The role of miRNA processing genes in Wilms tumor: Exploring the connection between mutations and tumorigenesis

Abstract

Micro-ribonucleic acids (miRNAs) are non-coding RNA molecules crucial in the post-transcriptional regulation of gene expression, via complementary binding to specific messenger RNAs (mRNAs). MiRNAs play a role in many biological processes, such as cell proliferation and differentiation. Consequently, tightly regulated miRNA expression is important in organogenesis, whereas dysregulation is related to various diseases, including cancer. In Wilms tumor, the most common form of pediatric kidney cancer, differences in miRNA profiles between the blastemal and recessive subtypes are found. In addition, mutations in miRNA biogenesis genes, DROSHA, DGCR8 and DICER1, are found in Wilms tumors. Patients with Perlman syndrome, who show increased susceptibility to Wilms tumor formation, harbor biallelic mutations in DIS3L2. DIS3L2 is an exoribonuclease involved in miRNA degradation, specifically important in the DIS3L2-LIN28-let-7 pathway. Besides, recently germline as well as somatic second hit mutations in DIS3L2 were found in a higher-than-expected number of sporadic Wilms tumors. These findings suggest an important role of miRNA processing enzymes in Wilms carcinogenesis. Therefore, we investigated the correlation between various subtypes of Wilms tumors, focusing on exploring the similarities in Wilms tumor development in patients carrying mutations in general miRNA processing genes, DROSHA, DGCR8 and DICER1, compared to mutations DIS3L2. Current identified germline and somatic mutations in Wilms tumor patients are described, and their effect on miRNA levels and tumorigenesis is investigated. Overall, mutations in all investigated genes resulted in increased cell proliferation in vitro, which is an important cancer characteristic. Wilms tumor harboring mutations in general miRNA processing genes showed decreased mature miRNA expression, whereas the effect of mutations in DIS3L2 on miRNA levels is less well understood. Multiple studies have identified Wilms tumor patients carrying germline DIS3L2 as well as second somatic hit mutations, implying DIS3L2 to be a Wilms tumor predisposition gene. However, studies investigating the role of specific DIS3L2 mutations on aberrant miRNA levels and Wilms tumorigenesis are warranted to strengthen this statement. Ultimately, the identification of specific miRNAs disturbed in Wilms tumors, potentially let-7, can serve as prognostic markers as well as novel therapeutic options.