Transcriptomic landscape of TIMP3 oncosuppressor activity in thyroid carcinoma
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PROVIDER: PRJNA852599 | ENA |
REPOSITORIES: ENA
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Project description:In thyroid tumors TIMP3 methylation, and hence its downregulation, has been reported (Hoque MO et al, J Clin Endocrinol Metabolism 2005) and also found significantly associated with several aggressive features of PTC, including extrathyroidal invasion, lymph node metastasis, multifocality, advanced tumor stages and BRAF mutation (Hu S et al, Int J Cancer 2006). In a previous work, in addition to confirming TIMP3 downregulation in a consistent fraction of PTC, we evaluated the functional consequences of TIMP3 downregulation in a PTC-derived cell line model. We found that TIMP3 restoration in NIM1 cell line, in which the expression of TIMP3 is silenced by promoter hypermethylation, reduced in vitro migration, invasion and anchorage-independent growth. Using a mouse xenograft model we demonstrated that restoration of TIMP3 activity reduces tumor growth, concomitantly with reduction of angiogenesis and macrophage recruitment at tumor site (Anania et al, Oncogene 2011). Papillary thyroid cancer (PTC) is the most frequent thyroid tumor. The tissue inhibitor of metalloproteinase-3 (TIMP3) gene encodes a matrix metalloproteinases inhibitor that exerts a tumor suppressor role in several tumor types. TIMP3 is frequently downregulated in PTC by promoter methylation. We have previously functionally demonstrated that TIMP3 exerts an oncosuppressor role in PTC: TIMP3 restoration in the PTC-derived NIM1 cell line affects in vitro migration, invasion and adhesive capability, while reduces tumor growth, angiogenesis and macrophage recruitment in vivo. To have a broader view on the mediators of TIMP3 oncosuppressor activity in thyroid tumors, here we focused on the TIMP3 related transcriptome.By interrogating the TCGA data set and performing a genome-wide expression analysis of NIM1 cell line TIMP3 in vitro model, we show that different expression levels of TIMP3 lead to transcriptional changes that modulate, among other, inflammatory functions.
2022-12-21 | GSE206915 | GEO
Project description:Papillary thyroid carcinoma (PTC) is the most common malignant phenotype of thyroid cancer, with a rapidly increasing number of new cases globally. Multifocality is a common phenomenon in patients with PTC. The tumor microenvironment (TME) plays a pivotal role in cancer progression in papillary thyroid carcinoma (PTC), yet the composition and phenotype of cells within TME in bilateral PTCs are poorly understood.
2022-04-13 | GSE191288 | GEO
Project description:BackgroundPapillary thyroid cancer (PTC) is the most frequent thyroid tumor. The tissue inhibitor of metalloproteinase-3 (TIMP3) gene encodes a matrix metalloproteinases inhibitor that exerts a tumor suppressor role in several tumor types. TIMP3 is frequently downregulated in PTC by promoter methylation. We have previously functionally demonstrated that TIMP3 exerts an oncosuppressor role in PTC: TIMP3 restoration in the PTC-derived NIM1 cell line affects in vitro migration, invasion and adhesive capability, while reduces tumor growth, angiogenesis and macrophage recruitment in vivo. To get a deeper insight on the mediators of TIMP3 oncosuppressor activity in thyroid tumors, here we focused on the TIMP3 related transcriptome.MethodsTCGA database was used for investigating the genes differentially expressed in PTC samples with low and high TIMP3 expression. Genome wide expression analysis of clones NIM1-T23 (expressing a high level of TIMP3 protein) and NIM1-EV (control empty vector) was performed. Gene sets and functional enrichment analysis with clusterProfiler were applied to identify the modulated biological processes and pathways. CIBERSORT was used to evaluate the distribution of different immunological cell types in TCGA-PTC tumor samples with different TIMP3 expression levels. Real time PCR was performed for the validation of selected genes.ResultsThyroid tumors with TIMP3-high expression showed a down-modulation of inflammation-related gene sets, along with a reduced protumoral hematopoietic cells fraction; an enrichment of cell adhesion functions was also identified. Similar results were obtained in the TIMP3-overexpessing NIM1 cells in vitro model, where a down-regulation of immune-related function gene sets, some of which also identified in tumor samples, was observed. Interestingly, through enrichment analysis, were also recognized terms related to cell adhesion, extracellular matrix organization, blood vessel maintenance and vascular process functions that have been found modulated in our previous in vitro and in vivo functional studies.ConclusionsOur results highlight the correlation of TIMP3 expression levels with the regulation of inflammatory functions and the immune infiltration composition associated with different PTC prognosis, thus providing a broader view on the oncosuppressor role of TIMP3 in PTC.
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Project description:Follicular thyroid tumours were investigated using global gene expression analysis. Aim of this study was the identification of new markers for follicular thyroid carcinoma. Keywords: cell type comparison
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Project description:Anaplastic thyroid carcinoma (ATC) has among the worst prognosis of any solid malignancy. The low incidence of the disease has in part precluded systematic clinical trials and tissue collection, and there has been little progress in developing effective therapies. BRAF and TP53 mutations co-occur in a high proportion of ATC, particularly those associated with a precursor papillary thyroid carcinoma (PTC). In order to develop an adult-onset model of BRAF-mutant anaplastic thyroid carcinoma, we generated a novel thyroid-specific CreER transgenic mouse. We utilize a Cre-regulated BrafV600E mouse and a conditional Trp53 allelic series to demonstrate that p53 constrains progression from papillary to anaplastic thyroid carcinoma. Gene expression and immunohistochemical analyses of murine tumors identified the cardinal features of human ATC including loss of differentiation, local invasion, distant metastasis and rapid lethality. We employed small animal ultrasound imaging to monitor autochthonous tumors, and show that treatment with the selective BRAF inhibitor PLX4720 improved survival, but did not lead to tumor regression or suppress signaling through the MAPK pathway. Combination of PLX4720 and the MEK inhibitor PD0325901 more completely suppressed MAPK pathway activation in mouse and human ATC cell lines, and improved the structural response and survival of ATC-bearing animals. This model expands the limited repertoire of autochthonous models of clinically aggressive thyroid cancer, and these data suggest that small molecule MAPK pathway inhibitors hold clinical promise in the treatment of advanced thyroid carcinoma. Total RNA from five murine papillary thyroid carcinoma (PTC) tumors and five murine anaplastic thyroid carcinoma (ATC) tumors was analyzed.
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