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1.
Medicine (Baltimore) ; 99(34): e21882, 2020 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-32846846

RESUMO

Thyroid cancer (TC) is the most well-known endocrine neoplasia as well as a common malignant tumor in the head and neck. Our study was designed to assess the prognostic meaningful of TNFRSF12A expression in TC dependent on data acquired from TCGA and so as to increase further knowledge into the biological pathways involved in TC pathogenesis related TNFRSF12A.Information on gene expression and comparing clinical data were identified and downloaded from TCGA. Gene set enrichment analysis (GSEA) created an arranged list of all genes indicated by their connection with TNFRSF12A expression.Our study cohort included 370 (73.1%) female and 136 (26.9%) male patients. The scatter plot and paired plot showed the difference of TNFRSF12A expression between normal and tumor samples (P < .01). The univariate analysis suggested that TNFRSF12A-low associated essentially with age (HR: 1.15; 95%CI: 1.08-1.22; P < .01), stage (HR: 2.79; 95%CI: 1.43-5.46; I vs IV; P = .003) and tumor stage (HR: 2.39; 95%CI: 1.08-5.30; P = .031). The GSEA results show that type II diabetes mellitus, pantothenate and CoA biosynthesis, adipocytokine signaling pathway, PPAR signaling pathway, mTOR signaling pathway, insulin signaling pathway, are enriched in TNFRSF12A low expression phenotype.TNFRSF12A expression may be a potential useful prognostic molecular biomarker of bad survival in thyroid cancer, in addition, PPAR signaling pathway, insulin signaling pathway, mTOR signaling pathway may be the key pathway controlled by TNFRSF12A in thyroid cancer. Further experimental ought to be performed to demonstrate the biologic effect of TNFRSF12A.


Assuntos
Transdução de Sinais , Receptor de TWEAK/genética , Neoplasias da Glândula Tireoide/genética , Adipocinas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Diabetes Mellitus Tipo 2/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias/métodos , Receptores Ativados por Proliferador de Peroxissomo/genética , Valor Preditivo dos Testes , Prognóstico , Serina-Treonina Quinases TOR/genética , Neoplasias da Glândula Tireoide/mortalidade , Neoplasias da Glândula Tireoide/patologia
2.
Nat Commun ; 11(1): 3981, 2020 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-32769997

RESUMO

Thyroid stimulating hormone (TSH) is critical for normal development and metabolism. To better understand the genetic contribution to TSH levels, we conduct a GWAS meta-analysis at 22.4 million genetic markers in up to 119,715 individuals and identify 74 genome-wide significant loci for TSH, of which 28 are previously unreported. Functional experiments show that the thyroglobulin protein-altering variants P118L and G67S impact thyroglobulin secretion. Phenome-wide association analysis in the UK Biobank demonstrates the pleiotropic effects of TSH-associated variants and a polygenic score for higher TSH levels is associated with a reduced risk of thyroid cancer in the UK Biobank and three other independent studies. Two-sample Mendelian randomization using TSH index variants as instrumental variables suggests a protective effect of higher TSH levels (indicating lower thyroid function) on risk of thyroid cancer and goiter. Our findings highlight the pleiotropic effects of TSH-associated variants on thyroid function and growth of malignant and benign thyroid tumors.


Assuntos
Pleiotropia Genética , Estudo de Associação Genômica Ampla , Neoplasias da Glândula Tireoide/genética , Tireotropina/genética , Loci Gênicos , Predisposição Genética para Doença , Bócio/genética , Humanos , Análise da Randomização Mendeliana , Herança Multifatorial/genética , Mutação de Sentido Incorreto/genética , Fenótipo , Mapeamento Físico do Cromossomo , Prevalência , Fatores de Risco , Tireoglobulina/genética , Neoplasias da Glândula Tireoide/epidemiologia
3.
PLoS One ; 15(6): e0234566, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32603365

