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Characterization of Functionally Associated miRNAs in Glioblastoma and their Engineering into Artificial Clusters for Gene Therapy
Published on: October 4, 2019
Modulation of microRNA editing, expression and processing by ADAR2 deaminase in glioblastoma
Sara Tomaselli1, Federica Galeano2, Shahar Alon3
1Department of Pediatric Oncohaematology, RNA Editing Laboratory, Bambino Gesù Children's Hospital IRCCS, Piazza S. Onofrio 4, Rome, 00165, Italy. sara.tomaselli@opbg.net.
Background:
ADAR enzymes convert adenosines to inosines within double-stranded RNAs, including microRNA (miRNA) precursors, with important consequences on miRNA retargeting and expression. ADAR2 activity is impaired in glioblastoma and its rescue has anti-tumoral effects. However, how ADAR2 activity may impact the miRNome and the progression of glioblastoma is not known.
Results:
By integrating deep-sequencing and array approaches with bioinformatics analyses and molecular studies, we show that ADAR2 is essential to edit a small number of mature miRNAs and to significantly modulate the expression of about 90 miRNAs in glioblastoma cells. Specifically, the rescue of ADAR2 activity in cancer cells recovers the edited miRNA population lost in glioblastoma cell lines and tissues, and rebalances expression of onco-miRNAs and tumor suppressor miRNAs to the levels observed in normal human brain. We report that the major effect of ADAR2 is to reduce the expression of a large number of miRNAs, most of which act as onco-miRNAs. ADAR2 can edit miR-222/221 and miR-21 precursors and decrease the expression of the corresponding mature onco-miRNAs in vivo and in vitro, with important effects on cell proliferation and migration.
Conclusions:
Our findings disclose an additional layer of complexity in miRNome regulation and provide information to better understand the impact of ADAR2 editing enzyme in glioblastoma. We propose that ADAR2 is a key factor for maintaining edited-miRNA population and balancing the expression of several essential miRNAs involved in cancer.
Insights
Adenosine deaminase acting on RNA 2 (ADAR2) enzyme activity is crucial for regulating microRNA (miRNA) expression in glioblastoma. Restoring ADAR2 function rebalances onco-miRNAs and tumor suppressors, impacting cancer progression.
Area of Science:
- Biochemistry
- Molecular Biology
- Genomics
Background:
- Adenosine deaminase acting on RNA (ADAR) enzymes modify double-stranded RNAs, including microRNA (miRNA) precursors, affecting miRNA expression and targeting.
- ADAR2 activity is reduced in glioblastoma, and its restoration shows anti-tumoral effects, but its precise impact on the glioblastoma miRNome remains unclear.
Purpose of the Study:
- To investigate the role of ADAR2 in regulating the miRNome in glioblastoma.
- To understand how ADAR2 activity influences glioblastoma progression through miRNA modulation.
Main Methods:
- Deep-sequencing and array-based approaches.
- Bioinformatics and molecular analyses.
- In vivo and in vitro studies.
Main Results:
- ADAR2 editing is essential for a subset of mature miRNAs and significantly modulates the expression of approximately 90 miRNAs in glioblastoma cells.
- Restoring ADAR2 activity in cancer cells re-establishes the edited miRNA population and rebalances onco-miRNAs and tumor suppressor miRNAs.
- ADAR2 primarily reduces the expression of numerous onco-miRNAs, including editing of miR-222/221 and miR-21 precursors, affecting cell proliferation and migration.
Conclusions:
- ADAR2 plays a critical role in maintaining the edited miRNA population and balancing miRNA expression in glioblastoma.
- These findings reveal a new layer of miRNome regulation and highlight ADAR2's significance in glioblastoma pathogenesis.
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