An imbalance between proliferation and differentiation underlies the development of microRNA-defective pineoblastoma.

Autor:	Fraire CR; Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX USA., Desai K; Division of Oncology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA USA.; University of Pennsylvania Perelman School of Medicine, Philadelphia, PA USA., Obalapuram UA; Emory University, Atlanta, GA USA., Mendyka LK; Geisel School of Medicine, Dartmouth College, Hanover, NH USA., Rajaram V; Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX USA., Sebastian T; Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX USA., Wang Y; Department of Pathology and Laboratory Medicine, University of British Columbia and Department of Molecular Oncology, British Columbia Cancer Research Institute, Vancouver, BC, Canada., Onel K; Department of Cancer Prevention and Control, Roswell Park Comprehensive Cancer Center, Buffalo, NY USA., Lee J; Lyda Hill Department of Bioinformatics, UT Southwestern Medical Center, Dallas, TX USA., Skapek SX; Department of Pediatrics, Duke University, Durham, NC USA., Chen KS; Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX USA.; Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX USA.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2024 Oct 22. Date of Electronic Publication: 2024 Oct 22.
DOI:	10.1101/2024.04.23.590638
Abstrakt:	Mutations in the microRNA processing genes DICER1 and DROSHA drive several cancers that resemble embryonic progenitors. To understand how microRNAs regulate tumorigenesis, we ablated Drosha or Dicer1 in the developing pineal gland to emulate the pathogenesis of pineoblastoma, a brain tumor that resembles undifferentiated precursors of the pineal gland. Accordingly, these mice develop pineal tumors marked by loss of microRNAs, including the let-7/miR-98-5p family, and de-repression of microRNA target genes. Pineal tumors driven by loss of Drosha or Dicer1 mimic tumors driven by Rb1 loss, as they exhibit upregulation of S-phase genes and homeobox transcription factors that regulate pineal development. Blocking proliferation of these tumors facilitates expression of pinealocyte maturation markers, with a concomitant reduction in embryonic markers. Select embryonic markers remain elevated, however, as the microRNAs that normally repress these target genes remain absent. One such microRNA target gene is the oncofetal transcription factor Plagl2 , which regulates expression of pro-growth genes, and inhibiting their signaling impairs tumor growth. Thus, we demonstrate that tumors driven by loss of microRNA processing may be therapeutically targeted by inhibiting downstream drivers of proliferation. Competing Interests: The authors have no competing interests to declare.
Databáze:	MEDLINE
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