RESUMO

Hashimoto's thyroiditis (HT) is present in the background of around 30% of papillary thyroid carcinomas (PTCs). The genetic predisposition effect of this autoimmune condition is not thoroughly understood. We analyzed the microarray expression profiles of 13 HT, eight PTCs with (w/) coexisting HT, six PTCs without (w/o) coexisting HT, six micro PTCs (mPTCs), and three normal thyroid (TN) samples. Based on a false discovery rate (FDR)-adjusted p-value ≤ 0.05 and a fold change (FC) > 2, four comparison groups were defined, which were HT vs. TN; PTC w/ HT vs. TN; PTC w/o HT vs. TN; and mPTC vs. TN. A Venn diagram displayed 15 different intersecting and non-intersecting differentially expressed gene (DEG) sets, of which a set of 71 DEGs, shared between the two comparison groups HT vs. TN ∩ PTC w/ HT vs. TN, harbored the relatively largest number of genes related to immune and inflammatory functions; oxidative stress and reactive oxygen species (ROS); DNA damage and DNA repair; cell cycle; and apoptosis. The majority of the 71 DEGs were upregulated and the most upregulated DEGs included a number of immunoglobulin kappa variable genes, and other immune-related genes, e.g., CD86 molecule (CD86), interleukin 2 receptor gamma (IL2RG), and interferon, alpha-inducible protein 6 (IFI6). Upregulated genes preferentially associated with other gene ontologies (GO) were, e.g., STAT1, MMP9, TOP2A, and BRCA2. Biofunctional analysis revealed pathways related to immunogenic functions. Further data analysis focused on the set of non-intersecting 358 DEGs derived from the comparison group of HT vs. TN, and on the set of 950 DEGs from the intersection of all four comparison groups. In conclusion, this study indicates that, besides immune/inflammation-related genes, also genes associated with oxidative stress, ROS, DNA damage, DNA repair, cell cycle, and apoptosis are comparably more deregulated in a data set shared between HT and PTC w/ HT. These findings are compatible with the conception of a genetic sequence where chronic inflammatory response is accompanied by deregulation of genes and biofunctions associated with oncogenic transformation. The generated data set may serve as a source for identifying candidate genes and biomarkers that are practical for clinical application.


Assuntos
Perfilação da Expressão Gênica , Doença de Hashimoto/genética , Câncer Papilífero da Tireoide/genética , Neoplasias da Glândula Tireoide/genética , Adolescente , Adulto , Idoso , Transformação Celular Neoplásica/genética , Feminino , Predisposição Genética para Doença , Doença de Hashimoto/complicações , Humanos , Inflamação/genética , Masculino , Pessoa de Meia-Idade , Câncer Papilífero da Tireoide/complicações , Neoplasias da Glândula Tireoide/complicações , Regulação para Cima
4.
J Clin Pathol ; 73(9): 527-530, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32699115

RESUMO

The GLIS 1-3 genes belong to a family of transcription factors, the Krüppel-like zinc finger proteins. The GLIS proteins function primarily as activators of transcription (GLIS 1 and 3), while GLIS 2 functions as a repressor. Collectively, the GLIS proteins are involved in a variety of diseases in several organs ranging from Alzheimer's disease, facial dysmorphism, neonatal diabetes mellitus, breast and colon cancers and leukaemia. In particular, loss-of-function mutations in GLIS2 are responsible for an autosomal recessive cystic kidney disease called nephronophthisis, which is characterised by tubular atrophy, interstitial fibrosis and corticomedullary cysts.Of diagnostic value in current practice are the presence of GLIS 3 and 1 fusions with PAX8 in almost 100% of hyalinising trabecular tumours of the thyroid gland. This enables its separation from papillary thyroid cancer.


Assuntos
Proteínas de Ligação a DNA/genética , Fatores de Transcrição Kruppel-Like/genética , Proteínas Repressoras/genética , Câncer Papilífero da Tireoide/genética , Neoplasias da Glândula Tireoide/genética , Transativadores/genética , Fatores de Transcrição/genética , Proteínas de Ligação a DNA/metabolismo , Fusão Gênica , Humanos , Fatores de Transcrição Kruppel-Like/metabolismo , Mutação com Perda de Função , Fator de Transcrição PAX8/genética , Fator de Transcrição PAX8/metabolismo , Proteínas Repressoras/metabolismo , Glândula Tireoide/patologia , Transativadores/metabolismo , Fatores de Transcrição/metabolismo
5.
Anticancer Res ; 40(7): 3801-3809, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32620619

