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1.
Front Oncol ; 10: 217, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32219060

RESUMO

Background: Patients with metastatic radioiodine-refractory papillary thyroid carcinoma (PTC) have limited treatment options and a poor prognosis. There is an urgent need to develop new drugs targeting PTC for clinical application. Apatinib, a novel small-molecule tyrosine kinase inhibitor (TKI), is highly selective for vascular endothelial growth factor receptor-2 (VEGFR2) and exhibits antitumor effects in a variety of solid tumors. Although apatinib has been shown to be safe and efficacious in radioiodine-refractory differentiated thyroid cancer, the mechanism underlying its antitumor effect is unclear. In this report, we explored the effects of apatinib on PTC in vitro and in vivo. Methods: VEGFR2 expression levels were evaluated by immunohistochemistry (IHC), qPCR, and western blotting (WB). The effects of apatinib on cell viability, colony formation, and migration in the Transwell assay were assessed in vitro, and its effect on tumor growth rate was assessed in vivo. In addition, the levels of proteins in signaling pathways were determined by WB. Finally, the autophagy level was assessed by WB, immunofluorescence (IF), and transmission electron microscopy. Results: We found that high VEGFR2 expression is associated with tumor size, T stage, and lymph node metastasis in patients with PTC and that apatinib inhibits PTC cell growth, promotes apoptosis, and induces cell cycle arrest through the PI3K/Akt/mTOR signaling pathway. Moreover, apatinib induces autophagy, and pharmacological inhibition of autophagy or small interfering RNA (siRNA)-mediated targeting of autophagy-associated gene 5 (ATG5) can further increase PTC cell apoptosis. Conclusion: Our data suggest that apatinib can induce apoptosis and autophagy via the PI3K/Akt/mTOR signaling pathway for the treatment of PTC and that autophagy is a potential novel target for future therapy in resistant PTC.

2.
Int J Clin Oncol ; 25(1): 59-66, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31414270

RESUMO

BACKGROUND: The aim of this study was to evaluate the prognostic veracity for disease-specific survival (DSS) of the eighth edition of the American Joint Committee on Cancer/Union for International Cancer Control tumor-node-metastasis staging system (TNM-8) compared with the seventh edition (TNM-7) in a Chinese population of patients with differentiated thyroid carcinoma (DTC) and to evaluate the impact of N1b redefinition and reclassification on prediction of survival. METHODS: A total of 569 DTC patients who underwent thyroid surgery in two Chinese hospitals were included in analysis to assess the predictive accuracy and N1b changes of TNM-8. Data from the Surveillance, Epidemiology and End Results (SEER) program were applied to validate the findings on N1b changes of TNM-8. Unadjusted DSS was calculated using the Kaplan-Meier method. Multivariable Cox proportional hazards models were used to evaluate the association of stage and lymph node metastasis (LNM) status with survival. The proportion of variation explained (PVE), Akaike information criterion (AIC), and Bayesian information criterion (BIC) were evaluated to compare model performance. RESULTS: When TNM-8 was applied, 39.7% of patients were downstaged relative to TMN-7. In comparison of TNM-7 and TMN-8, the PVE was 18.68% and 22.33%, the AIC was 704.22 and 680.50, and the BIC was 702.98 and 679.24, respectively. In 569 Chinese patients with DTC, levels I-V LNM was significantly related to poorer DSS compared with N0 and level VI LNM. Among patients aged ≥ 55 years, those with levels I-V and VII LNM had significantly worse DSS than those with N0 and Level VI LNM. In the SEER dataset, patients with levels I-V and VII LNM had significantly worse DSS compared with those with N0 and Level VI LNM, especially in older patients (age ≥ 55 years). CONCLUSIONS: TNM-8 staged a significant number of Chinese patients into lower stages and improved the accuracy of predicting DSS compared with TNM-7. However, changes in lateral LNM definition and classification of TNM-8 have a significant prognostic implication for patients with DTC, especially older patients (≥ 55 years). Our data suggest that a modified TNM staging system would be more useful for predicting mortality and determining a proper treatment strategy in patients with DTC.


