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1.
Arch Endocrinol Metab ; 63(5): 536-544, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31482959

RESUMO

Thyroid cancer has been rapidly increasing in prevalence among humans in last 2 decades and is the most prevalent endocrine malignancy. Overall, thyroid-cancer patients have good rates of long-term survival, but a small percentage present poor outcome. Thyroid cancer aggressiveness is essentially related with thyroid follicular cell loss of differentiation and metastasis. The discovery of oncogenes that drive thyroid cancer (such as RET, RAS, and BRAF), and are aligned in the MAPK/ERK pathway has led to a new perspective of thyroid oncogenesis. The uncovering of additional oncogene-modulated signaling pathways revealed an intricate and active signaling cross-talk. Among these, microRNAs, which are a class of small, noncoding RNAs, expanded this cross-talk by modulating several components of the oncogenic network - thus establishing a new layer of regulation. In this context, TGFß signaling plays an important role in cancer as a dual factor: it can exert an antimitogenic effect in normal thyroid follicular cells, and promote epithelial-to-mesenchymal transition, cell migration, and invasion in cancer cells. In this review, we explore how microRNAs influence the loss of thyroid differentiation and the increase in aggressiveness of thyroid cancers by regulating the dual function of TGFß. This review provides directions for future research to encourage the development of new strategies and molecular approaches that can improve the treatment of aggressive thyroid cancer.


Assuntos
MicroRNAs/metabolismo , Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/patologia , Fator de Crescimento Transformador beta/metabolismo , Transformação Celular Neoplásica , Progressão da Doença , Humanos , Invasividade Neoplásica , Metástase Neoplásica , Transdução de Sinais , Neoplasias da Glândula Tireoide/metabolismo
2.
Clin Nucl Med ; 44(9): e546-e547, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31283604

RESUMO

Neuroendocrine tumors (NETs) of the thyroid gland are generally considered to be derived from parafollicular endocrine or C cells and are known as medullary thyroid carcinomas. Non-calcitonin-producing NETs of the thyroid are extremely rare in occurrence and pose a significant diagnostic dilemma for the physician and pathologist. We describe a case of a 58-year-old woman who was diagnosed as having primary NET thyroid with normal calcitonin levels and Ga DOTANOC PET-CT scan findings which were done for initial extent evaluation of the disease.


Assuntos
Carcinoma Neuroendócrino/diagnóstico por imagem , Carcinoma Neuroendócrino/metabolismo , Tumores Neuroendócrinos/diagnóstico por imagem , Tumores Neuroendócrinos/metabolismo , Compostos Organometálicos , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Neoplasias da Glândula Tireoide/diagnóstico por imagem , Neoplasias da Glândula Tireoide/metabolismo , Calcitonina/metabolismo , Carcinoma Neuroendócrino/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Tumores Neuroendócrinos/patologia , Neoplasias da Glândula Tireoide/patologia
3.
Bioengineered ; 10(1): 306-315, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31299871

RESUMO

Long non-coding RNA H19 (H19) is highly expressed in cancers and is considered to highly correlate with the extent of malignant degree. The present study was performed to determine the expression levels of H19 in anaplastic thyroid carcinoma (ATC) tissues and the role of H19 in ATC 8505C cells in vitro and in vivo. Expression of H19 was detected in 19 ATC and 19 normal thyroid tissues by real-time quantitative polymerase chain reaction. Utilizing the siRNA or short hairpin RNA (shRNA) directed against human H19 (H19 siRNA or shRNA H19) depleted H19 in ATC 8505C cells and characterized the outcomes. The results showed that H19 was overexpressed in ATC tissues. Targeting H19 inhibited proliferation, migration, and invasion and induced apoptosis in 8505C cells in vitro and inhibited tumorigenesis and metastasis in vivo. Therefore, the H19 might be an effective target for ATC molecular therapy.


Assuntos
Carcinogênese/genética , Regulação Neoplásica da Expressão Gênica , Terapia de Alvo Molecular/métodos , RNA Longo não Codificante/genética , Carcinoma Anaplásico da Tireoide/genética , Neoplasias da Glândula Tireoide/genética , Animais , Apoptose/genética , Carcinogênese/metabolismo , Carcinogênese/patologia , Estudos de Casos e Controles , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Feminino , Humanos , Metástase Linfática , Camundongos , Camundongos Nus , Invasividade Neoplásica , RNA Longo não Codificante/antagonistas & inibidores , RNA Longo não Codificante/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Transdução de Sinais , Carcinoma Anaplásico da Tireoide/metabolismo , Carcinoma Anaplásico da Tireoide/patologia , Carcinoma Anaplásico da Tireoide/cirurgia , Neoplasias da Glândula Tireoide/metabolismo , Neoplasias da Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/cirurgia , Nódulo da Glândula Tireoide/genética , Nódulo da Glândula Tireoide/metabolismo , Nódulo da Glândula Tireoide/patologia , Nódulo da Glândula Tireoide/cirurgia , Tireoidectomia , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Georgian Med News ; (290): 116-120, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31322526