RESUMO

AIM: Cancer stem-like cell (CSC) markers and the role of CSCs derived from papillary thyroid carcinoma (PTC) in pathogenesis are unclear. This study aimed to investigate CSC properties using tumor spheres from passaged PTC cells but without sorting CSCs. MATERIALS AND METHODS: To identify the properties of CSCs derived from PTC, the expression of SRY-box transcription factor 2(SOX2), octamer-binding transcription factor 4 (OCT4), Nanog homeobox (NANOG), thyroglobulin (TG), thyroid-stimulating hormone receptor (TSHR), E-cadherin, YES-associated protein 1 (YAP1), and signal transducer and activator of transcription 3 (STAT3) was investigated in tumor spheres serially passaged without sorting CSCs. RESULTS: The cultured tumor spheres had cancer stemness; high expression of OCT4, SOX2, NANOG, and YAP1; low expression of E-cadherin; and varied expression of TG, TSHR, and STAT3. PTC tumor spheres transfected with small interfering RNA targeting YAP1 had fewer CSC properties than the non-transfected tumor spheres did. CONCLUSION: Tumor spheres derived from PTC cells by passaging without sorting CSCs have more stem-like cell properties, and less differentiation potential. Thus, this simple and cost-effective method can be used for the enrichment of PTC stemness for employment in cell-based models, reducing the need for use of animal models.


Assuntos
Células-Tronco Neoplásicas/patologia , Câncer Papilífero da Tireoide/patologia , Neoplasias da Glândula Tireoide/patologia , Proteínas Adaptadoras de Transdução de Sinal/biossíntese , Proteínas Adaptadoras de Transdução de Sinal/genética , Antígenos CD/biossíntese , Antígenos CD/genética , Biomarcadores Tumorais/biossíntese , Biomarcadores Tumorais/genética , Caderinas/biossíntese , Caderinas/genética , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Humanos , Células-Tronco Neoplásicas/metabolismo , Fator 3 de Transcrição de Octâmero/biossíntese , Fator 3 de Transcrição de Octâmero/genética , Fator de Transcrição STAT3/biossíntese , Fator de Transcrição STAT3/genética , Esferoides Celulares , Câncer Papilífero da Tireoide/genética , Câncer Papilífero da Tireoide/metabolismo , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/metabolismo , Fatores de Transcrição/biossíntese , Fatores de Transcrição/genética
6.
Am Surg ; 86(5): 450-457, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32684022

RESUMO

This study analyzed the characteristics of BRAFV600E mutation in papillary thyroid carcinoma (PTC) in Chinese coastal areas. We intended to identify noninvasive methods to determine BRAFV600E status in thyroid nodules prior to surgery. BRAFV600E mutation and the sonographic characteristics of thyroid nodules were investigated in 670 PTC patients in our hospital. We aimed to determine the relationship between BRAFV600E mutation and the clinicopathological and sonographic imaging characteristics of PTC. The mutation rate of the BRAFV600E was 78.2%. BRAFV600E mutation was significantly associated with central node (univariate analyses, P = .005; multivariate analyses, P < .001, odds ratio [OR] = 10.255) and lateral node metastases (univariate analyses, P = .001; multivariate analyses, P < .001, OR = 22). It was less frequent in PTC coexisting with Hashimoto's thyroiditis (univariate analyses, P = .016; multivariate analyses, P < .001, OR = .034). Nodules without blood flow had a significantly higher mutation rate of BRAFV600E in PTC patients (univariate analyses, P = .026). BRAFV600E mutation was significantly associated with high suspicion in the Thyroid Imaging Reporting and Data System 5 (univariate analyses, P = .004; multivariate analyses, P = .014, OR = 6.456). Our results strongly suggest that BRAFV600E mutation plays a potential role in lymph node metastasis (central node metastasis, OR = 10.225; lateral node metastasis, OR = 22). Some sonographic imaging features might be helpful in estimating the status of BRAFV600E preoperatively.


Assuntos
Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Câncer Papilífero da Tireoide/diagnóstico por imagem , Câncer Papilífero da Tireoide/genética , Neoplasias da Glândula Tireoide/diagnóstico por imagem , Neoplasias da Glândula Tireoide/genética , Nódulo da Glândula Tireoide/genética , Adulto , China , Correlação de Dados , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ultrassonografia
7.
Proc Natl Acad Sci U S A ; 117(27): 15846-15851, 2020 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-32561648

