Abstract
Ewing sarcoma (ES) is a highly malignant primary bone tumor with poor prognosis. Studies have shown that abnormal expression of lncRNA influences the prognosis of tumor patients. Herein, we established that FOXP4-AS1 was up-regulated in ES and this correlated with poor prognosis. Further analysis illustrated that FOXP4-AS1 down-regulation repression growth, migration, along with invasion of ES. On the contrary, up-regulation of FOXP4-AS1 promoted the growth, migration, as well as invasion of ES. To explore the mechanism of FOXP4-AS1, Spearman correlation analysis was carried out to determine genes that were remarkably linked to FOXP4-AS1 expression. The potential functions and pathways involving FOXP4-AS1 were identified by GO analysis, Hallmark gene set enrichment analysis, GSEA, and GSVA. The subcellular fractionation results illustrated that FOXP4-AS1 was primarily located in the cytoplasm of ES cells. Then a ceRNA network of FOXP4-AS1 was constructed. Analysis of the ceRNA network and GSEA yielded two candidate mRNAs for FOXP4-AS1. Results of the combined survival analysis led us to speculate that FOXP4-AS1 may affect the expression of TMPO by sponging miR-298, thereby regulating the malignant phenotype of ES. Finally, we found that FOXP4-AS1 may modulates the tumor immune microenvironment in an extracellular vesicle-mediated manner. In summary, FOXP4-AS1 correlates with poor prognosis of ES. It promotes the growth, migration, as well as invasion of ES cells and may modulate the tumor immune microenvironment.
Highlights
Ewing sarcoma (ES), known as Ewing family tumors, includes Ewing sarcoma, extraosseous Ewing sarcoma (EES), PNET, chest malignant small-cell tumor (Askin sarcoma), and aberrant Ewing sarcoma [1]
We analyzed patterns of lncRNA expression between ES and normal muscle tissues based on the GSE dataset (GSE17674)
We integrated the GSE datasets (GSE48022, GSE90970, GSE70826, GSE17618) analyzed expression of FOXP4-AS1 between ES and MSCs, and found that FOXP4-AS1 was upregulated in ES cells relative to MSCs (Figure 1C). Quantitative real-time PCR (qRT-PCR) results corroborated these results, as evidenced by a significant FOXP4-AS1 upregulation in ES cell line A673 and SK-N-MC (Figure 1D)
Summary
Ewing sarcoma (ES), known as Ewing family tumors, includes Ewing sarcoma, extraosseous Ewing sarcoma (EES), PNET, chest malignant small-cell tumor (Askin sarcoma), and aberrant Ewing sarcoma [1]. ES, a primary, and highly malignant bone tumor of the bone marrow that mainly occurs in children, as well as adolescents, is typified by an incidence rate of 1/1.5 million, with the highest incidence recorded in 15-year-olds [2]. The disease is highly malignant, and is further characterized by a short course, and rapid metastasis [4], with approximately 30% of patients manifesting apparent metastases at diagnosis. Metastasis predominantly occurs in the lungs, bones, and the bone marrow [5]. ES has dismal prognosis, exhibiting a five-year survival rate of 70-80%, which worsens to 30% in patients with metastatic tumors [6,7,8]. Understanding occurrence and the underlying mechanism of ES development will aid in identification of novel biomarkers for development of early diagnostic and treatment therapies, thereby improving and reducing survival and recurrence rates, respectively
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