RESUMO

Investigated 62 sample of thyroid gland obtained after surgical intervention, including: HT (n=27), RT (n=9), Graves' disease (n=17) and papillary thyroid carcinoma (n = 10). The slides were studied using classical histological and immunohistochemical methods: H&E, TTF1, TSH, S100-protein, CD56 and p63. Dispite of the histological and immunohistochemical heterogeneity of Thyroiditis HT and RT, the progressive involution of the glandular tissue with the replacement by the sever fibrosis, in some cases by the scar tissue is observed as damage sign. In Hashimoto thyroiditis, the foci of follicular epithelium dysplasia were determined, with p63 positive and CD56 negative reactions. Graves' disease is characterized by high TSH expression as well as lymphoproliferation with the formation of large fused nodules with germinative centers. With Riedel's thyroiditis, there is a moderate expression of TTF-1 in the stroma and capillary endotheliocytes, as well as diffuse-focal moderate expression of S100 protein in cells of neuroectodermal population. The reaction to malignant transformation markers - CD56 and p63 - in the tissue of Thyroid gland with Thyroiditis, Riedel was definitely negative.


Assuntos
Doença de Hashimoto/metabolismo , Câncer Papilífero da Tireoide/metabolismo , Glândula Tireoide/metabolismo , Neoplasias da Glândula Tireoide/metabolismo , Tireoidite/metabolismo , Doenças Autoimunes , Doença de Hashimoto/patologia , Humanos , Receptores da Tireotropina/metabolismo , Proteínas S100/metabolismo , Câncer Papilífero da Tireoide/patologia , Neoplasias da Glândula Tireoide/patologia , Fator Nuclear 1 de Tireoide/metabolismo , Tireoidite/patologia
5.
Surg Clin North Am ; 99(4): 587-598, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31255193

RESUMO

Cytologically indeterminate thyroid nodules are associated with a broad range (5%-75%) of malignant risk and accurately informing definitive management poses a challenge. Advancements in molecular testing of fine-needle aspiration biopsies have improved preoperative diagnostic accuracy and prognostication. For indeterminate nodules, such testing ideally will reduce the need for surgery for benign nodules and potentially guide appropriate extent of initial surgery for malignancy.


Assuntos
Biomarcadores Tumorais/análise , Tomada de Decisões , Neoplasias da Glândula Tireoide/diagnóstico , Nódulo da Glândula Tireoide/diagnóstico , Biópsia por Agulha Fina , Diagnóstico Diferencial , Humanos , Neoplasias da Glândula Tireoide/metabolismo , Nódulo da Glândula Tireoide/metabolismo
6.
Anticancer Res ; 39(6): 2715-2720, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31177106

RESUMO

Thyroid cancer (TC) is a common malignancy of the endocrine system. The global incidence of TC has increased dramatically in recent years. The available tumor biomarkers are not specific to TC and therefore finding new markers which could be helpful in the diagnostic process, prognosis and treatment of TC patients is a great challenge facing present and future researchers. Chemokines are small chemotactic proteins which play a significant role in the migration of leukocytes to many sites of the inflammatory process. It has been suggested that these molecules are able to promote cancer development by mediating inflammation. This paper presents the general structure of chemokines and their receptors as well as their potential significance in TC. The final aspect of this review is a summary of current knowledge and research results concerning the potential significance of selected chemokines and their specific receptors as candidates for novel tumor markers of TC.


Assuntos
Biomarcadores Tumorais/metabolismo , Quimiocinas/metabolismo , Neoplasias da Glândula Tireoide/metabolismo , Humanos , Prognóstico , Receptores Acoplados a Proteínas-G/metabolismo
7.
Anticancer Res ; 39(6): 2811-2819, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31177118