RESUMO

Combination use of BRAF V600E inhibitor dabrafenib and MEK inhibitor trametinib has become a standard treatment for human cancers harboring BRAF V600E. Its anticancer efficacies vary, however, with dramatic efficacy in some patients and drug resistance/tumor recurrence in others, which is poorly understood. Using thyroid cancer, melanoma, and colon cancer cell models, we showed that dabrafenib and trametinib induced robust apoptosis of cancer cells harboring both BRAF V600E and TERT promoter mutations but had little proapoptotic effect in cells harboring only BRAF V600E. Correspondingly, the inhibitors nearly completely abolished the growth of in vivo tumors harboring both mutations but had little effect on tumors harboring only BRAF V600E. Upon drug withdrawal, tumors harboring both mutations remained hardly measurable but tumors harboring only BRAF V600E regrew rapidly. BRAF V600E/MAP kinase pathway is known to robustly activate mutant promoter of TERT, a strong apoptosis suppressor. Thus, for survival, cancer cells harboring both mutations may have evolved to rely on BRAF V600E-promoted and high-TERT expression-mediated suppression of apoptosis. As such, inhibition of BRAF/MEK can trigger strong apoptosis-induced cell death and hence tumor abolishment. This does not happen in cells harboring only BRAF V600E as they have not developed reliance on TERT-mediated suppression of apoptosis due to the lack of mutant promoter-driven high-TERT expression. TERT promoter mutation governs BRAF-mutant cancer cells' apoptotic and hence therapeutic responses to BRAF/MEK inhibitors. Thus, the genetic duet of BRAF V600E and TERT promoter mutation represents an Achilles Heel for effective therapeutic targeting and response prediction in cancer.


Assuntos
Apoptose/efeitos dos fármacos , Mutação , Regiões Promotoras Genéticas/efeitos dos fármacos , Regiões Promotoras Genéticas/genética , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas B-raf/efeitos dos fármacos , Proteínas Proto-Oncogênicas B-raf/genética , Telomerase/genética , Animais , Morte Celular , Linhagem Celular Tumoral , Neoplasias do Colo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Humanos , Imidazóis/farmacologia , Melanoma/genética , Camundongos Nus , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Oximas/farmacologia , Piridonas/farmacologia , Pirimidinonas/farmacologia , Neoplasias da Glândula Tireoide/genética , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Virchows Arch ; 477(4): 597-601, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32239274

RESUMO

Poorly differentiated thyroid carcinoma (PDTC) refers to a malignant tumour that displays an intermediate prognosis between well-differentiated carcinomas and anaplastic thyroid carcinomas (ATC). In the thyroid, pleomorphic giant cells are observed in ATC or in some non-neoplastic thyroid diseases. We described the case of a 43-year-old woman with a 34-mm nodule in her thyroid right lobe. Microscopic examination revealed an encapsulated tumour with a main solid growth pattern and extensive capsular invasion. Multiple images of angioinvasion were observed. There was neither necrosis nor inflammation. Most of the tumour cells were medium-sized and intermingled with pleomorphic giant tumour cells with bizarre features. The immunoprofile (keratins +, TTF1+, Pax 8+) proved their thyroid origin. By NGS, no molecular alteration was identified. The patient was treated by surgery and radioiodine therapy and she has no recurrence after a follow-up of 24 months. Our case meets all the histological criteria of the Turin proposal for PDTC but with pleomorphic giant cells and is very different from ATC according to clinical, histological and immunohistochemical features. Pleomorphic tumour giant cells in thyroid carcinomas could be present in PDTC and do not always represent dedifferentiation and more aggressive carcinoma, thyroid neoplasm.


Assuntos
Carcinoma de Células Gigantes/patologia , Diferenciação Celular , Células Gigantes/patologia , Neoplasias da Glândula Tireoide/patologia , Adulto , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/genética , Carcinoma de Células Gigantes/química , Carcinoma de Células Gigantes/genética , Carcinoma de Células Gigantes/terapia , Feminino , Células Gigantes/química , Humanos , Queratinas/análise , Fator de Transcrição PAX8/análise , Radioterapia Adjuvante , Neoplasias da Glândula Tireoide/química , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/terapia , Fator Nuclear 1 de Tireoide/análise , Tireoidectomia , Resultado do Tratamento
11.
Gene ; 746: 144611, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32240776

RESUMO

Thyroid cancer is one of the few malignancies whose incidence is increasing in the last decades. Advances in understanding the molecular mechanisms lead to provide opportunity for prevention, effective early identification and targeted therapies for management. A total of 63 patients with participated in this study Genomic DNA samples were obtained from the samples formalin- embedded tissue and peripheral blood. Following polymerase chain reaction amplification of the 6 RET key exons (10, 11, 13, 14, 15, and 16) were applied and PCR products were subjected to next generation DNA sequencing (ABI 3730). Results revealed that; genotype frequencies were for rs1800961 (G > T) , GG 6 (%9.5), GT 17 (%27) TT40 (%63.5) for rs2472732 (G > A), GG31 (%49.2) GA29 (%46) AA3 (%4.8,) for rs1799939, (G > A) GG42 (%66.7) GA19 (%30.2) AA2 (%3.2), for rs1800962, (C > T) CC54 (%85.7) CT9 (%14.3), for rs1800863 (C > G), CC39 (%61.9) CG22 (%34.9) GG2 (%3.2), for rs3026272 (C > G) CC 13 (%20.6) CG 50 (%79.4). Additionally 15 potential novel genetic variants were identified in these key exons. Detailed information was given both known and new detected variants in supplementary table. Genetic variants distribution frequencies and new variants represented in Turkish thyroid cancer patients for RET proto-oncogene and that results would provide contribution to the literature.


