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Integrated Analysis of Thyroid Cancer Public Datasets Reveals Role of Post-Transcriptional Regulation on Tumor Progression by Targeting of Immune System Mediators.

Geraldo MV, Kimura ET - PLoS ONE (2015)

Bottom Line: Our results show miRNA-mRNA interaction that could contribute with the de-regulation of key tumor-host mediators, such as extra-cellular matrix molecules, interleukins and interleukin receptors, which could drive a more aggressive behavior and tumor progression.In conclusion, we shed light on the post-transcriptional regulation of gene expression in differentiated and undifferentiated thyroid cancers, revealing a potential role of miRNAs in modulation of tumor-host interaction molecules, particularly ECM molecules and immune system mediators, which could stimulate crosstalk between tumors and the immune system to generate a more aggressive behavior.We propose a novel putative miRNA:mRNA network that could lead to a new path toward functional studies.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil.

ABSTRACT
Papillary thyroid carcinoma (PTC) is a well-differentiated thyroid tumor that accounts for approximately 80% of thyroid cancer cases. On other hand, anaplastic thyroid carcinoma (ATC) is a less frequent, but aggressive subtype, with poor prognosis. MicroRNAs (miRNAs), small non-coding RNAs, have emerged as potent post-transcriptional regulators of gene expression, which modulate the expression of cancer-related genes. Computational analyses estimate that a single miRNA may modulate hundreds of mRNA targets and, at the same time, cooperate with others to regulate one single mRNA transcript. Due to the large number of predicted targets and possible interactions, only a small number of miRNAs have characterized biological roles, and the panorama of miRNA-mediated regulation in thyroid cancer remains to be understood. Taking into consideration the large amount of gene expression data deposited in public databases we aligned miRNA target prediction and gene expression data from public PTC and ATC datasets to construct a network of post-transcriptional regulation in thyroid cancer. After a gene set enrichment analysis we identified signaling pathways and biological processes potentially modulated by the miRNAs deregulated in PTC and ATC. Our results show miRNA-mRNA interaction that could contribute with the de-regulation of key tumor-host mediators, such as extra-cellular matrix molecules, interleukins and interleukin receptors, which could drive a more aggressive behavior and tumor progression. Moreover, our analysis through The Cancer Genome Atlas (TCGA) database revealed that aberrant expression of ECM and cytokines genes is frequent in PTC and is associated with aggressive behavior and decreased overall survival rate. In conclusion, we shed light on the post-transcriptional regulation of gene expression in differentiated and undifferentiated thyroid cancers, revealing a potential role of miRNAs in modulation of tumor-host interaction molecules, particularly ECM molecules and immune system mediators, which could stimulate crosstalk between tumors and the immune system to generate a more aggressive behavior. We propose a novel putative miRNA:mRNA network that could lead to a new path toward functional studies.

No MeSH data available.


Related in: MedlinePlus

Abnormal expression of target genes in PTC is associated with increased risk, extra-thyroidal extension and lymphnode metastasis in PTC.Non-parametric Mann-Whitney test was performed comparison between groups. * p-value<0.05, ** p-value<0.01, *** p-value<0.001.
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pone.0141726.g006: Abnormal expression of target genes in PTC is associated with increased risk, extra-thyroidal extension and lymphnode metastasis in PTC.Non-parametric Mann-Whitney test was performed comparison between groups. * p-value<0.05, ** p-value<0.01, *** p-value<0.001.

Mentions: We then analyzed the gene expression pattern of the enriched miRNA target genes used to construct the regulatory networks shown in Figs 3 and 4. In PTC, the differential expression of TGF-β, Wnt, insulin pathway members and the adipocytokine receptor 2 is significantly correlated with increased risk, extra-thyroidal extension and presence of lymphnode metastasis (Fig 6). Interestingly, although the enrichment of ECM remodeling molecules and cytokines and cytokine receptors was observed only in ATC datasets, the dysregulation of these genes in PTC samples is associated with aggressive phenotype (Figs 7 and 8). The alterations found in these genes are predominantly at gene expression level and is observed in 33% (125 of 388) and 18% (69 of 388) of the cases, for ECM remodeling genes and cytokine and cytokine receptor gene, respectively (Fig 9). When comparing patients with and without abnormal expression of these genes, the group of patients with aberrant gene expression of at least one of the ECM remodeling and cytokine genes presents diminished overall survival rate in comparison with those without alterations in these genes (Fig 10). When we considered all the list of targets identified by the GSEA, gene expression abnormality in ECM-receptor interaction and Cytokines-cytokine receptors ontology classes is present in 60% and 46% of the samples, respectively, however without statistical significance in overall survival curves (data not shown). Any statistical significance could be observed in overall survival curves regarding differential expression of genes enriched in Wnt, TGF-β, Hedgehog, cell cycle and MAPK ontology classes in PTC (data not shown).