RESUMO

BACKGROUND/AIM: Recent knowledge implicates a differential expression of the insulin-like growth factor-I (IGF-I) mRNA splice variants (i.e., IGF-IEa, IGF-IEb and IGF-IEc) in cancerous tissues, implying possible specific roles of the encoded IGF-I protein isoforms in cancer biology. In particular, there is growing evidence that the IGF-IEc isoform may play a distinct biological role in various types of cancers. The present study investigated whether IGF-IEc expression is associated with a particular type of thyroid cancer. MATERIALS AND METHODS: Formalin-fixed paraffin-embedded tissue specimens of different types of thyroid cancers from 92 patients were assessed for IGF-IEc expression by immunohistochemistry. In addition, thyroid cancer biopsies of different TNM staging histological types were evaluated for mRNA expression of the IGF-IEc transcript by real-time polymerase chain reaction (PCR). RESULTS: From the total number of 92 samples, 2 were anaplastic, 10 medullary, 4 hyperplasias of C-cells, 11 follicular, 5 hurtle cell carcinomas, 2 poorly differentiated, 5 nodular hyperplasias, 1 lymphoma and 52 were papillary thyroid cancers. The age of cancer diagnosis or tumor size did not significantly affect the IGF-IEc expression. Among all types of cancers, IGF-IEc was expressed in papillary differentiated thyroid cancer. Its expression/localization was mainly cytoplasmic and significantly associated with TNM staging and the presence of muscular and capsule cancerous invasion (p<0.05). Similarly, a differential profile was revealed regarding the mRNA expression of the IGF-IEc transcript, that exhibited a higher expression in aggressive compared to the non-aggressive papillary cancers. CONCLUSION: IGF-IEc isoform expression in thyroid cancer is positively associated with more advanced stages of papillary thyroid cancer.


Assuntos
Processamento Alternativo , Fator de Crescimento Insulin-Like I/genética , Fator de Crescimento Insulin-Like I/metabolismo , Câncer Papilífero da Tireoide/patologia , Neoplasias da Glândula Tireoide/patologia , Regulação para Cima , Adolescente , Adulto , Idoso , Citoplasma/genética , Citoplasma/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Estudos Retrospectivos , Câncer Papilífero da Tireoide/genética , Câncer Papilífero da Tireoide/metabolismo , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/metabolismo , Carga Tumoral , Adulto Jovem
8.
Clin Nucl Med ; 44(9): 752-753, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31135518

RESUMO

Incidental thyroid uptake is found in approximately 2.5% of patients who undergo FDG PET for nonthyroid malignancy; approximately a third of the FDG PET thyroid incidentalomas are malignant, including primary thyroid malignancies and metastasis. We describe a 50-year-old woman, a potential heart transplant candidate with history of breast cancer, who was found by FDG PET/CT to harbor a large thyroid mass with intense FDG uptake. Biopsy and molecular study demonstrated that the thyroid mass was a Hürthle cell adenoma. This case highlights that Hürthle cell neoplasm should be included in the differential diagnosis of a thyroid nodule with very high FDG avidity.


Assuntos
Adenoma Oxífilo/diagnóstico por imagem , Adenoma Oxífilo/patologia , Fluordesoxiglucose F18/metabolismo , Células Oxífilas/metabolismo , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Neoplasias da Glândula Tireoide/diagnóstico por imagem , Neoplasias da Glândula Tireoide/patologia , Adenoma Oxífilo/metabolismo , Transporte Biológico , Diagnóstico Diferencial , Feminino , Humanos , Achados Incidentais , Pessoa de Meia-Idade , Neoplasias da Glândula Tireoide/metabolismo
9.
Int J Mol Sci ; 20(9)2019 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-31027376

RESUMO

We previously reported that upregulation of mortalin (HSPA9/GRP75), the mitochondrial HSP70 chaperone, facilitates tumor cell proliferation and survival in human medullary thyroid carcinoma (MTC), proposing mortalin as a novel therapeutic target for MTC. In this report, we show that mortalin is also upregulated in other thyroid tumor types, including papillary thyroid carcinoma (PTC), follicular thyroid carcinoma (FTC), and anaplastic thyroid carcinoma (ATC), and that mortalin depletion can effectively induce growth arrest and cell death in human PTC (TPC-1), FTC (FTC133), and ATC (8505C and C643) cells in culture. Intriguingly, mortalin depletion induced varied effects on cell cycle arrest (G0/G1 phase arrest in TPC-1 and C643, G2/M phase arrest in 8505C, and mild G2/M phase arrest with increased sub-G0/G1 population in FTC133) and on the levels of TP53, E2F-1, p21CIP1, p27KIP1, and poly (ADP-ribose) polymerase cleavage in these cells, suggesting that thyroid tumor cells respond to mortalin depletion in a cell type-specific manner. In these cells, we also determined the efficacy of triphenyl-phosphonium-carboxy-proxyl (Mito-CP) because this mitochondria-targeted metabolism interfering agent exhibited similar tumor suppressive effects as mortalin depletion in MTC cells. Indeed, Mito-CP also induced robust caspase-dependent apoptosis in PTC and ATC cell lines in vitro, exhibiting IC50 lower than PLX4032 in 8505C cells and IC50 lower than vandetanib and cabozantinib in TPC-1 cells. Intriguingly, Mito-CP-induced cell death was partially rescued by mortalin overexpression, suggesting that Mito-CP may inactivate a mechanism that requires mortalin function. These findings support the significance of mortalin and mitochondrial activity in a broad spectrum of thyroid cancer.


