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Exploring the dosage-dependent role of Dicer1 in thyroid tumorigenesis: insights from in vitro and in vivo models

par Rojo Pardillo, María
Président du jury Dewachter, Laurence
Promoteur Maenhaut, Carine
Publication Non publié, 2025-06-05

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Résumé :

The abnormal expression of miRNAs has been linked to the development of multiple tumors, including thyroid tumors. Dicer1 is an essential enzyme for the biogenesis of microRNAs that has been found to be dysregulated in various cancers, notably, its expression is decreased in papillary thyroid carcinoma (PTC). Multiple studies suggest Dicer1 as haploinsufficient tumor suppressor gene: while the loss of one allele promotes tumorigenesis, the complete loss of Dicer1 prevents tumor formation. So far, the impact of partial or total loss of Dicer1 in thyroid cancer has never been addressed. The effect of partial or complete loss of Dicer1 was evaluated using two parallel models in vitro and in vivo. Stable Dicer1 (+/-) cell lines were generated by Crispr-Cas9 from TPC1 cells, a PTC derived cell line. No Dicer1 (-/-) cell lines could be generated, supporting the idea that Dicer1 loss is lethal. Therefore, siRNA against Dicer1 was transfected into these cells to further decrease its expression. Transcriptomic analysis revealed alterations in cell proliferation and locomotion. Further analysis after Dicer1 loss revealed a slow-down of the cell cycle, with lower percentages of cells in S-phase and higher percentages of cells in G0-G1-phase and downregulated cyclin E expression, upregulated apoptosis and decreased number of invasive and migrating cells. These results were confirmed in two supplementary thyroid cell lines, BCPAP and HTori3.In parallel, the impact of Dicer1 partial or total inactivation was assessed in vivo. We inactivated one (+/-) or both (-/-) alleles of Dicer1 in thyroid cells in a RET/PTC3 transgenic mice model developing a PTC. No differences were observed following heterozygous inactivation of Dicer1. However, homozygous Dicer1 inactivation led to a significant decrease in tumor growth and increased apoptosis. Globally, our results allow us to better understand the function of Dicer1 in thyroid cancer tumorigenesis and suggest Dicer1 as an attractive target for novel therapeutic strategies.