The tumor suppressor miR-642a-5p targets Wilms Tumor 1 gene and cell-cycle progression in prostate cancer

Dianne J Beveridge,Kirsty L Richardson,Michael R Epis,Rikki A M Brown,Andrew J Woo,Peter J Leedman,Lisa M Stuart

doi:10.1038/s41598-021-97190-x

Abstract

RNA-based therapeutics are emerging as innovative options for cancer treatment, with microRNAs being attractive targets for therapy development. We previously implicated microRNA-642a-5p (miR-642a-5p) as a tumor suppressor in prostate cancer (PCa), and here we characterize its mode of action, using 22Rv1 PCa cells. In an in vivo xenograft tumor model, miR-642a-5p induced a significant decrease in tumor growth, compared to negative control. Using RNA-Sequencing, we identified gene targets of miR-642a-5p which were enriched for gene sets controlling cell cycle; downregulated genes included Wilms Tumor 1 gene (WT1), NUAK1, RASSF3 and SKP2; and upregulated genes included IGFBP3 and GPS2. Analysis of PCa patient datasets showed a higher expression of WT1, NUAK1, RASSF3 and SKP2; and a lower expression of GPS2 and IGFBP3 in PCa tissue compared to non-malignant prostate tissue. We confirmed the prostatic oncogene WT1, as a direct target of miR-642a-5p, and treatment of 22Rv1 and LNCaP PCa cells with WT1 siRNA or a small molecule inhibitor of WT1 reduced cell proliferation. Taken together, these data provide insight into the molecular mechanisms by which miR-642a-5p acts as a tumor suppressor in PCa, an effect partially mediated by regulating genes involved in cell cycle control; and restoration of miR-642-5p in PCa could represent a novel therapeutic approach.

Highlights

RNA-based therapeutics are emerging as innovative options for cancer treatment, with microRNAs being attractive targets for therapy development
There is little known about the functional role of miR-642a-5p and cancer, and here we characterize its mode of action as a tumor suppressor in 22Rv1 and LNCaP prostate cancer (PCa) cells, both being models of C RPC34
Overexpression of miR-642a-5p resulted in a considerable decrease in xenograft tumor growth in vivo, and its overexpression dysregulated genes involved in DNA replication and cell cycle progression

Summary

Introduction

RNA-based therapeutics are emerging as innovative options for cancer treatment, with microRNAs being attractive targets for therapy development. We confirmed the prostatic oncogene WT1, as a direct target of miR642a-5p, and treatment of 22Rv1 and LNCaP PCa cells with WT1 siRNA or a small molecule inhibitor of WT1 reduced cell proliferation Taken together, these data provide insight into the molecular mechanisms by which miR-642a-5p acts as a tumor suppressor in PCa, an effect partially mediated by regulating genes involved in cell cycle control; and restoration of miR-642-5p in PCa could represent a novel therapeutic approach. MicroRNAs (miRNAs) are a family of ~ 22 nucleotide noncoding RNAs that are powerful regulators of gene expression via targeting of the 3′untranslated region (3′UTR) of specific genes leading to translational repression or message decay[12] With their aberrant expression known to play a pivotal role in the regulation of a variety of developmental processes and diseases, miRNAs have therapeutic potential for the treatment of cancer and other illnesses[13]. These studies emphasize the potential for miRNAs to become cancer therapeutics, and provides an opportunity to identify downregulated tumor suppressor miRNAs, the replacement of which could be a new strategy in the treatment of PCa

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