Assuntos
Proliferação de Células/fisiologia , Sobrevivência Celular/fisiologia , Proteínas de Choque Térmico HSP70/metabolismo , Proteínas de Membrana/metabolismo , Proteínas Mitocondriais/metabolismo , Neoplasias da Glândula Tireoide/metabolismo , Pontos de Checagem do Ciclo Celular/genética , Pontos de Checagem do Ciclo Celular/fisiologia , Linhagem Celular Tumoral , Proliferação de Células/genética , Sobrevivência Celular/genética , Proteínas de Choque Térmico HSP70/genética , Proteínas de Choque Térmico HSP70/fisiologia , Humanos , Lentivirus/genética , Proteínas de Membrana/genética , Mitocôndrias/metabolismo , Proteínas Mitocondriais/genética
10.
Med Sci Monit ; 25: 2984-2992, 2019 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-31012438

RESUMO

BACKGROUND Thyroid cancer is a type of endocrine cancers with rapidly increased incidence. Recent studies have indicated long non-coding RNAs (lncRNAs) played crucial roles in thyroid cancer tumorigenesis and progression. However, the roles of most lncRNAs in thyroid cancer were still unclear. MATERIAL AND METHODS We used TCGA (The Cancer Genome Atlas), GSE50901, GSE29265, and GSE33630 datasets to analyze the expression pattern of ZFAS1 (ZNFX1 antisense RNA 1). The correlation between ZFAS1 and clinicopathological features in thyroid cancer was analyzed. Cell proliferation and cell cycle assays were used to validate the roles of ZFAS1 in thyroid cancer cell lines. DAVID (the database for annotation, visualization and integrated discover) system was used to perform GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway analysis. The starBase datasets and Cytoscape was used to perform ceRNA (competitive endogenous RNA) network. RESULTS We demonstrated ZFAS1 was highly expressed in thyroid cancer compared to normal samples. Moreover, upregulation of ZFAS1 was positively correlated with clinicopathological features and poor prognosis in thyroid cancer. Functional validation showed knockdown of ZFAS1 suppressed cell proliferation and cell cycle in thyroid cancer cells. Bioinformatics analysis showed ZFAS1 was associated with translation, rRNA processing, intra-Golgi vesicle-mediated transport, ribosome, and ubiquitin-mediated proteolysis. CONCLUSIONS Our study suggested ZFAS1 could serve as a biomarker for thyroid cancer.


Assuntos
RNA Longo não Codificante/genética , Neoplasias da Glândula Tireoide/genética , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinogênese , Ciclo Celular/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Bases de Dados Genéticas , Progressão da Doença , Transição Epitelial-Mesenquimal , Ontologia Genética , Humanos , Invasividade Neoplásica , Prognóstico , RNA Longo não Codificante/metabolismo , Neoplasias da Glândula Tireoide/metabolismo , Neoplasias da Glândula Tireoide/patologia
11.
BMC Cancer ; 19(1): 297, 2019 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-30940124

RESUMO

BACKGROUND: Papillary thyroid cancer (PTC) is the most frequent type of thyroid malignancy. In this study, we investigated the mechanisms whereby long non-coding RNAs (lncRNAs) are associated with PTC pathogenesis. METHODS: Microarray analysis was used to determine differentially expressed lncRNAs between paired PTC tissues and normal adjacent thyroid tissues. Quantitative RT-PCR was used for validation in 86 PTC cases. Small interfering RNA (siRNA) transfection assays were then performed to assess how a novel lncRNA affected key proliferation and cell death pathways in IHH4 PTC cells. RESULTS: We identified 1878 differentially expressed lncRNAs versus matched control samples (fold change ≥2.0, P < 0.05), of which 429 were upregulated and 1449 were downregulated. ENST00000539653.1 (ENS-653), one of the top hits in this microarray, was selected for further study. Higher ENS-653 expression was observed in PTC tissue samples versus adjacent normal tissues, and was associated with a larger tumor size and a more advanced clinical stage. In the Cancer Genome Atlas (TCGA) PTC cohort, higher ENS-653 expression was correlated with more frequent BRAF (V600E) mutation and poorer disease-free survival. Furthermore, ENS-653 downregulation reduced the proliferation of PTC cells and led to G1-S arrest, but had no impact on apoptosis. ENS-653 downregulation also inactivated ERK1/2 and ERK5, causing partial MAPK cascade suppression. CONCLUSION: ENS-653 exhibits oncogenic properties in PTC, and could be a diagnostic and/or prognostic PTC biomarker, in addition to possibly being a future target for therapy.