Assuntos
Adenocarcinoma Papilar/patologia , Estadiamento de Neoplasias/normas , Neoplasias da Glândula Tireoide/patologia , Adenocarcinoma Papilar/mortalidade , Adenocarcinoma Papilar/cirurgia , Adulto , Grupo com Ancestrais do Continente Asiático , Feminino , Hospitais , Humanos , Linfonodos/patologia , Masculino , Oncologia/organização & administração , Oncologia/normas , Pessoa de Meia-Idade , Prognóstico , Análise de Sobrevida , Neoplasias da Glândula Tireoide/mortalidade , Neoplasias da Glândula Tireoide/cirurgia
3.
Oncol Lett ; 18(6): 6670-6678, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31814850

RESUMO

The mechanisms underlying the pathogenesis of papillary thyroid carcinoma (PTC) have not yet been elucidated. The aim of the current study was to identify potential pathogenic biomarkers in PTC by comprehensively analyzing gene expression and methylation profiles, and to increase the understanding of PTC pathogenesis. The gene expression profiles of the GSE97001 and GSE83520 datasets, the miRNA expression profiles of the GSE73182 dataset, and the DNA methylation profiles of the GSE86961 and GSE97466 datasets were downloaded from Gene Expression Omnibus database. The differentially expressed genes (DEGs) and the differentially expressed microRNAs (DEMs) were identified using the limma package in R, and the differentially methylated sites (DMSs) were identified using the ß distribution and two-sample t-tests. The Database for Annotation, Visualization and Integrated Discovery, Kyoto Encyclopedia of Genes and Genomes (KEGG) and Reactome were subsequently used to perform functional and pathway enrichment analysis. The miRNA target genes were predicted using the online databases miRWalk. The protein-protein interactions (PPI) were analyzed using the Search Tool for the Retrieval of Interacting Genes/Proteins. The regulatory network was constructed, and the gene expression and methylation levels of the key nodes were detected using reverse-transcription quantitative-polymerase chain reaction (PCR) and methylation-specific PCR. A total of 155 overlapping DEGs were identified between the GSE97001 and GSE83520 datasets, and 19 DEMs between PTC tissue and normal tissue samples were identified in the GSE73182 set. In the GSE86961 and GSE97466 datasets, 2,910 overlapping DMSs that were associated with 38 downregulated methylated genes were identified. The overlapping DEGs were enriched in 46 Gene Ontology terms and one KEGG pathway. A total of 60 PPI pairs were identified for the overlapping DEGs and 12 negative miRNA-gene pairs were identified for the DEMs. The expression levels of hsa-miR-199a-5p and decorin (DCN) were decreased in patients with PTC. C-X-C motif chemokine ligand 12 (CXCL12) was hypermethylated and had a decreased expression level in PTC tissues. LDL receptor related protein 4 (LRP4) and carbonic anhydrase 12 (CA12) were hypomethylated and had an increased expression level. The present study revealed that hsa-miR-199a-5p, DCN, CXCL12, LRP4 and CA12 may serve important roles in the pathogenesis of PTC.

