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Updated: Jun 27, 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, Uma A Obalapuram4
1Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX USA.
Abstract:
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.
Insights
Loss of microRNA processing genes DICER1 and DROSHA in mice causes pineal tumors. These tumors can be targeted by inhibiting downstream proliferation drivers like PLAGL2.
Area of Science:
- Developmental biology
- Cancer research
- Genetics
Background:
- Mutations in microRNA processing genes DICER1 and DROSHA are implicated in cancers resembling embryonic progenitors.
- MicroRNAs play a crucial role in regulating tumorigenesis.
Purpose of the Study:
- To investigate the role of microRNAs in pineoblastoma pathogenesis by ablating Drosha or Dicer1 in the developing pineal gland.
- To understand how microRNA loss affects tumor development and identify potential therapeutic targets.
Main Methods:
- Ablation of Drosha or Dicer1 in the developing pineal gland of mice.
- Analysis of microRNA expression, target gene de-repression, and cellular markers in resulting pineal tumors.
- Assessment of tumor growth inhibition by targeting downstream proliferation drivers.
Main Results:
- Mice with Drosha or Dicer1 ablation developed pineal tumors with loss of microRNAs, including the let-7/miR-98-5p family.
- Tumors showed de-repression of microRNA target genes, upregulation of S-phase genes, and homeobox transcription factors, mimicking Rb1-loss tumors.
- Inhibiting the oncofetal transcription factor PLAGL2 impaired tumor growth, demonstrating a therapeutic vulnerability.
Conclusions:
- Loss of microRNA processing genes drives pineal tumorigenesis by de-regulating key developmental pathways.
- Therapeutic strategies targeting downstream effectors, such as PLAGL2, show promise for treating microRNA-driven tumors.
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