Assuntos
Sistema de Sinalização das MAP Quinases , RNA Longo não Codificante/metabolismo , Câncer Papilífero da Tireoide/metabolismo , Neoplasias da Glândula Tireoide/metabolismo , Adulto , Idoso , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Câncer Papilífero da Tireoide/genética , Neoplasias da Glândula Tireoide/genética
12.
Cell Prolif ; 52(3): e12564, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30938030

RESUMO

OBJECTIVES: Thyroid carcinoma (TC) represents a malignant neoplasm affecting the thyroid. Current treatment strategies include the removal of part of the thyroid; however, this approach is associated with a significant risk of developing hypothyroidism. In order to adequately understand the expression profiles of TNRC6C-AS1 and STK4 and their potential functions in TC, an investigation into their involvement with Hippo signalling pathway and the mechanism by which they influence TC apoptosis and autophagy were conducted. METHODS: A microarray analysis was performed to screen differentially expressed lncRNAs associated with TC. TC cells were employed to evaluate the role of TNRC6C-AS1 by over-expression or silencing means. The interaction of TNRC6C-AS1 with methylation of STK4 promoter was evaluated to elucidate its ability to elicit autophagy, proliferation and apoptosis. RESULTS: TNRC6C-AS1 was up-regulated while STK4 was down-regulated, where methylation level was elevated. STK4 was verified as a target gene of TNRC6C-AS1, which was enriched by methyltransferase. Methyltransferase's binding to STK4 increased expression of its promoter. Over-expressed TNRC6C-AS1 inhibited STK4 by promoting STK4 methylation and reducing the total protein levels of MST1 and LATS1/2. The phosphorylation of YAP1 phosphorylation was decreased, which resulted in the promotion of SW579 cell proliferation and tumorigenicity. CONCLUSION: Based on our observations, we subsequently confirmed the anti-proliferative, pro-apoptotic and pro-autophagy capabilities of TNRC6C-AS1 through STK4 methylation via the Hippo signalling pathway in TC.


Assuntos
Proteínas Serina-Treonina Quinases/genética , RNA Longo não Codificante/antagonistas & inibidores , RNA Longo não Codificante/genética , Proteínas de Ligação a RNA/antagonistas & inibidores , Proteínas de Ligação a RNA/genética , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/metabolismo , Animais , Apoptose/genética , Autofagia/genética , Sequência de Bases , Linhagem Celular Tumoral , Proliferação de Células/genética , Desmetilação do DNA , Regulação para Baixo , Xenoenxertos , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Modelos Biológicos , RNA Antissenso/genética , Transdução de Sinais , Neoplasias da Glândula Tireoide/patologia , Regulação para Cima
13.
Zhonghua Zhong Liu Za Zhi ; 41(4): 276-281, 2019 Apr 23.
Artigo em Chinês | MEDLINE | ID: mdl-31014052

RESUMO

Objective: To explore the effect of aspirin combined with metformin on the apoptosis of thyroid cancer TPC-1 cells and its mechanism. Methods: The proliferation and apoptosis of TPC-1 cells treated with different concentrations of aspirin and metformin were detected using cell count kit-8 (CCK-8) assay and flow cytometry, respectively. Western blot was used to detect the expressions of microtubule-associated protein light chain 3 (LC3), p62 and cysteinyl aspartate specific proteinase 3 (caspase-3) after treatment with aspirin, metformin and 3-Methyladenine (3-MA). Results: The relative cell viability of TPC-1 cells treated with 0.5, 1.0, 2.0, 4.0 mmol/L aspirin for 24 and 48 hours were (85.6±9.1)%, (79.9±8.6)%, (57.0±5.3)%, (55.7±5.4)%; (76.7±2.8)%, (75.4±6.1)%, (46.1±4.1)%, (36.3±3.2)%, respectively. The value of half maximal inhibitory concentration (IC(50)) for 24 and 48 hours were 4.297 mmol/L, 2.133 mmol/L, respectively. The apoptotic rate in the 1 mmol/L aspirin treatment group and negative control group were (29.2±8.5)%, (4.2±2.9)%, respectively (P<0.05). Moreover, treatment with metformin increased the protein expression of LC3Ⅱ/Ⅰ ratio, and decreased the expression of p62, while treatment with aspirin decreased the expression of LC3Ⅱ/Ⅰ ratio and increased the expression of p62. The relative cell viability of TPC-1 cells treated with metformin, 3-MA, an autophagy inhibitor, and 3-MA combined with metformin were (73.2±9.2)%, (95.8±3.3)%, (59.9±9.2)%, respectively. The apoptotic rates in these groups were (35.5±1.5)%, (12.3±1.4)%, (49.9±5.4)%, respectively. Compared with the metformin group, the relative cell viability in metformin combined with 3-MA group was significantly lower while the apoptotic rate was higher (P<0.05), which indicated that treatment with 3-MA enhanced the metformin-induced apoptosis of TPC-1 cells. The relative cell viability of TPC-1 cells in metformin group, aspirin group, metformin combined with aspirin group were (87.3±11.8)%, (85.7±9.6)%, (72.4±8.8)%, respectively. The apoptotic rates in these groups were (29.7±4.0)%, (30.5±6.5)%, (52.5±4.6)%, respectively. Compared with the metformin or aspirin group, the relative cell viability in metformin combined with aspirin group was significantly lower, while the apoptotic rate was higher (P<0.05), which indicated that aspirin enhanced the metformin-induced apoptosis of TPC-1 cells. Conclusions: Our findings indicate that metformin-mediated autophagy plays a protective role in metformin-induced apoptosis and proliferation inhibition. Aspirin enhances the metformin-induced apoptosis of thyroid cancer TPC-1 cells through inhibition of autophagy.