4.
Onco Targets Ther ; 12: 6937-6945, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31695409

RESUMO

Background: Anaplastic thyroid carcinoma (ATC) is the most aggressive cancer in humans with no optimal treatment strategy available. The molecular mechanisms of ATC remain unclear. The aim of this study was to investigate the prognostic value and role of BRMS1 in the progression of ATC. Methods: BRMS1 expression was examined in thyroid cell lines using Western blot analysis. Immunohistochemistry was also performed to assess BRMS1 expression in ATC and papillary thyroid cancer (PTC) tissue. Cell proliferation assays, colony formation analysis, cell migration assays, cell apoptosis analysis, and animal studies were used to examine the effects of BRMS1 expression on ATC progression. Results: The expression of BRMS1 was significantly lower in ATC than in PTC and was associated with poor prognosis in ATC patients. Downregulation of BRMS1 expression promoted the proliferation and migration of 8505C cells and decreased their expression of CX43. Over-expressed BRMS1 promoted the apoptosis and impaired the proliferation and migration of CAL-62 cells via upregulated CX43. In vivo, BRMS1 significantly promoted apoptosis and impaired cell proliferation. Conclusion: Taken together, these findings demonstrate that decreased expression of BRMS1 is a poor prognostic biomarker in ATC patients. BRMS1 significantly promoted apoptosis and impaired cell proliferation via CX43 and P53. Loss of BRMS1 expression is therefore, one of the key pathomechanisms in ATC.

5.
Cancer Res ; 79(14): 3608-3621, 2019 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-31118200

RESUMO

Cancer-secreted, extracellular vesicle (EV)-encapsulated miRNAs enable cancer cells to communicate with each other and with noncancerous cells in tumor pathogenesis and response to therapies. Here, we show that treatment with a sublethal dose of chemotherapeutic agents induces breast cancer cells to secrete EV with the capacity to stimulate a cancer stem-like cell (CSC) phenotype, rendering cancer cells resistance to therapy. Chemotherapy induced breast cancer cells to secrete multiple EV miRNAs, including miR-9-5p, miR-195-5p, and miR-203a-3p, which simultaneously targeted the transcription factor One Cut Homeobox 2 (ONECUT2), leading to induction of CSC traits and expression of stemness-associated genes, including NOTCH1, SOX9, NANOG, OCT4, and SOX2. Inhibition of these miRNAs or restoration of ONECUT2 expression abolished the CSC-stimulating effect of EV from chemotherapy-treated cancer cells. In mice bearing xenograft mammary tumors, docetaxel treatment caused elevations of miR-9-5p, miR-195-5p, and miR-203a-3p in circulating EV and decreased ONECUT2 expression and increased levels of stemness-associated genes. These effects following chemotherapy were diminished in tumors deficient in exosome secretion. In human breast tumors, neoadjuvant chemotherapy decreased ONECUT2 expression in tumor cells. Our results indicate a mechanism by which cancer cells communicate with each other and self-adapt to survive in response to cytotoxic treatment. Targeting these adaptation mechanisms along with chemotherapy, such as by blocking the EV miRNA-ONECUT2 axis, represents a potential strategy to maximize the anticancer effect of chemotherapy and to reduce chemoresistance in cancer management. SIGNIFICANCE: These findings reveal a critical mechanism of resistance to chemotherapy by which breast cancer cells secrete miRNA-containing extracellular vesicles to stimulate cancer stem cell-like features.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Docetaxel/farmacologia , Doxorrubicina/farmacologia , Proteínas de Homeodomínio/genética , MicroRNAs/genética , Células-Tronco Neoplásicas/efeitos dos fármacos , Fatores de Transcrição/genética , Animais , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Vesículas Extracelulares/efeitos dos fármacos , Vesículas Extracelulares/genética , Vesículas Extracelulares/patologia , Feminino , Proteínas de Homeodomínio/metabolismo , Humanos , Células MCF-7 , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , MicroRNAs/metabolismo , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Fatores de Transcrição/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Thyroid ; 29(6): 809-823, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30924726

