Abstract
Wilms' tumor (WT) is the most common type of childhood kidney cancer, and most cases present with favorable histology and respond well to standard treatment. However, a subset of patients with WT is diagnosed with bilateral, relapsed, and high-risk tumors which remain the leading cause of cancer-related death in children. Long noncoding RNAs (lncRNAs) and their aberrant expression have currently been attracting great attention as oncogenes or tumor suppressors during tumor initiation and progression. So far, their roles and related competitive endogenous RNA (ceRNA) network remain unelucidated in nephroblastoma pathogenesis. We comprehensively integrated lncRNA, microRNA (miRNA), and messenger RNA (mRNA) expression profiles from the Therapeutically Applicable Research to Generate Effective Treatment (TARGET) database and screened out differentially expressed mRNAs (DEMs), lncRNAs (DELs), and miRNAs (DEMis) to construct a ceRNA network based on the information generated from miRcode, miRTarBase, TargetScan, and miRDB. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed to analyze the functional characteristics of DEMs in the ceRNA network. The interaction between protein molecules was also analyzed by establishing a protein-protein interaction network. Finally, prognosis-related biomarkers were identified via survival analysis. Initially, 1647 DELs, 115 DEMis, and 3280 DEMs (|log FC| > 2; FDR < 0.01) were obtained using the R package. Next, we constructed a lncRNA-miRNA-mRNA network (ceRNA network), in which 176 DELs, 24 DEMis, and 141 DEMs were identified. Furthermore, 148 functional enrichment terms from GO were identified and 29 KEGG pathways were found to be significantly enriched. We also integrated patient clinical information to analyze the association between DERNAs and patient prognosis. We found that high expression of 8 DELs (LINC00473, AL445228.2, DENND5B−AS1, DLEU2, AC123595.1, AC135178.1, LINC00535, and LMO7−AS1) and 4 DEMs (CEP55, DEPDC1, PHF19, and TRIM36) correlated with poor survival in a patient with WT, whereas high expression of 2 DELs (MEG3 and RMST), 1 DEM (KIAA0922), and 1 DEMi (hsa−mir−200a) could possibly lead to better clinical outcomes. For the first time, the present study provided a novel insight into lncRNA-related ceRNA networks and identified potential prognostic biomarkers in Wilms' tumor.
Highlights
Wilms’ tumor (WT), known as nephroblastoma, is an embryonal childhood tumor that accounts for 90% of childhood renal tumors and 7% of all childhood cancers [1]
Due to the successive clinical trials conducted by several collaborative clinical trial groups around the world, such as the International Society of Paediatric Oncology (SIOP), and the National Wilms’ Tumor Study Group (NWTSG), treatment regimen that the combination of nephrectomy and chemotherapy was found to BioMed Research International greatly improve overall survival (OS) rates exceeding 90% [2]
We used TargetScan, miRDB, and miRTarBase databases to predict interactions between miRNAs and messenger RNA (mRNA), and 1193 target genes simultaneously recognized by these three databases were considered as the target genes of 24 DEMis (Table 5). ese target genes intersected with 3280 differentially expressed mRNAs (DEMs), and we identified 141 mRNAs from the 3280 DEMs
Summary
Wilms’ tumor (WT), known as nephroblastoma, is an embryonal childhood tumor that accounts for 90% of childhood renal tumors and 7% of all childhood cancers [1]. Erefore, investigators continue to look for the molecular pathogenesis of WT with the belief that novel treatment strategies will be conducive to improving outcomes in patients with high-risk tumors. It was reported that lncRNAs play an important role in regulating tumor progression and tumor biological behaviors such as gene expression, cell proliferation, cell differentiation, immune responses, and apoptosis, with the most crucial process being the regulation of competing endogenous RNAs (ceRNAs) [7, 8]. The hypothesis states that, in the ceRNA gene interaction network, which consists of lncRNAs, miRNAs, and mRNAs, lncRNAs can act as miRNA sponges and inhibit miRNA functions by sharing miRNA response elements (MRE), thereby indirectly regulating mRNA expression levels [10]. The importance of the lncRNA-miRNA-mRNA ceRNA regulatory network has been confirmed in various types of cancers [11,12,13].
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