Assuntos
Genótipo , Polimorfismo Genético , Proteínas Proto-Oncogênicas c-ret/genética , Neoplasias da Glândula Tireoide/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Turquia
12.
Life Sci ; 253: 117693, 2020 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-32325133

RESUMO

AIMS: Thyroid cancer is a common endocrine malignancy and sex hormone plays an important role in it. We have previously shown that activation of estrogen receptor (ER) α promotes thyroid cancer cell proliferation and invasion. Here, we attempted to investigate the role of ETS variant 5 (ETV5) on estrogen drived thyroid malignancy. MAIN METHODS: Ten patients with follicular thyroid cancer were enrolled in this study. Cell proliferation and migration ability were analyzed by CCK-8 assay and cell migration assay, respectively. Chromatin immunoprecipitation-PCR and luciferase assay were conducted to analyze the relationship of ETV5 and PIK3CA. KEY FINDINGS: ETV5 is highly expressed in thyroid tissues from patients with follicular thyroid cancer as well as in FTC133 cells. 17b-estradiol or overexpression of ERα induced an increase in ETV5 protein level in FTC133 cells. Knockdown of ETV5 inhibited FTC133 cell proliferation, migration, and epithelial-mesenchymal transition, while 17b-estradiol could not correct this effect. Additionally, the level of PIK3CA was markedly decreased in ETV5 knockdown cells and had a positive correlation with ETV5 in thyroid cancer patients. Chromatin immunoprecipitation-PCR analysis and luciferase assay confirmed that ETV5 directly targeted PIK3CA and that ETV5 was bound to the promoter region of PIK3CA. In addition, PIK3CA overexpression abrogated ETV5-induced cell growth, migration and epithelial-mesenchymal transition. SIGNIFICANCE: ETV5 enhanced cell proliferation, migration, and epithelial-mesenchymal transition through the PIK3CA signaling pathway, indicating that ETV5 may be a therapeutic target in thyroid cancer.


Assuntos
Adenocarcinoma Folicular/patologia , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Proteínas de Ligação a DNA/genética , Neoplasias da Glândula Tireoide/patologia , Fatores de Transcrição/genética , Adenocarcinoma Folicular/genética , Adulto , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Imunoprecipitação da Cromatina , Progressão da Doença , Transição Epitelial-Mesenquimal/genética , Receptor alfa de Estrogênio/genética , Feminino , Técnicas de Silenciamento de Genes , Humanos , Pessoa de Meia-Idade , Transdução de Sinais , Neoplasias da Glândula Tireoide/genética
13.
Arch Endocrinol Metab ; 64(2): 185-189, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32236306

RESUMO

The EIF1AX gene mutations have been recently associated with papillary thyroid carcinoma and anaplastic thyroid cancer. According with these reports, the gene as been considered as a drive gene for thyroid cancer development. However, the occurrence of these alterations in benign thyroid lesions is not known and is still under investigation. Some authors have already reported the presence of EIF1AX variants in follicular adenomas and hyperplastic nodules. Here, we describe for the first time a case of a man with the EIF1AX c.338-2A>T splice site mutation in an indeterminate FNA lesion with trabecular adenoma at final histology in the absence of other pathogenetic mutations, demonstrating that further studies are required to better understand EIF1AX role in the tumorigenesis of thyroid carcinoma.