RESUMO

Background: Anaplastic thyroid carcinoma (ATC) is one of the most aggressive malignancies, with no effective treatment currently available. The molecular mechanisms of ATC carcinogenesis remain poorly understood. The objective of this study was to investigate the mechanisms and functions of super-enhancer (SE)-driven oncogenic transcriptional addiction in the progression of ATC and identify new drug targets for ATC treatments. Methods: High-throughput chemical screening was performed to identify new drugs inhibiting ATC cell growth. Cell viability assay, colony formation analysis, cell-cycle analysis, and animal study were used to examine the effects of drug treatments on ATC progression. Chromatin immunoprecipitation sequencing was conducted to establish a SE landscape of ATC. Integrative analysis of RNA sequencing, chromatin immunoprecipitation sequencing, and CRISPR/Cas9-mediated gene editing was used to identify THZ1 target genes. Drug combination analysis was performed to assess drug synergy. Patient samples were analyzed to evaluate candidate biomarkers of prognosis in ATC. Results: THZ1, a covalent inhibitor of cyclin-dependent kinase 7 (CDK7), was identified as a potent anti-ATC compound by high-throughput chemical screening. ATC cells, but not papillary thyroid carcinoma cells, are exceptionally sensitive to CDK7 inhibition. An integrative analysis of both gene expression profiles and SE features revealed that the SE-mediated oncogenic transcriptional amplification mediates the vulnerability of ATC cells to THZ1 treatment. Combining this integrative analysis with functional assays led to the discovery of a number of novel cancer genes of ATC, including PPP1R15A, SMG9, and KLF2. Inhibition of PPP1R15A with Guanabenz or Sephin1 greatly suppresses ATC growth. Significantly, the expression level of PPP1R15A is correlated with CDK7 expression in ATC tissue samples. Elevated expression of PPP1R15A and CDK7 are both associated with poor clinical prognosis in ATC patients. Importantly, CDK7 or PPP1R15A inhibition sensitizes ATC cells to conventional chemotherapy. Conclusions: Taken together, these findings demonstrate transcriptional addiction in ATC pathobiology and identify CDK7 and PPP1R15A as potential biomarkers and therapeutic targets for ATC.

7.
Onco Targets Ther ; 12: 1309-1318, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30863097

RESUMO

Background: NUCB2, a novel multifunctional protein containing several functional domains, was newly found to play important roles in many cancers, but its role in papillary thyroid cancer (PTC) is not well investigated. Therefore, our study was performed to explore the functions of NUCB2 in PTC. Methods: NUCB2 protein level was analyzed by immunohistochemistry. Data analyses were made by performing chi-squared test. Quantitative reverse-transcription PCR, Western blot, colony formation, MTT, and transwell invasion assays were performed to test the expression levels and functions of NUCB2 in PTC. Results: In PTC tissues, NUCB2 protein expression level was positively correlated with extrathyroidal extension, TNM stage, and tumor size of PTC patients. In vitro experiments demonstrated that knockdown of NUCB2 using specific shRNA for NUCB2 significantly impaired cell proliferation and invasion of PTC cell lines. In vivo, silencing of NUCB2 inhibited the growth of tumors in mice. Conclusion: These results suggested a novel function of NUCB2 in the process of proliferation and invasion in PTC. NUCB2 may be considered a potent prognostic factor in PTC.

8.
Endocr Relat Cancer ; 26(1): 153-164, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30139768

RESUMO

There is no effective treatment for patients with poorly differentiated papillary thyroid cancer or anaplastic thyroid cancer (ATC). Anlotinib, a multi-kinase inhibitor, has already shown antitumor effects in various types of carcinoma in a phase I clinical trial. In this study, we aimed to better understand the effect and efficacy of anlotinib against thyroid carcinoma cells in vitro and in vivo. We found that anlotinib inhibits the cell viability of papillary thyroid cancer and ATC cell lines, likely due to abnormal spindle assembly, G2/M arrest, and activation of TP53 upon anlotinib treatment. Moreover, anlotinib suppresses the migration of thyroid cancer cells in vitro and the growth of xenograft thyroid tumors in mice. Our data demonstrate that anlotinib has significant anticancer activity in thyroid cancer, and potentially offers an effective therapeutic strategy for patients of advanced thyroid cancer type.