Assuntos
Apoptose/efeitos dos fármacos , Aspirina/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Metformina/farmacologia , Neoplasias da Glândula Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/patologia , Autofagia , Caspase 3/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Interações de Medicamentos , Humanos , Concentração Inibidora 50 , Proteínas Associadas aos Microtúbulos/metabolismo , Proteínas de Ligação a RNA/metabolismo , Neoplasias da Glândula Tireoide/metabolismo , Fatores de Tempo
14.
BMC Cancer ; 19(1): 196, 2019 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-30832606

RESUMO

BACKGROUND: Treatment options for advanced thyroid cancer refractory to standard therapies are limited. The safety and efficacy of pembrolizumab were evaluated in patients with advanced differentiated thyroid cancer expressing programmed death ligand 1 (PD-L1). METHODS: Patients with advanced thyroid cancer were enrolled in the nonrandomized, phase Ib KEYNOTE-028 trial conducted to evaluate safety and antitumor activity of the anti-programmed death 1 (PD-1) antibody pembrolizumab in advanced solid tumors. Key eligibility criteria were advanced papillary or follicular thyroid cancer, failure of standard therapy, and PD-L1 expression in tumor or stroma cells (assessed by immunohistochemistry). Pembrolizumab 10 mg/kg was administered every 2 weeks up to 24 months or until confirmed progression or intolerable toxicity. The primary endpoint was objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors, version 1.1. RESULTS: Twenty-two patients were enrolled: median age was 61 years; 59% were women; and 68% had papillary carcinoma. Median follow-up was 31 months (range, 7-34 months). Treatment-related adverse events were observed in 18 (82%) patients; those occurring in ≥15% of patients were diarrhea (n = 7) and fatigue (n = 4). One grade ≥ 3 treatment-related adverse event occurred (colitis, grade 3); no treatment-related discontinuations or deaths occurred. Two patients had confirmed partial response, for an ORR of 9% (95% confidence interval [CI], 1-29%); response duration was 8 and 20 months. Median progression-free survival was 7 months (95% CI, 2-14 months); median overall survival was not reached (95% CI, 22 months to not reached). CONCLUSIONS: Results of this phase Ib proof-of-concept study suggest that pembrolizumab has a manageable safety profile and demonstrate evidence of antitumor activity in advanced differentiated thyroid cancer in a minority of patients treated. Further analyses are necessary to confirm these findings. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT02054806 . Registered 4 February 2014.


Assuntos
Adenocarcinoma Folicular/tratamento farmacológico , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Câncer Papilífero da Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/tratamento farmacológico , Adenocarcinoma Folicular/metabolismo , Adulto , Idoso , Antígeno B7-H1/metabolismo , Colite/induzido quimicamente , Diarreia/induzido quimicamente , Fadiga/induzido quimicamente , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Estudo de Prova de Conceito , Critérios de Avaliação de Resposta em Tumores Sólidos , Câncer Papilífero da Tireoide/metabolismo , Neoplasias da Glândula Tireoide/metabolismo , Resultado do Tratamento , Adulto Jovem
15.
Int J Mol Sci ; 20(5)2019 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-30841521

RESUMO

The diagnostic approach to thyroid cancer is one of the most challenging issues in oncology of the endocrine system because of its high incidence (3.8% of all new cancer cases in the US) and the difficulty to distinguish benign from malignant non-functional thyroid nodules and establish the cervical lymph node involvement during staging. Routine diagnosis of thyroid nodules usually relies on a fine-needle aspirate biopsy, which is invasive and often inaccurate. Therefore, there is an urgent need to identify novel, accurate, and non-invasive diagnostic procedures. Liquid biopsy, as a non-invasive approach for the detection of diagnostic biomarkers for early tumor diagnosis, prognosis, and disease monitoring, may be of particular benefit in this context. Extracellular vesicles (EVs) are a consistent source of tumor-derived RNA due to their prevalence in circulating bodily fluids, the well-established isolation protocols, and the fact that RNA in phospholipid bilayer-enclosed vesicles is protected from blood-borne RNases. Recent results in other types of cancer, including our recent study on plasma EVs from glioblastoma patients suggest that information derived from analysis of EVs from peripheral blood plasma can be integrated in the routine diagnostic tumor approach. In this review, we will examine the diagnostic and prognostic potential of liquid biopsy to detect tumor-derived nucleic acids in circulating EVs from patients with thyroid carcinoma.


