Understanding the dosage-dependent role of Dicer1 in thyroid tumorigenesis
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1140219 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR29996148_1.fastq.gz | Fastqsanger.gz | |||
| SRR29996148_2.fastq.gz | Fastqsanger.gz | |||
| SRR29996149_1.fastq.gz | Fastqsanger.gz | |||
| SRR29996149_2.fastq.gz | Fastqsanger.gz | |||
| SRR29996150_1.fastq.gz | Fastqsanger.gz |
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Project description:Understanding the dosage-dependent role of Dicer1 in thyroid tumorigenesis [2]
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Project description:Multiple studies suggest Dicer1 as a haploinsufficient tumor suppressor gene: while the loss of one allele promotes tumorigenesis, the complete loss of Dicer1 prevents tumor formation. To study the impact of Dicer1 partial or total loss in papillary thyroid carcinoma cells in vitro, we generated stable Dicer1 (+/-) cell lines by CRISPR-Cas9 from TPC1 cell line. No Dicer1 (-/-) cell lines could be generated. Therefore, siRNA against Dicer1 was transfected into Dicer1 (+/-) cell lines to further decrease its expression. RNA sequencing and transcriptomic analysis revealed alterations in proliferation, cell cycle and cell locomotion. BrdU staining 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. Furthermore, transwell invasion and migration assays showed a decrease of invasive and migrating cells following transfection of Dicer1 siRNA. These results were confirmed in two supplementary thyroid cell lines, BCPAP and H-Tori3. Additionally, to achieve high protein levels, we performed Dicer1 plasmid transfection and we observed reduced proliferation and invasion as well as 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.
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Project description:Multiple studies suggest Dicer1 as a haploinsufficient tumor suppressor gene: while the loss of one allele promotes tumorigenesis, the complete loss of Dicer1 prevents tumor formation. To study the impact of Dicer1 partial or total loss in papillary thyroid carcinoma cells in vitro, we generated stable Dicer1 (+/-) cell lines by CRISPR-Cas9 from TPC1 cell line. No Dicer1 (-/-) cell lines could be generated. Therefore, siRNA against Dicer1 was transfected into Dicer1 (+/-) cell lines to further decrease its expression. RNA sequencing and transcriptomic analysis revealed alterations in proliferation, cell cycle and cell locomotion. BrdU staining 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. Furthermore, transwell invasion and migration assays showed a decrease of invasive and migrating cells following transfection of Dicer1 siRNA. These results were confirmed in two supplementary thyroid cell lines, BCPAP and H-Tori3. Additionally, to achieve high protein levels, we performed Dicer1 plasmid transfection and we observed reduced proliferation and invasion as well as 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.
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Project description:Tumors originating from thyroid follicular cells are the most common endocrine tumors, with rising incidence. Despite a generally good prognosis, up to 20% of patients experience recurrence and persistence, highlighting the need to identify the underlying molecular mechanisms. Dicer1 has been found to be altered in papillary thyroid cancer (PTC). Studies suggest that Dicer1 functions as a haploinsufficient tumor suppressor gene: partial loss promotes tumorigenesis, while complete loss prevents it. To investigate the effects of partial or total Dicer1 loss in PTC in vitro, we generated stable Dicer1 (+/-) cell lines from TPC1 using CRISPR-Cas9, though no Dicer1 (-/-) lines could be produced. Therefore, siRNA against Dicer1 was transfected into Dicer1 (+/-) cell lines to further decrease its expression. Transcriptomic analysis revealed changes in proliferation and cell locomotion. BrdU staining indicated a slow-down of the cell cycle, with fewer cells in S phase and more in G0-G1-phase. Additionally, transwell assays showed decreased invasion and migration after Dicer1 knockdown by siRNA. Moreover, Dicer1 overexpression led to decreased proliferation, invasion, and increased apoptosis. Our findings deepen the understanding of Dicer1's role in thyroid cancer, demonstrating that both complete elimination and overexpression of Dicer1 inhibit thyroid oncogenesis, highlighting Dicer1 as a promising target for novel therapeutic strategies.
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Project description:Chromosomal instability (CIN) is thought to be a source of mutability in human cancer. However, CIN is highly deleterious for the cell, and the resulting aneuploidy induces metabolic stress and compromises cell fitness. Here we utilized the X-chromosome dosage compensation mechanism and changes in X-chromosome number to demonstrate in Drosophila epithelial cells the causal relationship between CIN, aneuploidy, gene dosage imbalance and tumorigenesis. Whereas the harmful effects of CIN can be buffered by resetting the X-chromosome dosage compensation to compensate for changes in X-chromosome number, interfering with the mechanisms of dosage compensation suffices to induce tumorigenesis. In addition, multiple mechanisms buffer the deleterious effects of CIN including DNA-damage repair, activation of the p38 signalling pathway, and induction of cytokine expression to promote compensatory cell proliferation. These data reveal a key role of gene dosage imbalances to CIN-induced programmed cell death and tumorigenesis and the existence of robust compensatory mechanisms.
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Project description:Germline and somatic alterations in DICER1 and DGCR8 microprocessors confer risk of developing benign and malignant thyroid lesions, yet the molecular events driving malignant transformation remain unclear. We trace the molecular trajectories from benignity to malignancy in DICER1/DGCR8-mutated thyroid lesions using multi-omic profiling on 27 DICER1/DGCR8-mutated samples. Our findings reveal a progressive, specific, and linear accumulation of genetic alterations, which when combined with enhanced downregulation of miRNAs distinguished DICER1/DGCR8-malignant lesions from their benign counterparts. Compensatory hypomethylation of miRNA encoding genes characterised DICER1/DGCR8-benign lesions, but as the tumors progressed to malignancy, methylation was partly reimposed, reversing the attempts to activate miRNA-encoded genes and further compromising miRNA production. Transcriptomic analyses revealed mutation-specific effects on the microenvironment, whereby DICER1 mutations activated canonical thyroid cancer progression pathways, whereas altered DGCR8 associated with immune-related alterations. This work unveils specific molecular events underlying malignant progression of miRNA-biogenesis related thyroid tumors and identifies potential biomarkers and disease etiology mechanisms.
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Project description:Germline and somatic alterations in DICER1 and DGCR8 microprocessors confer risk of developing benign and malignant thyroid lesions, yet the molecular events driving malignant transformation remain unclear. We trace the molecular trajectories from benignity to malignancy in DICER1/DGCR8-mutated thyroid lesions using multi-omic profiling on 27 DICER1/DGCR8-mutated samples. Our findings reveal a progressive, specific, and linear accumulation of genetic alterations, which when combined with enhanced downregulation of miRNAs distinguished DICER1/DGCR8-malignant lesions from their benign counterparts. Compensatory hypomethylation of miRNA encoding genes characterised DICER1/DGCR8-benign lesions, but as the tumors progressed to malignancy, methylation was partly reimposed, reversing the attempts to activate miRNA-encoded genes and further compromising miRNA production. Transcriptomic analyses revealed mutation-specific effects on the microenvironment, whereby DICER1 mutations activated canonical thyroid cancer progression pathways, whereas altered DGCR8 associated with immune-related alterations. This work unveils specific molecular events underlying malignant progression of miRNA-biogenesis related thyroid tumors and identifies potential biomarkers and disease etiology mechanisms.
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