Dicer1 Depletion Leads to DNA Damage Accumulation and Cell Death in a RET/PTC3 Papillary Thyroid Cancer Mouse Model, Thereby Inhibiting Tumor Progression

Beyond well-known genetic drivers, microRNA dysregulation has emerged as a key contributor to thyroid tumorigenesis. Central to this process is <i>Dicer1</i>, a ribonuclease essential for microRNA maturation, whose expression is often reduced in papillary thyroid carcinoma (PTC). Evidence from previous studies suggest <i>Dicer1</i> 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 <i>Dicer1</i> loss in thyroid cancer remain unclear. To explore this, we genetically inactivated one (heterozygous) or both (homozygous) <i>Dicer1</i> 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 <i>Dicer1</i> 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 <i>Dicer1</i> dosage in thyroid cancer progression and underscore its potential as a therapeutic target for aggressive PTC and other malignancies characterized by aberrant <i>Dicer1</i> expression.