Assuntos
Biomarcadores Tumorais/metabolismo , Vesículas Extracelulares/patologia , Neoplasias da Glândula Tireoide/patologia , Vesículas Extracelulares/metabolismo , Humanos , Neoplasias da Glândula Tireoide/metabolismo
16.
Molecules ; 24(4)2019 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-30813269

RESUMO

Boron neutron capture therapy (BNCT) is a binary cancer treatment modality where two different agents (10B and thermal neutrons) have to be present to produce an effect. A dedicated trial design is necessary for early clinical trials. The concentration of 10B in tissues is an accepted surrogate to predict BNCT effects on tissues. Tissue, blood, and urines were sampled after infusion of two different boron carriers, namely BSH and BPA in the frame of the European Organisation for Research and Treatment of Cancer (EORTC) trial 11001. In this study, urine samples were used to identify protein profiles prior and after drug infusion during surgery. Here, an approach that is based on the mass spectrometry (MS)-based proteomic analysis of urine samples from head and neck squamous cell carcinoma (HNSCC) and thyroid cancer patients is presented. This method allowed the identification of several inflammation- and cancer-related proteins, which could serve as tumor biomarkers. In addition, changes in the urinary proteome during and after therapeutic interventions were detected. In particular, a reduction of three proteins that were involved in inflammation has been observed: Galectin-3 Binding Protein, CD44, and osteopontin. The present work represents a proof of principle to follow proteasome changes during complex treatments based on urine samples.


Assuntos
Neoplasias de Cabeça e Pescoço/radioterapia , Proteômica/métodos , Carcinoma de Células Escamosas de Cabeça e Pescoço/radioterapia , Neoplasias da Glândula Tireoide/radioterapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos de Neoplasias/urina , Biomarcadores Tumorais/urina , Terapia por Captura de Nêutron de Boro/métodos , Proteínas de Transporte/urina , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Glicoproteínas/urina , Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/urina , Humanos , Receptores de Hialuronatos/metabolismo , Masculino , Pessoa de Meia-Idade , Osteopontina/urina , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/urina , Neoplasias da Glândula Tireoide/metabolismo , Resultado do Tratamento
17.
Genesis ; 57(5): e23292, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30884088

RESUMO

Medullary thyroid carcinoma (MTC) develops from hyperplasia of thyroid C cells and represents one of the major causes of thyroid cancer mortality. Mutations in the cysteine-rich domain (CRD) of the RET gene are the most prevalent genetic cause of MTC. The current consensus holds that such cysteine mutations cause ligand-independent dimerization and constitutive activation of RET. However, given the number of the CRD mutations left uncharacterized, our understanding of the pathogenetic mechanisms by which CRD mutations lead to MTC remains incomplete. We report here that RET(C618F), a mutation identified in MTC patients, displays moderately high basal activity and requires the ligand for its full activation. To assess the biological significance of RET(C618F) in organogenesis, we generated a knock-in mouse line conditionally expressing RET(C618F) cDNA by the Ret promoter. The RET(C618F) allele can be made to be Ret-null and express mCherry by Cre-loxP recombination, which allows the assessment of the biological influence of RET(C618F) in vivo. Mice expressing RET(C618F) display mild C cell hyperplasia and increased numbers of enteric neurons, indicating that RET(C618F) confers gain-of-function phenotypes. This mouse line serves as a novel biological platform for investigating pathogenetic mechanisms involved in MTC and enteric hyperganglionosis.