Assuntos
Antineoplásicos/uso terapêutico , Indóis/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Quinolinas/uso terapêutico , Câncer Papilífero da Tireoide/tratamento farmacológico , Carcinoma Anaplásico da Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/tratamento farmacológico , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Indóis/farmacologia , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Inibidores de Proteínas Quinases/farmacologia , Quinolinas/farmacologia , Câncer Papilífero da Tireoide/metabolismo , Câncer Papilífero da Tireoide/patologia , Carcinoma Anaplásico da Tireoide/metabolismo , Carcinoma Anaplásico da Tireoide/patologia , Neoplasias da Glândula Tireoide/metabolismo , Neoplasias da Glândula Tireoide/patologia , Proteína Supressora de Tumor p53/metabolismo
9.
Clin Cancer Res ; 24(10): 2370-2382, 2018 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-29500278

RESUMO

Purpose: Preoperative or neoadjuvant therapy (NT) is increasingly used in patients with locally advanced or inflammatory breast cancer to allow optimal surgery and aim for pathologic response. However, many breast cancers are resistant or relapse after treatment. Here, we investigated conjunctive chemotherapy-triggered events occurring systemically and locally, potentially promoting a cancer stem-like cell (CSC) phenotype and contributing to tumor relapse.Experimental Design: We started by comparing the effect of paired pre- and post-NT patient sera on the CSC properties of breast cancer cells. Using cell lines, patient-derived xenograft models, and primary tumors, we investigated the regulation of CSCs and tumor progression by chemotherapy-induced factors.Results: In human patients and mice, we detected a therapy-induced CSC-stimulatory activity in serum, which was attributed to therapy-associated monocytosis leading to systemic elevation of monocyte chemoattractant proteins (MCP). The post-NT hematopoietic regeneration in the bone marrow highlighted both altered monocyte-macrophage differentiation and biased commitment of stimulated hematopoietic stem cells toward monocytosis. Chemotherapeutic agents also induce monocyte expression of MCPs through a JNK-dependent mechanism. Genetic and pharmacologic inhibitions of the MCP-CCR2 pathway blocked chemotherapy's adverse effect on CSCs. Levels of nuclear Notch and ALDH1 were significantly elevated in primary breast cancers following NT, whereas higher levels of CCR2 in pre-NT tumors were associated with a poor response to NT.Conclusions: Our data establish a mechanism of chemotherapy-induced cancer stemness by linking the cellular events in the bone marrow and tumors, and suggest pharmacologic inhibition of CCR2 as a potential cotreatment during conventional chemotherapy in neoadjuvant and adjuvant settings. Clin Cancer Res; 24(10); 2370-82. ©2018 AACR.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/complicações , Neoplasias da Mama/metabolismo , Leucocitose/diagnóstico , Leucocitose/etiologia , Monócitos/patologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Imunofenotipagem , Camundongos , Células-Tronco Neoplásicas/patologia , Receptores CCR2/metabolismo , Receptores Notch/metabolismo , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Oncogene ; 37(21): 2773-2792, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29511350

RESUMO

The T-box transcription factor TBX3 has been implicated in the patterning and differentiation of a number of tissues during embryonic development, and is overexpressed in a variety of cancers; however, the precise function of TBX3 in papillary thyroid carcinoma (PTC) development remains to be determined. In the current study, we report downregulation of TBX3 in PTC cells delays the G1/S-phase transition, decreases cell growth in vitro, and inhibits tumor formation in vivo. We identified p57KIP2 as a novel downstream target that serves as the key mediator of TBX3's control over PTC cell proliferation. Reduced expression of TBX3 resulted in increased p57KIP2 level, while knockdown of p57KIP2 rescues the cell-cycle arrest phenotype. In clinical PTC specimens, the expression of TBX3 is markedly upregulated and significantly correlated with advanced tumor grade, but negatively correlated with the expression of p57KIP2. Mechanism investigation revealed that TBX3 directly binds to the CDKN1C gene promoter region, the coding gene of p57KIP2, and represses its transcription. Furthermore, recruitment of main components of the PRC2 complex as well as class I histone deacetylases, HDAC1 and HDAC2, is required for TBX3 to fulfill the transcriptional repression function. Our findings illustrate the previously unknown function and mechanism in cell proliferation regulation by the TBX3-p57KIP2 axis and provide evidence for the contribution of the PRC2 complex and HDAC1/2. Targeting of this pathway may present a novel and molecular defined strategy against PTC development.


