Abstract
Introduction: Synovial sarcoma (SS) is one of the most invasive soft tissue sarcomas, prone to recurrence and metastasis, and the efficacy of surgical treatment and chemotherapy for SS remains poor. Therefore, the diagnosis and treatment of SS remain a significant challenge. This study aimed to analyze the mutated genes of primary SS (PSS) and recurrent SS (RSS), discover whether these sarcomas exhibit some potential mutated genes, and then predict associated microRNAs (miRNA) and circular RNAs (circRNA) by analyzing the mutated genes. We focused on the regulation mechanism of the circRNA-miRNA-mutated hub gene in PSS and RSS.Methods: We performed a comprehensive genomic analysis of four pairs of formalin-fixed paraffin-embedded samples of PSS and RSS, using Illumina human exon microarrays. The gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) function, and pathway enrichment of the mutated genes were analyzed, and the protein-protein interaction (PPI) network was forecast using String software 11.0. The hub genes were then obtained using the Molecular Complex Detection (MCODE) plug-in for Cytoscape 3.7.2 and were used to analyze overall survival (OS) using the Gene Expression Profiling Interactive Analysis (GEPIA) database. The corresponding miRNAs were obtained from the miRDB 5.0 and TargetScan 7.2 databases. The corresponding circRNAs of the hub genes were found through the miRNAs from these databases: Circbank, CircInteractome, and StarBase v2.0. Thereafter we set up a competing endogenous RNA (ceRNA) network with circRNA-miRNA and miRNA-messenger RNA (mRNA) pairs.Results: Using the chi-squared test, 391 mutated genes were screened using a significance level of p-values < 0.01 from the four pairs of PSS and RSS samples. A GO pathway analysis of 391 mutated genes demonstrated that differential expression mRNAs (DEmRNAs) might be bound up with the “positive regulation of neurogenesis,” “cell growth,” “axon part,” “cell−substrate junction,” or “protein phosphatase binding” of SS. The PPI network was constructed using 391 mutated genes, and 53 hub genes were identified (p < 0.05). Eight variant hub genes were discovered to be statistically significant using the OS analysis (p < 0.05). The circRNA-miRNA-mRNA (ceRNA) network was constructed, and it identified two circRNAs (hsa_circ_0070557 and hsa_circ_0070558), 10 miRNAs (hsa-let-7a-3p, hsa-let-7b-3p, hsa-let-7f-1-3p, hsa-let-7f-2-3p, hsa-mir-1244, hsa-mir-1197, hsa-mir-124-3p, hsa-mir-1249-5p, hsa-mir-1253, and hsa-mir-1271-5p) and five hub genes (CENPE, ENPP3, GPR18, MDC1, and PLOD2).Conclusion: This study screened novel biological markers and investigated the differentiated circRNA-miRNA-mutated hub gene axis, which may play a pivotal role in the nosogenesis of PSS and RSS. Some circRNAs may be deemed new diagnostic or therapeutic targets that could be conducive to the future clinical treatment of SS.
Highlights
Synovial sarcoma (SS) is one of the most invasive soft tissue sarcomas, prone to recurrence and metastasis, and the efficacy of surgical treatment and chemotherapy for SS remains poor
gene ontology (GO) analysis showed that single nucleotide polymorphism (SNP) of 1828 are mainly concentrated in “metabolic process,” “biological regulation,” “multicellular organismal process”, “membranes,” “the nucleus,” “macromolecular complexes”, “protein binding,” “ion binding,” and “hydrolase activity” (Figure 2A)
The result of the GO analysis indicated that 391 variant genes of SNPs were mainly concentrated on “positive regulation of neurogenesis,” “cell growth,” “positive regulation of neuron differentiation”, “axon part,” “cell−substrate junction”, “protein phosphatase binding,” and “phosphatase binding” (Figure 2B)
Summary
Synovial sarcoma (SS) is one of the most invasive soft tissue sarcomas, prone to recurrence and metastasis, and the efficacy of surgical treatment and chemotherapy for SS remains poor. We focused on the regulation mechanism of the circRNA-miRNA-mutated hub gene in PSS and RSS. Some studies have shown that different genomic alterations were found in primary and recurrent tumors, including chromatin mutation, RNA splicing, and epigenomic regulation. Much work remains to be done to explore the different genomic alterations and investigate the natural history of primary SS (PSS) and recurrent SS (RSS). This could help guide the development of good clinical therapies for SS
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