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Identification of down-regulated microRNAs in thyroid cancer and their potential functions.

ABSTRACT: BACKGROUND:The mechanism of microRNAs (miRNAs) in thyroid cancer is still unclear. We identified miRNAs with differential expression in thyroid cancer versus normal tissues. METHODS:Microarray datasets were obtained from the GEO and ArrayExpress databases, and from publications found via PubMed, EMBASE, and Web of Science. Differentially expressed miRNAs were identified using the limma package, and their targets predicted using miRWalk. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and protein-protein interaction (PPI) network analyses were performed using these target genes to explore potential carcinogenic mechanisms. Correlations between target gene and miRNA expression levels were examined. Changes in target protein expression were confirmed using data from The Human Protein Atlas and the Cancer Genome Atlas. RESULTS:We ultimately included five datasets, and further analyzed the four miRNAs that were down-regulated in at least four datasets (miR-7-2-3p, miR-138-5p, miR-144-5p, miR-486-5p). Predicted targets were enriched in GO terms including extracellular matrix organization, cell surface, and receptor binding, and in KEGG cancer pathways. PPI analysis identified 10 hub genes as key potential targets of these miRNAs. The expression levels of eight target genes were negatively correlated with those of their respective miRNAs. Furthermore, eight predicted target genes in cancer-related pathways showed up-regulated protein and mRNA expression in thyroid cancer. CONCLUSION:Low miRNA expression in thyroid cancer might influence tumorigenesis via critical pathways. The genes identified here may act as a starting point for further investigation of the carcinogenic mechanisms of these miRNAs.

SUBMITTER: Pan D

PROVIDER: S-EPMC6129536 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Identification of down-regulated microRNAs in thyroid cancer and their potential functions.

Pan Denghua D Lin Peng P Wen Dongyue D Wei Yunpeng Y Mo Qiuyan Q Liang Liang L Chen Gang G He Yun Y Chen Junqiang J Yang Hong H

American journal of translational research 20180815 8

<h4>Background</h4>The mechanism of microRNAs (miRNAs) in thyroid cancer is still unclear. We identified miRNAs with differential expression in thyroid cancer versus normal tissues.<h4>Methods</h4>Microarray datasets were obtained from the GEO and ArrayExpress databases, and from publications found via PubMed, EMBASE, and Web of Science. Differentially expressed miRNAs were identified using the limma package, and their targets predicted using miRWalk. Gene Ontology (GO), Kyoto Encyclopedia of Ge ...[more]

PMID: 30210669

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Project description:BackgroundMicroRNA (miRNA) expression profiles have been described in pancreatic ductal adenocarcinoma (PDAC), but these have not been compared with pre-malignant pancreatic tumors. We wished to compare the miRNA expression signatures in pancreatic benign cystic tumors (BCT) of low and high malignant potential with PDAC, in order to identify miRNAs deregulated during PDAC development. The mechanistic consequences of miRNA dysregulation were further evaluated.MethodsTissue samples were obtained at a tertiary pancreatic unit from individuals with BCT and PDAC. MiRNA profiling was performed using a custom microarray and results were validated using RT-qPCR prior to evaluation of miRNA targets.ResultsWidespread miRNA down-regulation was observed in PDAC compared to low malignant potential BCT. We show that amongst those miRNAs down-regulated, miR-16, miR-126 and let-7d regulate known PDAC oncogenes (targeting BCL2, CRK and KRAS respectively). Notably, miR-126 also directly targets the KRAS transcript at a "seedless" binding site within its 3'UTR. In clinical specimens, miR-126 was strongly down-regulated in PDAC tissues, with an associated elevation in KRAS and CRK proteins. Furthermore, miR-21, a known oncogenic miRNA in pancreatic and other cancers, was not elevated in PDAC compared to serous microcystic adenoma (SMCA), but in both groups it was up-regulated compared to normal pancreas, implicating early up-regulation during malignant change.ConclusionsExpression profiling revealed 21 miRNAs down-regulated in PDAC compared to SMCA, the most benign lesion that rarely progresses to invasive carcinoma. It appears that miR-21 up-regulation is an early event in the transformation from normal pancreatic tissue. MiRNA expression has the potential to distinguish PDAC from normal pancreas and BCT. Mechanistically the down-regulation of miR-16, miR-126 and let-7d promotes PDAC transformation by post-transcriptional up-regulation of crucial PDAC oncogenes. We show that miR-126 is able to directly target KRAS; re-expression has the potential as a therapeutic strategy against PDAC and other KRAS-driven cancers.

Project description:Cardiomyocyte size in the healthy heart is in part determined by the level of circulating thyroid hormone (TH). Higher levels of TH induce ventricular hypertrophy, primarily in response to an increase in hemodynamic load. Normal cardiac function is maintained in this form of hypertrophy, whereas progressive contractile dysfunction is a hallmark of pathological hypertrophy. MicroRNAs (miRNAs) are important modulators of signal-transduction pathways driving adverse remodeling. Because little is known about the involvement of miRNAs in cardiac TH action and hypertrophy, we examined the miRNA expression profile of the hypertrophied left ventricle (LV) using a mouse model of TH-induced cardiac hypertrophy. C57Bl/6J mice were rendered hypothyroid by treatment with propylthiouracil and were subsequently treated for 3?days with TH (T3) or saline. T3 treatment increased LV weight by 38% (p?<?0.05). RNA was isolated from the LV and expression of 641 mouse miRNAs was determined using Taqman Megaplex arrays. Data were analyzed using RQ-manager and DataAssist. A total of 52 T3-regulated miRNAs showing a >2-fold change (p?<?0.05) were included in Ingenuity Pathway Analysis to predict target mRNAs involved in cardiac hypertrophy. The analysis was further restricted to proteins that have been validated as key factors in hypertrophic signal transduction in mouse models of ventricular remodeling. A total of 27 mRNAs were identified as bona fide targets. The predicted regulation of 19% of these targets indicates enhancement of physiological hypertrophy, while 56% indicates suppression of pathological remodeling. Our data suggest that cardiac TH action includes a novel level of regulation in which a unique set of TH-dependent miRNAs primarily suppresses pathological hypertrophic signaling. This may be relevant for our understanding of the progression of adverse remodeling, since cardiac TH levels are known to decrease substantially in various forms of pathological hypertrophy.

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Identification of down-regulated microRNAs in thyroid cancer and their potential functions.

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Identification of down-regulated microRNAs in thyroid cancer and their potential functions.

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