Assuntos
Carcinoma Neuroendócrino/genética , Proteínas Proto-Oncogênicas c-ret/genética , Neoplasias da Glândula Tireoide/genética , Animais , Carcinoma Neuroendócrino/metabolismo , Linhagem Celular Tumoral , Sistema Nervoso Entérico/metabolismo , Sistema Nervoso Entérico/patologia , Técnicas de Introdução de Genes/métodos , Mutação em Linhagem Germinativa , Humanos , Hiperplasia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mutação , Doenças do Sistema Nervoso/genética , Doenças do Sistema Nervoso/metabolismo , Doenças do Sistema Nervoso/patologia , Proteínas Proto-Oncogênicas c-ret/biossíntese , Proteínas Proto-Oncogênicas c-ret/metabolismo , Hiperplasia do Timo/genética , Hiperplasia do Timo/metabolismo , Glândula Tireoide/metabolismo , Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/metabolismo
18.
Cancer Biomark ; 24(4): 497-508, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30909188

RESUMO

OBJECTIVE: Schizandrin A (SchA) exerts anticancer potential. However, the effects of SchA on thyroid cancer (TC) have not been clear illuminated. Therefore, we investigated the effects of SchA on TC cell line TPC-1 and the underlying mechanisms. METHODS: TPC-1 cells were treated with SchA and/or transfected with miR-429 mimic, anti-miR-429 and their corresponding negative controls (NC). Cell viability, proliferation, migration, invasion and cell apoptosis were examined by CCK-8 assay, bromodeoxyuridine, modified two-chamber migration assay, Millicell Hanging Cell Culture and flow cytometry analysis, respectively. The expression of miR-429, p16, Cyclin D1, cyclin-dependent kinases 4 (CDK4), matrix metalloprotein (MMP)-2, MMP-9 and Vimentin was detected by qRT-PCR. All protein expression was examined by western blot. RESULTS: SchA inhibited cell proliferation, metastasis and induced cell apoptosis. Moreover, SchA negatively regulated miR-429 expression. Treatment with miR-429 mimic and SchA reversed the results led by SchA and NC. Furthermore, the phosphorylation ß-catenin, mitogen-activated protein kinase (MEK) and extracellular signal-regulated kinase (ERK) were statistically down-regulated by SchA while co-treatment with miR-429 mimic and SchA led to the opposite trend. Moreover, miR-429 knockdown showed contrary results. CONCLUSION: SchA inhibits cell proliferation, migration, invasion and inactivates Wnt/ß-catenin and MEK/ERK signaling pathways by down regulating miR-429.


Assuntos
Ciclo-Octanos/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Lignanas/farmacologia , MicroRNAs/genética , Compostos Policíclicos/farmacologia , Neoplasias da Glândula Tireoide/genética , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ciclo-Octanos/química , Humanos , Lignanas/química , Sistema de Sinalização das MAP Quinases , Compostos Policíclicos/química , Interferência de RNA , Neoplasias da Glândula Tireoide/metabolismo , Via de Sinalização Wnt
19.
J Hum Genet ; 64(5): 505-508, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30842597

RESUMO

Papillary thyroid carcinoma (PTC) is the most common thyroid malignancy, wherein diagnostic limitations and lack of accurate prognostic factors are important clinical challenges. In this study, we report the discovery of 234 novel miRNAs in non-neoplastic thyroid and PTC samples, obtained from publicly available small RNA sequencing datasets (TCGA and GEO). These sequences were observed to display similar molecular features compared to currently annotated miRNAs. These potentially novel miRNAs presented tissue-specificity and largely decreased expression in PTC compared to non-neoplastic samples. We showed that the disrupted novel miRNAs have diagnostic and prognostic potential, and were associated with BRAF mutation, a frequent alteration related to more aggressive PTC. In conclusion, our results expand the miRNA repertoire in thyroid tissues and highlight the potential biological role and clinical utility of previously unannotated miRNAs.


Assuntos
MicroRNAs , RNA Neoplásico , Câncer Papilífero da Tireoide , Neoplasias da Glândula Tireoide , Feminino , Humanos , Masculino , MicroRNAs/genética , MicroRNAs/metabolismo , Anotação de Sequência Molecular , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/metabolismo , RNA Neoplásico/genética , RNA Neoplásico/metabolismo , Câncer Papilífero da Tireoide/genética , Câncer Papilífero da Tireoide/metabolismo , Câncer Papilífero da Tireoide/patologia , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/metabolismo , Neoplasias da Glândula Tireoide/patologia
20.
Int J Mol Sci ; 20(6)2019 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-30897754

RESUMO

The new immunotherapy targeting the programmed cell death 1 (PD-1) receptor and its cognate ligand PD-L1 has renewed hopes of eradicating the most difficult human cancers to treat. Among these, there are the poorly differentiated and anaplastic thyroid cancers, unresponsive to all the therapies currently in use. In the present review we will summarize information regarding the expression of PD-L1 in the different thyroid cancer histotypes, its correlation with clinicopathological features, and its potential prognostic value. Then, we will evaluate the available data indicating the PD-1/PD-L1 axis as a promising target for thyroid cancer therapy.


Assuntos
Receptor de Morte Celular Programada 1/metabolismo , Neoplasias da Glândula Tireoide/metabolismo , Animais , Biomarcadores Tumorais/metabolismo , Humanos , Prognóstico , Neoplasias da Glândula Tireoide/patologia
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