Integrated Analysis of Thyroid Cancer Public Datasets Reveals Role of Post-Transcriptional Regulation on Tumor Progression by Targeting of Immune System Mediators.

Geraldo MV, Kimura ET - PLoS ONE (2015)

Abnormal expression of target genes in PTC is associated with increased risk, extra-thyroidal extension and lymphnode metastasis in PTC.Non-parametric Mann-Whitney test was performed comparison between groups. * p-value<0.05, ** p-value<0.01, *** p-value<0.001.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4633176&req=5

pone.0141726.g006: Abnormal expression of target genes in PTC is associated with increased risk, extra-thyroidal extension and lymphnode metastasis in PTC.Non-parametric Mann-Whitney test was performed comparison between groups. * p-value<0.05, ** p-value<0.01, *** p-value<0.001.
Mentions: We then analyzed the gene expression pattern of the enriched miRNA target genes used to construct the regulatory networks shown in Figs 3 and 4. In PTC, the differential expression of TGF-β, Wnt, insulin pathway members and the adipocytokine receptor 2 is significantly correlated with increased risk, extra-thyroidal extension and presence of lymphnode metastasis (Fig 6). Interestingly, although the enrichment of ECM remodeling molecules and cytokines and cytokine receptors was observed only in ATC datasets, the dysregulation of these genes in PTC samples is associated with aggressive phenotype (Figs 7 and 8). The alterations found in these genes are predominantly at gene expression level and is observed in 33% (125 of 388) and 18% (69 of 388) of the cases, for ECM remodeling genes and cytokine and cytokine receptor gene, respectively (Fig 9). When comparing patients with and without abnormal expression of these genes, the group of patients with aberrant gene expression of at least one of the ECM remodeling and cytokine genes presents diminished overall survival rate in comparison with those without alterations in these genes (Fig 10). When we considered all the list of targets identified by the GSEA, gene expression abnormality in ECM-receptor interaction and Cytokines-cytokine receptors ontology classes is present in 60% and 46% of the samples, respectively, however without statistical significance in overall survival curves (data not shown). Any statistical significance could be observed in overall survival curves regarding differential expression of genes enriched in Wnt, TGF-β, Hedgehog, cell cycle and MAPK ontology classes in PTC (data not shown).

Bottom Line: Our results show miRNA-mRNA interaction that could contribute with the de-regulation of key tumor-host mediators, such as extra-cellular matrix molecules, interleukins and interleukin receptors, which could drive a more aggressive behavior and tumor progression.In conclusion, we shed light on the post-transcriptional regulation of gene expression in differentiated and undifferentiated thyroid cancers, revealing a potential role of miRNAs in modulation of tumor-host interaction molecules, particularly ECM molecules and immune system mediators, which could stimulate crosstalk between tumors and the immune system to generate a more aggressive behavior.We propose a novel putative miRNA:mRNA network that could lead to a new path toward functional studies.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil.

ABSTRACT
Papillary thyroid carcinoma (PTC) is a well-differentiated thyroid tumor that accounts for approximately 80% of thyroid cancer cases. On other hand, anaplastic thyroid carcinoma (ATC) is a less frequent, but aggressive subtype, with poor prognosis. MicroRNAs (miRNAs), small non-coding RNAs, have emerged as potent post-transcriptional regulators of gene expression, which modulate the expression of cancer-related genes. Computational analyses estimate that a single miRNA may modulate hundreds of mRNA targets and, at the same time, cooperate with others to regulate one single mRNA transcript. Due to the large number of predicted targets and possible interactions, only a small number of miRNAs have characterized biological roles, and the panorama of miRNA-mediated regulation in thyroid cancer remains to be understood. Taking into consideration the large amount of gene expression data deposited in public databases we aligned miRNA target prediction and gene expression data from public PTC and ATC datasets to construct a network of post-transcriptional regulation in thyroid cancer. After a gene set enrichment analysis we identified signaling pathways and biological processes potentially modulated by the miRNAs deregulated in PTC and ATC. Our results show miRNA-mRNA interaction that could contribute with the de-regulation of key tumor-host mediators, such as extra-cellular matrix molecules, interleukins and interleukin receptors, which could drive a more aggressive behavior and tumor progression. Moreover, our analysis through The Cancer Genome Atlas (TCGA) database revealed that aberrant expression of ECM and cytokines genes is frequent in PTC and is associated with aggressive behavior and decreased overall survival rate. In conclusion, we shed light on the post-transcriptional regulation of gene expression in differentiated and undifferentiated thyroid cancers, revealing a potential role of miRNAs in modulation of tumor-host interaction molecules, particularly ECM molecules and immune system mediators, which could stimulate crosstalk between tumors and the immune system to generate a more aggressive behavior. We propose a novel putative miRNA:mRNA network that could lead to a new path toward functional studies.

No MeSH data available.


Related in: MedlinePlus