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Updated: Apr 24, 2026
In Vivo Inhibition of MicroRNA to Decrease Tumor Growth in Mice
Published on: August 23, 2019
Somatic mutations in DROSHA and DICER1 impair microRNA biogenesis through distinct mechanisms in Wilms tumours
Dinesh Rakheja1, Kenneth S Chen2, Yangjian Liu3
11] Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA [2] Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA [3] Division of Pathology and Laboratory Medicine, Children's Medical Center, Dallas, Texas 75235, USA [4] Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA [5].
Abstract:
Wilms tumour is the most common childhood kidney cancer. Here we report the whole-exome sequencing of 44 Wilms tumours, identifying missense mutations in the microRNA (miRNA)-processing enzymes DROSHA and DICER1, and novel mutations in MYCN, SMARCA4 and ARID1A. Examination of tumour miRNA expression, in vitro processing assays and genomic editing in human cells demonstrates that DICER1 and DROSHA mutations influence miRNA processing through distinct mechanisms. DICER1 RNase IIIB mutations preferentially impair processing of miRNAs deriving from the 5'-arm of pre-miRNA hairpins, while DROSHA RNase IIIB mutations globally inhibit miRNA biogenesis through a dominant-negative mechanism. Both DROSHA and DICER1 mutations impair expression of tumour-suppressing miRNAs, including the let-7 family, important regulators of MYCN, LIN28 and other Wilms tumour oncogenes. These results provide new insights into the mechanisms through which mutations in miRNA biogenesis components reprogramme miRNA expression in human cancer and suggest that these defects define a distinct subclass of Wilms tumours.
Insights
Wilms tumour, a common childhood kidney cancer, shows mutations in microRNA (miRNA) processing enzymes DROSHA and DICER1. These genetic defects disrupt miRNA biogenesis, impacting tumour-suppressing miRNAs and defining a new cancer subclass.
Area of Science:
- Genetics
- Molecular Biology
- Oncology
Background:
- Wilms tumour is the predominant form of kidney cancer in children.
- Understanding the genetic underpinnings of Wilms tumour is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate the genetic mutations associated with Wilms tumour development.
- To elucidate the mechanisms by which mutations in microRNA (miRNA) processing enzymes affect tumourigenesis.
Main Methods:
- Whole-exome sequencing of 44 Wilms tumours.
- Analysis of tumour miRNA expression.
- In vitro miRNA processing assays and genomic editing in human cells.
Main Results:
- Identified missense mutations in DROSHA and DICER1, and novel mutations in MYCN, SMARCA4, and ARID1A.
- Demonstrated distinct mechanisms of miRNA processing disruption by DICER1 and DROSHA mutations.
- Showed that both mutations impair tumour-suppressing miRNA expression, including let-7 family miRNAs.
Conclusions:
- Mutations in miRNA biogenesis components reprogram miRNA expression in Wilms tumours.
- These defects identify a distinct subclass of Wilms tumours.
- Findings offer new insights into miRNA's role in childhood kidney cancer.
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