Nephroblastoma, or named Wilms tumor, is the most common renal cancer in children. This study was aim to identify gene signatures and potential therapeutic target in nephroblastoma. Microarrays GSE11151 and GSE53224 were downloaded from GEO database. 53 Wilms tumor and five normal tissues profiles were screened by GO and KEGG enrichment analysis, and protein-protein interaction (PPI) network of the differentially expressed genes (DEGs) was constructed. In total, 404 DEGs were identified, including 385 up-regulated genes and 19 down-regulated genes. The biological processes of GO functional enrichment showed that up-regulated DEGs significantly involved in immune response, immune system process, and leukocyte cell-cell adhesion; while the down-regulated DEGS were related to excretion, metanephros development, and nephron development. In KEGG analysis, the DEGs were enriched in neuroactive ligand-receptor interaction, T cell receptor signaling pathway, and Chemokine signaling pathway. Five genes were identified as hub nodes from the PPI network, including PMCH, CCR5, CCR7, RGS1 and KNG1, which were mostly associated with Chemokine signaling pathway, G-protein coupled signaling pathway, and involved in shaping tumor microenvironment. In conclusion, the DEGs, particular hub genes, play significant roles in the development of nephroblastoma and might be the underlying target and diagnostic biomarkers for the treatment of nephroblastoma.