Assuntos
Adenoma/diagnóstico , Adenoma/genética , Fator de Iniciação 1 em Eucariotos/genética , Mutação/genética , Neoplasias da Glândula Tireoide/diagnóstico , Neoplasias da Glândula Tireoide/genética , Biópsia por Agulha Fina , Humanos , Masculino , Pessoa de Meia-Idade
14.
Nat Commun ; 11(1): 2056, 2020 04 28.
Artigo em Inglês | MEDLINE | ID: mdl-32345963

RESUMO

Papillary thyroid cancer (PTC) is the most common type of endocrine malignancy. By RNA-seq analysis, we identify a RET rearrangement in the tumour material of a patient who does not harbour any known RAS or BRAF mutations. This new gene fusion involves exons 1-4 from the 5' end of the Trk fused Gene (TFG) fused to the 3' end of RET tyrosine kinase leading to a TFG-RET fusion which transforms immortalized human thyroid cells in a kinase-dependent manner. TFG-RET oligomerises in a PB1 domain-dependent manner and oligomerisation of TFG-RET is required for oncogenic transformation. Quantitative proteomic analysis reveals the upregulation of E3 Ubiquitin ligase HUWE1 and DUBs like USP9X and UBP7 in both tumor and metastatic lesions, which is further confirmed in additional patients. Expression of TFG-RET leads to the upregulation of HUWE1 and inhibition of HUWE1 significantly reduces RET-mediated oncogenesis.


Assuntos
Proteínas de Fusão Oncogênica/genética , Proteínas/genética , Proteogenômica , Proteínas Proto-Oncogênicas c-ret/genética , Câncer Papilífero da Tireoide/genética , Neoplasias da Glândula Tireoide/genética , Sequência de Aminoácidos , Sequência de Bases , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular , Transformação Celular Neoplásica/patologia , Humanos , Concentração Inibidora 50 , Metástase Linfática/patologia , Mutação/genética , Proteínas de Fusão Oncogênica/metabolismo , Multimerização Proteica , Proteínas/química , Proteínas/metabolismo , Proteínas Proto-Oncogênicas c-ret/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Ubiquitina/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação , Regulação para Cima
15.
PLoS One ; 15(4): e0231341, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32315324

RESUMO

BACKGROUND: Papillary thyroid carcinoma (PTC) is the most common malignant thyroid neoplasm comprising 80-90% of all thyroid malignancies. Molecular changes in thyroid follicular cells are likely associated with the development of PTC. Mutations in serine/threonine-protein kinase (BRAF) and Rat sarcoma viral oncogene homolog (RAS) are commonly seen in PTC. METHODS: In total, 90 cases of PTC are randomly selected from archive paraffin blocks and 10µm sections were cut and processed for DNA extraction. BRAF V600E mutation and 8 types of KRAS mutations were investigated using Real Time PCR. RESULTS: BRAF V600E mutation was identified in 46% of PTC while KRAS mutations were seen in 11% of PTC. There was significant correlation between BRAF V600E mutation and PTC larger than 5cm in diameter, positive surgical margin and lymph node metastasis. BRAF V600E mutation was significantly higher in patients with less than 55-year of age than those more than 55-year of age. BRAF V600E mutation was significantly higher in patients with family history of thyroid cancer than those without. There was no significant difference in BRAFV600E mutation between males and females, PTC classic and follicular variants, unifocal and multifocal PTC. There was a significant higher percentage of BRAF V600E mutation in classic PTC than papillary microcarcinoma variant. There was no significant age, gender, histologic type, tumor size, lymph node metastasis, tumor focality, and surgical margin status differences between KRAS mutated and non-mutated PTC. CONCLUSION: BRAF V600E and KRAS mutation are seen in a significant number of PTC in the UAE. BRAF mutation is significantly correlated with large tumor size, positive surgical margins and lymph node metastasis suggesting an association between BRAF V600E mutation and tumor growth and spread.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Câncer Papilífero da Tireoide/patologia , Neoplasias da Glândula Tireoide/patologia , Adulto , Índice de Massa Corporal , Feminino , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Polimorfismo de Nucleotídeo Único , Câncer Papilífero da Tireoide/genética , Neoplasias da Glândula Tireoide/genética , Emirados Árabes Unidos
16.
PLoS One ; 15(4): e0231629, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32324757