Assuntos
Inibidor de Quinase Dependente de Ciclina p57/genética , Complexo Repressor Polycomb 2/metabolismo , Proteínas com Domínio T/metabolismo , Câncer Papilífero da Tireoide/patologia , Neoplasias da Glândula Tireoide/patologia , Regulação para Cima , Animais , Linhagem Celular Tumoral , Proliferação de Células , Inibidor de Quinase Dependente de Ciclina p57/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Histona Desacetilases/metabolismo , Humanos , Masculino , Camundongos , Estadiamento de Neoplasias , Transplante de Neoplasias , Regiões Promotoras Genéticas , Câncer Papilífero da Tireoide/genética , Câncer Papilífero da Tireoide/metabolismo , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/metabolismo
12.
Development ; 144(21): 3957-3967, 2017 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-28947533

RESUMO

The Hippo pathway modulates the transcriptional activity of Yap to regulate the differentiation of the inner cell mass (ICM) and the trophectoderm (TE) in blastocysts. Yet how Hippo signaling is differentially regulated in ICM and TE cells is poorly understood. Through an inhibitor/activator screen, we have identified Rho as a negative regulator of Hippo in TE cells, and PKA as a positive regulator of Hippo in ICM cells. We further elucidated a novel mechanism by which Rho suppresses Hippo, distinct from the prevailing view that Rho inhibits Hippo signaling through modulating cytoskeleton remodeling and/or cell polarity. Active Rho prevents the phosphorylation of Amot Ser176, thus stabilizing the interaction between Amot and F-actin, and restricting the binding between Amot and Nf2. Moreover, Rho attenuates the interaction between Amot and Nf2 by binding to the coiled-coil domain of Amot. By blocking the association of Nf2 and Amot, Rho suppresses Hippo in TE cells.


Assuntos
Blastocisto/citologia , Blastocisto/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Proteínas dos Microfilamentos/metabolismo , Neurofibromina 2/metabolismo , Transdução de Sinais , Proteínas rho de Ligação ao GTP/metabolismo , Actinas/metabolismo , Animais , Linhagem Celular , Membrana Celular/metabolismo , Polaridade Celular , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Citoesqueleto/metabolismo , Ectoderma/citologia , Ectoderma/metabolismo , Feminino , Peptídeos e Proteínas de Sinalização Intercelular/química , Camundongos Endogâmicos ICR , Proteínas dos Microfilamentos/química , Modelos Biológicos , Fosforilação , Ligação Proteica , Domínios Proteicos , Quinases Associadas a rho/metabolismo
13.
Sci Rep ; 7: 43396, 2017 02 23.
Artigo em Inglês | MEDLINE | ID: mdl-28230092

RESUMO

Thyroid is a one of the most important endocrine organs. Understanding the molecular mechanism underlying thyroid development and function, as well as thyroid diseases, is beneficial for the clinical treatment of thyroid diseases and tumors. Through genetic linkage analysis and exome sequencing, we previously identified an uncharacterized gene C14orf93 (RTFC, mouse homolog: 4931414P19Rik) as a novel susceptibility gene for familial non-medullary thyroid carcinoma, and demonstrated its function in promoting thyroid tumor. However, the role of RTFC in thyroid development and function remains unexplored. In this study, we found that knockout of Rtfc compromises the in vitro thyroid differentiation of mouse embryonic stem cells. In contrast, Rtfc-/- mice are viable and fertile, and the size and the morphology of thyroid are not affected by Rtfc knockout. However, female Rtfc-/- mice, but not male Rtfc-/- mice, display mild hypothyroidism. In summary, our data suggest the roles of Rtfc in in vitro thyroid differentiation of embryonic stem cells, and in vivo thyroid function.


