Related Experiment Video
Updated: May 12, 2025
Characterization of Functionally Associated miRNAs in Glioblastoma and their Engineering into Artificial Clusters for Gene Therapy
Published on: October 4, 2019
An imbalance between proliferation and differentiation underlies the development of microRNA-defective pineoblastoma
Claudette R Fraire1, Kavita Desai2,3, Indumathy Jagadeeswaran1
1Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
Abstract:
Mutations in the microRNA processing genes DROSHA and DICER1 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, particularly the let-7/miR-98-5p family, and derepression 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 progrowth 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.
Insights
Mutations in microRNA processing genes DROSHA and DICER1 cause cancers resembling embryonic cells. Ablating these genes in mice led to pineal tumors, offering therapeutic targets by inhibiting proliferation drivers.
Area of Science:
- Oncology
- Developmental Biology
- Molecular Biology
Background:
- Mutations in microRNA processing genes DROSHA and DICER1 are implicated in cancers resembling embryonic progenitors.
- MicroRNAs (miRNAs) are crucial regulators of gene expression, and their dysregulation can contribute to tumorigenesis.
Purpose of the Study:
- To investigate the role of microRNA processing in tumorigenesis by studying the effects of DROSHA and DICER1 ablation in the developing pineal gland.
- To emulate the pathogenesis of pineoblastoma, a brain tumor associated with undifferentiated pineal gland precursors.
Main Methods:
- Ablation of Drosha or Dicer1 in the developing mouse pineal gland.
- Analysis of miRNA expression, miRNA target gene derepression, and tumor characteristics.
- Assessment of proliferation markers, pinealocyte maturation markers, and embryonic markers.
Main Results:
- Mice with Drosha or Dicer1 loss developed pineal tumors with reduced microRNAs, including the let-7/miR-98-5p family.
- These tumors exhibited derepression of miRNA target genes, upregulation of S-phase genes, and homeobox transcription factors, mimicking Rb1-loss tumors.
- Inhibiting proliferation led to increased pinealocyte maturation markers but persistent elevation of some embryonic markers, such as the oncofetal transcription factor Plagl2.
Conclusions:
- Tumors driven by the loss of microRNA processing exhibit distinct molecular features and can be therapeutically targeted.
- Inhibiting downstream drivers of proliferation, like Plagl2 signaling, shows promise for treating these microRNA-deficient tumors.
More Related Videos
Related Concept Videos
02:23Abnormal Proliferation
01:22MicroRNAs