RESUMO

INTRODUCTION: Recently, the rise in the incidences of thyroid cancer worldwide renders it to be the sixth most common cancer among women. Commonly, Fine Needle Aspiration biopsy predominantly facilitates the diagnosis of the nature of thyroid nodules. However, it is inconsiderable in determining the tumor's state, i.e., benign or malignant. This study aims to identify the key RNA transcripts that can segregate the early and late-stage samples of Thyroid Carcinoma (THCA) using RNA expression profiles. MATERIALS AND METHODS: In this study, we used the THCA RNA-Seq dataset of The Cancer Genome Atlas, consisting of 500 cancer and 58 normal (adjacent non-tumorous) samples obtained from the Genomics Data Commons (GDC) data portal. This dataset was dissected to identify key RNA expression features using various feature selection techniques. Subsequently, samples were classified based on selected features employing different machine learning algorithms. RESULTS: Single gene ranking based on the Area Under the Receiver Operating Characteristics (AUROC) curve identified the DCN transcript that can classify the early-stage samples from late-stage samples with 0.66 AUROC. To further improve the performance, we identified a panel of 36 RNA transcripts that achieved F1 score of 0.75 with 0.73 AUROC (95% CI: 0.62-0.84) on the validation dataset. Moreover, prediction models based on 18-features from this panel correctly predicted 75% of the samples of the external validation dataset. In addition, the multiclass model classified normal, early, and late-stage samples with AUROC of 0.95 (95% CI: 0.84-1), 0.76 (95% CI: 0.66-0.85) and 0.72 (95% CI: 0.61-0.83) on the validation dataset. Besides, a five protein-coding transcripts panel was also recognized, which segregated cancer and normal samples in the validation dataset with F1 score of 0.97 and 0.99 AUROC (95% CI: 0.91-1). CONCLUSION: We identified 36 important RNA transcripts whose expression segregated early and late-stage samples with reasonable accuracy. The models and dataset used in this study are available from the webserver CancerTSP (http://webs.iiitd.edu.in/raghava/cancertsp/).


Assuntos
Biomarcadores Tumorais/genética , Regulação Neoplásica da Expressão Gênica , Câncer Papilífero da Tireoide/genética , Câncer Papilífero da Tireoide/patologia , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/patologia , Área Sob a Curva , Biomarcadores Tumorais/metabolismo , Humanos , Internet , Aprendizado de Máquina , Estadiamento de Neoplasias , Fases de Leitura Aberta/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Curva ROC
17.
Gene ; 750: 144681, 2020 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-32304784

RESUMO

Thyroid cancer (THCA) is one of the most common endocrine tumors and keeps rapidly increasing worldwide. Acidic nuclear phosphoprotein 32 family member E (ANP32E) is a H2A.Z histone chaperone that regulates the expression of various genes. It has been shown that ANP32E promotes breast cancer development, whereas its role in THCA remains unknown. In this study, we found that ANP32E was significantly overexpressed in THCA tissues. Down-regulation of ANP32E inhibited the growth, cell cycle progression, DNA synthesis, glycolysis, migration and increased apoptosis in K1 and TPC-1 cells. Opposite results were observed in ANP32E-overexpressing THCA cells. At the molecular level, ANP32E up-regulated MMP9 and MMP13, and activated AKT/mTOR/HK2 signaling in THCA cells. Positive correlation between ANP32E and HK2 was found in THCA tissues. Importantly, silencing of HK2 repressed glycolysis. Inhibition of AKT/mTOR reduced cell proliferation, cell cycle progression and migration in THCA cells. Our findings suggest that ANP32E promotes THCA cell proliferation and migration via potentiating AKT/mTOR/HK2-mediated glycolysis.


Assuntos
Chaperonas Moleculares/genética , Chaperonas Moleculares/metabolismo , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/metabolismo , Adulto , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Feminino , Glicólise , Hexoquinase/metabolismo , Humanos , Masculino , Proteínas Nucleares/genética , Nucleossomos/genética , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Neoplasias da Glândula Tireoide/patologia , Ativação Transcricional
18.
Neoplasma ; 67(3): 604-613, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32266816

RESUMO

Papillary thyroid carcinoma (PTC) is the prevalent histotype of thyroid cancer, with increasing incidence worldwide. MicroRNAs (miRNAs) could play an important role in the development and progression of human cancers. Interestingly, miR-326 was validated as one of the downregulated miRNAs in PTC. Therefore, it is necessary to research the function of miR-326 involved in the progression of PTC. In the current study, we detected the downregulation of miR-326 in PTC tissues and cell lines. The miR-326 overexpression or knockdown was conducted in TPC-1 or HTh83 PTC cells. miR-326 mimics decreased the proliferation, clone formation ability and caused G1-phase accumulation. In addition, the reduction of migration and invasion abilities was induced by miR-326 mimics. Western blot analysis showed that the cells with miR-326 mimics exhibited the inhibition of vimentin and N-cadherin, as well as enhancement of E-cadherin. Importantly, miR-326 could directly target mitogen activated protein kinase 1 (MAPK1) and epidermal growth factor receptor 4 (ERBB4). MAPK1 or ERBB4 overexpression rescued the effects of miR-326 on proliferation, migration, and invasion in PTC cells. Notably, miR-326 reduced tumorigenesis in vivo, including the decrease of tumor volume and weight, suppression of Ki-67, N-cadherin, MAPK1 and ERBB4. In all, these results might provide a new therapeutic target for the diagnosis of PTC.


