tissues. After luciferase reporter and EGFP/RFP reporter assays, we confirmed that circRNA_104670 directly bound to miR-17-3p, while MMP-2 was the direct target of miR-17-3p. The receiver-operating characteristic (ROC) curve showed that circRNA_104670 and miR-17-3p had good diagnostic significance for IDD (AUC circRNA_104670 = 0.96; AUC miRNA-17-3p = 0.91). A significant correlation was detected between the Pfirrmann grade and expression of circRNA_104670 (r = 0.63; p = 0.00) and miR-17-3p (r = −0.62; p = 0.00). Flow-cytometric analysis and the MTT assay showed that interfering with circRNA_104670 using small interfering RNA (siRNA) inhibited NP cell apoptosis (p < 0.01), and this inhibition was reduced by interfering with miR-17-3p. Interfering with circRNA_104670 suppressed MMP-2 expression and increased extracellular matrix (ECM) formation, which were also reduced by interfering with miR-17-3p. Finally, an MRI evaluation showed that circRNA_104670 inhibition mice had a lower IDD grade compared with control mice (p < 0.01), whereas circRNA_104670 and miRNA-17-3p inhibition mice had a higher IDD grade compared with circRNA_104670 inhibition mice (p < 0.05). CircRNA_104670 is highly expressed in the NP tissues of IDD and acts as a ceRNA during NP degradation. ‘RNA sponges’ may provoke lower back pain by soaking up regulatory RNAs that normally protect the protein infrastructure surrounding cells in intervertebral discs. Many people suffer from lower back pain arising from disc degeneration (IDD). A team led by Fei-Zou and Jian-Yuan Jiang at Fudan University, Shanghai, China set out to identify molecular mechanisms that might contribute to IDD. They focused on circular RNAs, non-protein coding RNAs that have been linked to a variety of diseases. The researchers learned that IDD is associated with strongly elevated expression of a circular RNA that acts as an ‘RNA sponge’, binding to and thereby inactivating other RNA molecules. This inactivation ultimately results in the excessive production of an enzyme that can damage the protein matrix that supports cells within spinal discs, potentially setting up the conditions for IDD.
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