Assuntos
Células-Tronco Embrionárias/metabolismo , Hipotireoidismo/genética , Proteínas de Neoplasias/genética , Glândula Tireoide/metabolismo , Animais , Sequência de Bases , Diferenciação Celular , Linhagem Celular , Células-Tronco Embrionárias/patologia , Feminino , Expressão Gênica , Ligação Genética , Humanos , Hipotireoidismo/metabolismo , Hipotireoidismo/patologia , Masculino , Camundongos , Camundongos Knockout , Proteínas de Neoplasias/metabolismo , Fatores Sexuais , Glândula Tireoide/crescimento & desenvolvimento , Glândula Tireoide/patologia
14.
Oncol Lett ; 14(6): 7153-7160, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29344146

RESUMO

MicroRNAs (miRNAs/miRs) are small non-coding RNAs identified in plants, animals and certain viruses; they function in RNA silencing and post-transcriptional regulation of gene expression. miRNAs also serve an important role in the pathogenesis, diagnosis and treatment of tumors. However, few studies have investigated the role of miRNAs in thyroid tumors. In the present study, the expression of miRNA and mRNA was compared between follicular thyroid carcinoma (FTC) and follicular thyroid adenoma (FA) samples, and then miRNA-mRNA regulatory network analysis was performed. Microarray datasets (GSE29315 and GSE62054) were downloaded from the Gene Expression Omnibus, and profiling data were processed with R software. Differentially expressed miRNAs (DEMs) and differentially expressed genes (DEGs) were determined, and Gene Ontology enrichment analysis was subsequently performed for DEGs using the Database for Annotation, Visualization and Integrated Discovery. The target genes of the DEMs were identified with miRWalk, miRecords and TarMir databases. Network analysis of the DEMs and DEMs-targeted DEGs was performed using Cytoscape software. In GSE62054, 23 downregulated and 9 upregulated miRNAs were identified. In GSE29315, 42 downregulated and 44 upregulated mRNAs were identified. A total of 36 miRNA-gene pairs were also identified. Network analysis indicated a co-regulatory association between miR-296-5p, miR-10a, miR-139-5p, miR-452, miR-493, miR-7, miR-137, miR-144, miR-145 and corresponding targeted mRNAs, including TNF receptor superfamily member 11b, benzodiazepine receptor (peripheral) -associated protein 1, and transforming growth factor ß receptor 2. These results suggest that miRNA-mRNAs networks serve an important role in the pathogenesis, diagnosis and treatment of FTC and FA.

15.
Biochem Biophys Res Commun ; 482(4): 590-596, 2017 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-27864143

RESUMO

The genetic causes for familial nonmedullary thyroid cancer (FNMTC) remain largely unknown. Through genetic linkage analysis and exome sequencing, C14orf93 (RTFC), PYGL, and BMP4 were identified as susceptibility gene candidates in a FNMTC family. By examining the expression and the oncogenic functions of these candidate genes, PYGL and BMP4 were excluded. We further characterized the functions of the uncharacterized gene RTFC in thyroid cancer. RTFC promotes thyroid cancer cell survival under starving conditions, and thyroid cancer cell migration. The R115Q, V205M and G209D RTFC mutants enhance the colony forming capacity of thyroid cancer cells, and are able to transform normal thyroid cells. In summary, our data suggest the roles of RTFC in thyroid carcinogenesis.


Assuntos
Carcinoma/genética , Carcinoma/patologia , Proteínas de Neoplasias/genética , Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/patologia , Sequência de Bases , Carcinoma Papilar , Exoma , Feminino , Ligação Genética , Predisposição Genética para Doença , Humanos , Masculino , Linhagem , Mutação Puntual , Câncer Papilífero da Tireoide , Glândula Tireoide/metabolismo
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