Assuntos
Carcinoma Papilar/patologia , MicroRNAs/genética , Câncer Papilífero da Tireoide/patologia , Neoplasias da Glândula Tireoide/patologia , Carcinoma Papilar/genética , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Humanos , Proteína Quinase 1 Ativada por Mitógeno , Invasividade Neoplásica , Receptor ErbB-4 , Câncer Papilífero da Tireoide/genética , Neoplasias da Glândula Tireoide/genética
19.
Cancer Sci ; 111(6): 2163-2173, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32187423

RESUMO

Papillary thyroid carcinoma (PTC) is the most common malignancy of the thyroid gland, with a relatively high cure rate. Distant metastasis (DM) of PTC is uncommon, but when it occurs, it significantly decreases the survival of PTC patients. The molecular mechanisms of DM in PTC have not been systematically studied. We performed whole exome sequencing and GeneseeqPrime (425 genes) panel sequencing of the primary tumor, plasma and matched white blood cell samples from 20 PTC with DM and 46 PTC without DM. We identified somatic mutations, gene fusions and copy number alterations and analyzed their relationships with DM of PTC. BRAF-V600E was identified in 73% of PTC, followed by RET fusions (14%) in a mutually exclusive manner (P < 0.0001). We found that gene fusions (RET, ALK or NTRK1) (P < 0.01) and chromosome 22q loss (P < 0.01) were independently associated with DM in both univariate and multivariate analyses. A nomogram model consisting of chromosome 22q loss, gene fusions and three clinical variables was built for predicting DM in PTC (C-index = 0.89). The plasma circulating tumor DNA (ctDNA) detection rate in PTC was only 38.9%; however, it was significantly associated with the metastatic status (P = 0.04), tumor size (P = 0.001) and invasiveness (P = 0.01). In conclusion, gene fusions and chromosome 22q loss were independently associated with DM in PTC and could serve as molecular biomarkers for predicting DM. The ctDNA detection rate was low in non-DM PTC but significantly higher in PTC with DM.


Assuntos
Biomarcadores Tumorais/genética , Invasividade Neoplásica/genética , Câncer Papilífero da Tireoide/genética , Câncer Papilífero da Tireoide/patologia , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/patologia , Adolescente , Adulto , Idoso , Criança , Feminino , Fusão Gênica , Rearranjo Gênico , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Estudos Retrospectivos , Sequenciamento Completo do Exoma , Adulto Jovem
20.
J Surg Oncol ; 121(7): 1053-1057, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32115718

RESUMO

BACKGROUND AND OBJECTIVES: The Afirma gene expression classifier (AGEC) has not been tested or validated in a high-risk group, such as patients with Hashimoto's thyroiditis (HT). We hypothesized that AGEC would perform worse in patients with HT. METHODS: A retrospective review of patient charts in a single academic institution who underwent thyroidectomy between 2012 and 2017 was conducted. Patients with HT who underwent AGEC were identified to calculate sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). RESULTS: We identified 69 patients with HT and atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS) on cytology who underwent AGEC analysis. The mean age of AGEC cohort was 50 years (range, 26-77 years) with 90% female. The median nodule size was 1.9 cm (interquartile range [IQR], 1.2-2.7 cm). Of the 69 patients, 62 showed suspicious AGEC of which 26 showed TC on surgical pathology. Of the seven benign AGEC, two showed TC on surgical pathology. The sensitivity, specificity, PPV, and NPV were 93%, 12%, 42%, and 71%, respectively. Of the entire AGEC cohort, 17 (43%) showed multicentric disease. CONCLUSIONS: We observed a lower NPV for AGEC to rule out thyroid cancer in patients with HT, which reduces the utility of the test for this population.


Assuntos
Doença de Hashimoto/genética , Neoplasias da Glândula Tireoide/genética , Adulto , Idoso , Estudos de Coortes , Feminino , Perfilação da Expressão Gênica/métodos , Doença de Hashimoto/patologia , Doença de Hashimoto/cirurgia , Humanos , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Estudos Retrospectivos , Neoplasias da Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/cirurgia , Nódulo da Glândula Tireoide/genética , Nódulo da Glândula Tireoide/patologia , Nódulo da Glândula Tireoide/cirurgia , Tireoidectomia
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