Dataset Information

Effect of ret/PTC 1 rearrangement on transcription and post-transcriptional regulation in a papillary thyroid carcinoma model.

ABSTRACT:

Background

microRNAs (miRNAs) are a group of non-coding single stranded RNAs measuring approximately 22 nt in length that have been found to control cell growth, differentiation and apoptosis. miRNAs negatively regulate their target genes and recently have been implicated in tumourigenesis. Furthermore, miRNA expression profiling correlates with various cancers, with these genes thought to act as both tumour suppressors and oncogenes. ret/PTC 1 is an oncogene with constitutive kinase activity implicated in the development of papillary thyroid carcinoma (PTC). This rearrangement leads to aberrant MAPK activation that is implicated in PTC tumourigenesis.

Aim

The aim of this study was to identify the effect that ret/PTC 1 has on transcription and post-transcriptional regulation in PTC by using DNA microarray and microRNA analysis.

Results

DNA microarray analysis revealed a group of genes differentially expressed between normal thyroid cell lines and those harbouring a ret/PTC 1 rearrangement.Furthermore, a unique miRNA expression signature differentiated between PTC cell lines with ret/PTC 1 and a normal thyroid cell line. 21 miRNAs showed significant overexpression and 14 miRNAs showed underexpression in these cell lines when compared to normal thyroid. Several of these up/down regulated miRNAs may be involved in PTC pathogenesis.

SUBMITTER: Cahill S

PROVIDER: S-EPMC1713250 | biostudies-literature | 2006 Dec

REPOSITORIES: biostudies-literature

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Publications

Effect of ret/PTC 1 rearrangement on transcription and post-transcriptional regulation in a papillary thyroid carcinoma model.

Cahill Susanne S Smyth Paul P Finn Stephen P SP Denning Karen K Flavin Richard R O'Regan Esther M EM Li Jinghuan J Potratz Astrid A Guenther Simone M SM Henfrey Richard R O'Leary John J JJ Sheils Orla O

Molecular cancer 20061211

<h4>Background</h4>microRNAs (miRNAs) are a group of non-coding single stranded RNAs measuring approximately 22 nt in length that have been found to control cell growth, differentiation and apoptosis. miRNAs negatively regulate their target genes and recently have been implicated in tumourigenesis. Furthermore, miRNA expression profiling correlates with various cancers, with these genes thought to act as both tumour suppressors and oncogenes. ret/PTC 1 is an oncogene with constitutive kinase act ...[more]

PMID: 17156473

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Project description:RET/PTC rearrangements, resulting in aberrant activity of the RET protein tyrosine kinase receptor, occur exclusively in papillary thyroid cancer (PTC). In this study, we examined the association between RET/PTC rearrangements and thyroid hormone homeostasis, and explored whether concomitant diseases such as nodular goiter and Hashimoto's thyroiditis influenced this association. A total of 114 patients diagnosed with PTC were enrolled in this study. Thyroid hormone levels, clinicopathological parameters and lifestyle were obtained through medical records and surgical pathology reports. RET/PTC rearrangements were detected using TaqMan RT-PCR and validated by direct sequencing. No RET/PTC rearrangements were detected in benign thyroid tissues. RET/PTC rearrangements were detected in 23.68% (27/114) of PTC tissues. No association between thyroid function, clinicopathological parameters and lifestyle was observed either in total thyroid cancer patients or the subgroup of patients with concomitant disease. In the subgroup of PTC patients without concomitant disease, RET/PTC rearrangement was associated with multifocal cancer (P = 0.018). RET/PTC rearrangement was also correlated with higher TSH levels at one month post-surgery (P = 0.037). Based on likelihood-ratio regression analysis, the RET/PTC-positive PTC cases showed an increased risk of multifocal cancers in the thyroid gland (OR = 5.57, 95% CI, 1.39-22.33). Our findings suggest that concomitant diseases such as nodular goiter and Hashimoto's thyroiditis in PTC may be a confounding factor when examining the effects of RET/PTC rearrangements. Excluding the potential effect of this confounding factor showed that RET/PTC may confer an increased risk for the development of multifocal cancers in the thyroid gland. Aberrantly increased post-operative levels of TSH were also associated with RET/PTC rearrangement. Together, our data provides useful information for the treatment of papillary thyroid cancer.

