• Xin Luo, Junjun Dong, Xingyue He, Lianju Shen, Chunlan Long, Feng Liu, Xing Liu, Tao Lin, Dawei He, and Guanghui Wei.
• Chongqing Key Laboratory of Children Urogenital Development and Tissue Engineering, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders (Chongqing), China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, PR China; Department of Pediatric Urology Surgery, Children's Hospital of Chongqing Medical University, Chongqing 400014, PR China.
• Biomed. Pharmacother. 2020 May 1; 125: 109880.

BackgroundMicroRNA-155-5p (miR-155-5p) has been reported to play an oncogenic role in different human malignancies; however, its role in Wilms tumor (WT) remains unclear.MethodsDifferentially expressed miRNAs (DE-miRNAs) and mRNAs (DEGs) in WT blood and tissues were identified by using miRNA microarray and RNA-sequencing. Bioinformatics prediction and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were used to predict the potential functions of DE-miRNAs. DE-miRNAs and DEGs in WT obtained from Gene Expression Omnibus (GEO) and Therapeutically Applicable Research to Generate Effective Treatments (TARGET) were identified by using the "edgeR" package. RT-qPCR was used to explore miR-155-5p and IGF2 expression and their clinical significance in WT specimens. A rhabdoid cell line (G401) and Ewing sarcoma cell line (SK-NEP-1) were used. Immunohistochemical staining, western blotting and dual-luciferase reporter assays were performed to study the mechanisms involved. The CCK-8, flow cytometry, wound healing and transwell assays were performed to identify the effects of miR-155-5p and IGF2 knockdown on cell proliferation, apoptosis, migration and invasion, respectively.ResultsMiR-155-5p was downregulated in both blood and tissues from WT patients who did not receive chemotherapy before surgery but was upregulated in tissues from WT patients who had received chemotherapy before surgery. IGF2, PI3K, AKT and mTOR were found to be upregulated in WT tissues. Additionally, miR-155-5p and IGF2 were significantly correlated with TNM stage and lymphatic metastasis in WT patients. Molecular mechanism exploration indicated that IGF2 was downregulated by miR-155-5p via direct binding to its 3' untranslated region in cell lines. Furthermore, IGF2, PI3K, AKT and mTOR expression was inversely correlated with miR-155-5p expression, and PI3K, AKT and mTOR expression was positively correlated with IGF2 expression in cell culture. Functional studies demonstrated that miR-155-5p upregulation and IGF2 knockdown suppressed cell proliferation, migration and invasion and induced cell apoptosis. Moreover, the tumor-suppressing effects of miR-155-5p in cells were abrogated by miR-155-5p inhibitor treatment.ConclusionsTaken together, these findings suggest that miR-155-5p functions as a tumor suppressor in WT through inactivating the PI3K/AKT/mTOR signaling pathway by directly targeting IGF2. Thus, miR-155-5p might be a novel therapeutic target for WT.Copyright © 2020 The Authors. Published by Elsevier Masson SAS.. All rights reserved.

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