Abstract
BackgroundOsteosarcoma 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.MethodsThe 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.ResultsA 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.ConclusionOverall, 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.
Highlights
Osteosarcoma is a common malignant primary bone tumor in adolescents and children (Luetke et al, 2014)
GSE99671 is a dataset of expression profiling by high throughput sequencing, containing 18 osteosarcoma samples and 18 corresponding normal bone samples, which was used to screen for differentially expressed mRNAs
The Cancer Genome Atlas (TCGA)2 is a landmark cancer genomics program demonstrating the genomic alterations associated with 33 cancer types. 88 osteosarcoma samples were obtained from the database
Summary
Osteosarcoma is a common malignant primary bone tumor in adolescents and children (Luetke et al, 2014). This tumor is most likely to happen in the metaphysis regions of long bones (Cortini et al, 2017). Early screening and diagnosis of osteosarcoma are arduous due to the lack of adequate diagnostic markers (Li and Wang, 2020). It is urgent to figure out the underlying pathogenesis of osteosarcoma, and to discover potential targets for earlier diagnosis and potential drugs for better treatment. Osteosarcoma is a common malignant primary bone tumor in adolescents and children. The role of circRNAs in osteosarcoma remains unclear. We aimed to explore the regulatory network among circRNA-miRNA-mRNA in osteosarcoma
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