Project description:BackgroundRadiomics strategies exhibit great promise in the context of thyroid nodule diagnosis. This study aimed to compare radiomics features of different sizes of medullary thyroid carcinoma (MTC) and papillary thyroid carcinoma (PTC) tumors and to compare the efficiency of radiomics approaches as a means of differentiating between these tumor types.MethodsIn total, 86 MTC and 330 PTC nodules were divided into the macronodular (>10 mm) and micronodular (⩽10 mm) categories. The radiomics features of these nodules were analyzed to identify independent prognosis factors and evaluate the efficacy of individual and combined indicators as predictors of tumor type.ResultsIn total, 12 radiomics features were found to differ significantly between MTC and PTC macronodules, while 6 differed significantly between MTC and PTC micronodules. Shape 2D_Sphericity, firstorder_Skewness, glrlm_RunLengthNonUniformity, glszm_GrayLevelNonUniformity, and glszm_SizeZoneNonUniformity were features that were independently associated with the differential diagnoses of MTC and PTC macronodules. Receiver operating characteristic (ROC) curve analyses of the efficacy of these 5 single indicators and a combined indicator composed thereof yielded area under the curve (AUC) values of 0.621, 0.678, 0.704, 0.762, 0.747, and 0.824, respectively, with respective sensitivities of 55.3%, 43.0%, 53.1%, 56.3%, 46.9%, and 65.6%, and respective specificity values of 65.6%, 89.1%, 81.6%, 88.8%, 95.0%, and 91.1%. The glrlm_RunEntropy and glszm_SizeZoneNonUniformity features were identified as independent factors associated with the differential diagnoses of MTC and PTC micronodules. Receiver operating characteristic curve analyses of the efficacy of these 2 single indicators and a combined indicator composed thereof yielded respective AUC values of 0.678, 0.678, and 0.771; Sensitivities of 57.0%, 72.7%, and 72.7%; and specificities of 77.3%, 64.2%, and 77.5%.ConclusionsA range of different radiomics features can enable effective differentiation between MTC and PTC nodules of different sizes. Moreover, analyses of combinations of radiomics features yielded diagnostic efficiency values higher than those associated with single radiomics features, highlighting a more reliable approach to diagnosing MTC and PTC tumors.

Project description:BackgroundHashimoto Thyroiditis (H.T.) is a destructive autoimmune thyroid condition whose precise molecular pathogenesis remains unclear. ret/PTC-1 is a chimeric transcript which has been described in autoimmune thyroid disease (AITD) and thyroid neoplasia. The purpose of this study was to observe the immunogenic effect exposure to H.T. and control lymphocyte supernatant would have on normal (Nthy-ori) and ret/PTC-1 (TPC-1) expressing thyroid cell line models.ResultsA 2 x 2 matrix comprising Nthy-ori and TPC-1 cell lines and H.T. and control lymphocyte supernatant was designed and utilised as follows; activated lymphocytic supernatant from a H.T. and normal control were co-cultured with a cell line derived from normal thyroid (Nthy-ori) and also a cell line derived from a papillary thyroid carcinoma that endogenously expresses ret/PTC-1 (TPC-1). The co-cultures were harvested at 0, 6 and 18 hour time points. Gene expression analysis was performed on RNA extracted from thyrocytes using TaqMan Immune profiling Low-Density Arrays (Applied Biosystems, CA, USA) comprising gene expression markers for 93 immune related targets plus 3 endogenous controls. Stimulation of the normal thyroid cell line model with activated T cell supernatant from the H.T. donor yielded global up-regulation of immune targets when compared with control supernatant stimulation. In particular, a cohort of targets (granzyme B, CD3, CD25, CD152, CD45) associated with cytotoxic cell death; T cell receptor (TCR) and T cell signaling were up-regulated in the normal cell line model. When the ret/PTC-1 expressing thyroid cell line was co-cultured with H.T. lymphocyte supernatant, in comparison to control supernatant stimulation, down-regulation of the same subset of immune targets was seen.ConclusionCo-culturing H.T. lymphocyte supernatant with a normal thyroid cell line model leads to over-expression of a subset of targets which could contribute to the pathogenesis of H.T. via cytotoxic cell death and TCR signalling. Stimulation of the ret/PTC-1 positive cell line with the same stimulus led to a down-regulated shift in the gene expression pattern of the cohort of immune targets. We hypothesize that ret/PTC-1 activation may dampen immunogenic responses in the thyroid, which could possibly facilitate papillary thyroid carcinoma development.

Dataset Information

Effect of ret/PTC 1 rearrangement on transcription and post-transcriptional regulation in a papillary thyroid carcinoma model.

Background

Aim

Results

Publications

Effect of ret/PTC 1 rearrangement on transcription and post-transcriptional regulation in a papillary thyroid carcinoma model.

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