He Yi, Zhou Haiting, Wang Wei, Xu Haoran, Cheng Hao
Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Front Genet. 2021 May 17;12:632359. doi: 10.3389/fgene.2021.632359. eCollection 2021.
Osteosarcoma is a common malignant primary bone tumor in adolescents and children. Numerous studies have shown that circRNAs were involved in the proliferation and invasion of various tumors. However, the role of circRNAs in osteosarcoma remains unclear. Here, we aimed to explore the regulatory network among circRNA-miRNA-mRNA in osteosarcoma.
The circRNA (GSE140256), microRNA (GSE28423), and mRNA (GSE99671) expression profiles of osteosarcoma were collected from the Gene Expression Omnibus (GEO) database. Differentially expressed circRNAs, miRNAs and mRNAs were identified. CircRNA-miRNA interactions and miRNA-mRNA interactions were determined by Circular RNA Interactome (CircInteractome) database and microRNA Data Integration Portal (mirDIP) database, respectively. Then, we constructed a regulatory network. Function enrichment analysis of miRNA and mRNA was performed by DIANA-miRPath v3.0 and Metascape database, respectively. mRNAs with significant prognostic value were identified based on expression profiles from The Cancer Genome Atlas (TCGA) database, and we constructed a subnetwork for them. To make the most of the network, we used the CLUE database to predict potential drugs for the treatment of osteosarcoma based on mRNA expression in the network. And we used the STITCH database to analyze and validate the interactions among these drugs and mRNAs, and to further screen for potential drugs.
A total of 9 circRNAs, 19 miRNAs, 67 mRNAs, 54 pairs of circRNA-miRNA interactions and 110 pairs of miRNA-mRNA interactions were identified. A circRNA-miRNA-mRNA network was constructed. Function enrichment analysis indicated that these miRNAs and mRNAs in the network were involved in the process of tumorigenesis and immune response. Among these mRNAs, STC2 and RASGRP2 with significantly prognostic value were identified, and we constructed a subnetwork for them. Based on mRNA expression in the network, three potential drugs, quinacridine, thalidomide and zonisamide, were screened for the treatment of osteosarcoma. Among them, quinacridine and thalidomide have been proved to have anti-tumor effects in previous studies, while zonisamide has not been reported. And a corresponding drug-protein interaction network was constructed.
Overall, we constructed a circRNA-miRNA-mRNA regulatory network to investigate the possible mechanism in osteosarcoma, and predicted that quinacridine, thalidomide and zonisamide could be potential drugs for the treatment of osteosarcoma.
骨肉瘤是青少年和儿童常见的原发性恶性骨肿瘤。众多研究表明，环状RNA（circRNA）参与了多种肿瘤的增殖和侵袭。然而，circRNA在骨肉瘤中的作用仍不清楚。在此，我们旨在探索骨肉瘤中circRNA- miRNA- mRNA之间的调控网络。
从基因表达综合数据库（GEO）收集骨肉瘤的circRNA（GSE140256）、微小RNA（miRNA，GSE28423）和信使核糖核酸（mRNA，GSE99671）表达谱。鉴定差异表达的circRNA、miRNA和mRNA。circRNA与miRNA的相互作用以及miRNA与mRNA的相互作用分别通过环状RNA相互作用组数据库（CircInteractome）和微小RNA数据整合门户（mirDIP）数据库确定。然后，我们构建了一个调控网络。分别通过DIANA - miRPath v3.0和Metascape数据库对miRNA和mRNA进行功能富集分析。基于癌症基因组图谱（TCGA）数据库的表达谱鉴定具有显著预后价值的mRNA，并为它们构建一个子网。为了充分利用该网络，我们使用CLUE数据库根据网络中的mRNA表达预测治疗骨肉瘤的潜在药物。并且我们使用STITCH数据库分析和验证这些药物与mRNA之间的相互作用，并进一步筛选潜在药物。
共鉴定出9种circRNA、19种miRNA、67种mRNA、54对circRNA - miRNA相互作用和110对miRNA - mRNA相互作用。构建了一个circRNA - miRNA - mRNA网络。功能富集分析表明，网络中的这些miRNA和mRNA参与了肿瘤发生和免疫反应过程。在这些mRNA中，鉴定出具有显著预后价值的STC2和RASGRP2，并为它们构建了一个子网。基于网络中的mRNA表达，筛选出三种治疗骨肉瘤的潜在药物，即喹吖因、沙利度胺和唑尼沙胺。其中，喹吖因和沙利度胺在先前的研究中已被证明具有抗肿瘤作用，而唑尼沙胺尚未见报道。并构建了相应药物 - 蛋白质相互作用网络。
总体而言，我们构建了一个circRNA - miRNA - mRNA调控网络来研究骨肉瘤可能的机制，并预测喹吖因、沙利度胺和唑尼沙胺可能是治疗骨肉瘤的潜在药物。
