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In Vivo Inhibition of MicroRNA to Decrease Tumor Growth in Mice
Published on: August 23, 2019
Dicer1 Depletion Leads to DNA Damage Accumulation and Cell Death in a RET/PTC3 Papillary Thyroid Cancer Mouse Model,
Maria Rojo-Pardillo1, Alice Augenlicht1, Geneviève Dom1
1IRIBHM J. E. Dumont, Université Libre de Bruxelles,1070 Brussels, Belgium.
Abstract:
Beyond well-known genetic drivers, microRNA dysregulation has emerged as a key contributor to thyroid tumorigenesis. Central to this process is Dicer1, a ribonuclease essential for microRNA maturation, whose expression is often reduced in papillary thyroid carcinoma (PTC). Evidence from previous studies suggest Dicer1 functions as a context-dependent haplo-insufficient tumor suppressor gene: partial loss may promote tumor development, whereas complete loss may disrupt essential cellular functions, causing cell death and tumor suppression. However, the effects of partial or complete Dicer1 loss in thyroid cancer remain unclear. To explore this, we genetically inactivated one (heterozygous) or both (homozygous) Dicer1 alleles specifically in thyroid follicular cells of a RET/PTC3 transgenic mouse model using an inducible Cre-Lox system. Our findings deepen the current understanding of the RET/PTC3-driven PTC model by revealing an increased number of vimentin-positive cells and disruption in redox homeostasis. Additionally, whereas heterozygous Dicer1 loss did not alter tumor progression in RET/PTC3 mice, total loss reduced tumor growth and led to accumulated DNA damage and cell death. These findings highlight the crucial role of Dicer1 dosage in thyroid cancer progression and underscore its potential as a therapeutic target for aggressive PTC and other malignancies characterized by aberrant Dicer1 expression.
Insights
Dicer1 dosage is critical in thyroid cancer. Partial loss did not affect tumor growth, but complete Dicer1 loss suppressed papillary thyroid carcinoma (PTC) growth by causing DNA damage and cell death.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- MicroRNA (miRNA) dysregulation is implicated in thyroid tumorigenesis.
- Dicer1, essential for miRNA maturation, is frequently downregulated in papillary thyroid carcinoma (PTC).
- Dicer1 acts as a context-dependent haplo-insufficient tumor suppressor, with partial loss potentially promoting and complete loss inhibiting tumor development.
Purpose of the Study:
- To investigate the effects of partial (heterozygous) and complete (homozygous) Dicer1 loss in a RET/PTC3 transgenic mouse model of papillary thyroid carcinoma.
- To elucidate the role of Dicer1 dosage in thyroid cancer progression and identify potential therapeutic targets.
Main Methods:
- Genetic inactivation of one or both Dicer1 alleles in thyroid follicular cells of RET/PTC3 transgenic mice using an inducible Cre-Lox system.
- Analysis of tumor progression, cell characteristics (vimentin expression), redox homeostasis, DNA damage, and cell death.
Main Results:
- Heterozygous Dicer1 loss did not alter tumor progression in the RET/PTC3 model.
- Homozygous Dicer1 loss reduced tumor growth, increased DNA damage, and induced cell death.
- Dicer1 loss was associated with increased vimentin-positive cells and disrupted redox homeostasis.
Conclusions:
- Dicer1 dosage plays a crucial role in thyroid cancer progression.
- Complete Dicer1 loss can suppress tumor growth, suggesting its potential as a therapeutic target in aggressive PTC and other cancers with altered Dicer1 expression.
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