DROSHA Regulates Mesenchymal Gene Expression in Wilms Tumor.

Autor:	Tiburcio PDB; Department of Pediatrics, UT Southwestern, Dallas, Texas., Desai K; Division of Oncology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.; University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania., Kim J; Department of Pediatrics, UT Southwestern, Dallas, Texas.; Quantitative Biomedical Research Center, Peter O'Donnell Jr. School of Public Health, UT Southwestern, Dallas, Texas., Zhou Q; Department of Pediatrics, UT Southwestern, Dallas, Texas.; Quantitative Biomedical Research Center, Peter O'Donnell Jr. School of Public Health, UT Southwestern, Dallas, Texas., Guo L; Department of Pediatrics, UT Southwestern, Dallas, Texas.; Quantitative Biomedical Research Center, Peter O'Donnell Jr. School of Public Health, UT Southwestern, Dallas, Texas., Xiao X; Department of Pediatrics, UT Southwestern, Dallas, Texas.; Quantitative Biomedical Research Center, Peter O'Donnell Jr. School of Public Health, UT Southwestern, Dallas, Texas., Zhou L; Biospecimen Research Services, Children's Cancer Research Unit, Kids Research, The Children's Hospital at Westmead, Westmead, Australia., Yuksel A; Biospecimen Research Services, Children's Cancer Research Unit, Kids Research, The Children's Hospital at Westmead, Westmead, Australia., Catchpoole DR; Biospecimen Research Services, Children's Cancer Research Unit, Kids Research, The Children's Hospital at Westmead, Westmead, Australia., Amatruda JF; Cancer and Blood Disease Institute, Children's Hospital Los Angeles, Los Angeles, California.; Department of Pediatrics, University of Southern California Keck School of Medicine, Los Angeles, California.; Department of Medicine, University of Southern California Keck School of Medicine, Los Angeles, California., Xu L; Department of Pediatrics, UT Southwestern, Dallas, Texas.; Quantitative Biomedical Research Center, Peter O'Donnell Jr. School of Public Health, UT Southwestern, Dallas, Texas., Chen KS; Department of Pediatrics, UT Southwestern, Dallas, Texas.; Children's Medical Center Research Institute, UT Southwestern, Dallas, Texas.; Gill Center for Cancer and Blood Disorders, Children's Health Children's Medical Center, Dallas, Texas.
Jazyk:	angličtina
Zdroj:	Molecular cancer research : MCR [Mol Cancer Res] 2024 Aug 02; Vol. 22 (8), pp. 711-720.
DOI:	10.1158/1541-7786.MCR-23-0930
Abstrakt:	Wilms tumor, the most common pediatric kidney cancer, resembles embryonic renal progenitors. Currently, there are no ways to therapeutically target Wilms tumor driver mutations, such as in the microRNA processing gene DROSHA. In this study, we used a "multiomics" approach to define the effects of DROSHA mutation in Wilms tumor. We categorized Wilms tumor mutations into four mutational subclasses with unique transcriptional effects: microRNA processing, MYCN activation, chromatin remodeling, and kidney developmental factors. In particular, we find that DROSHA mutations are correlated with de-repressing microRNA target genes that regulate differentiation and proliferation and a self-renewing, mesenchymal state. We model these findings by inhibiting DROSHA expression in a Wilms tumor cell line, which led to upregulation of the cell cycle regulator cyclin D2 (CCND2). Furthermore, we observed that DROSHA mutations in Wilms tumor and DROSHA silencing in vitro were associated with a mesenchymal state with aberrations in redox metabolism. Accordingly, we demonstrate that Wilms tumor cells lacking microRNAs are sensitized to ferroptotic cell death through inhibition of glutathione peroxidase 4, the enzyme that detoxifies lipid peroxides. Implications: This study reveals genotype-transcriptome relationships in Wilms tumor and points to ferroptosis as a potentially therapeutic vulnerability in one subset of Wilms tumor. (©2024 American Association for Cancer Research.)
Databáze:	MEDLINE
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