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1.
Cancer Sci ; 112(4): 1624-1632, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33540491

RESUMO

Lysophosphatidic acid receptor 5 (LPAR5) is involved in mediating thyroid cancer progression, but the underlying mechanism needs to be further revealed. In this study, we confirmed that LPAR5 is upregulated in papillary thyroid carcinoma (PTC), especially in BRAF-like PTC, by analyzing The Cancer Genome Atlas (TCGA) database and performing immunohistochemistry assay in human thyroid cancer tissues. LPAR5-specific antagonist TC LPA5 4 treatment inhibited CGTH-W3, TPC-1, B-CPAP, and BHT-101 cell proliferation, CGTH-W3 and TPC-1 cell migration significantly. In vivo, TC LPA5 4 treatment could delay CGTH-W3 xenograft growth in nude mice. We also found that LPAR5-specific antagonist TC LPA5 4, PI3K inhibitor wortmannin, or mTOR inhibitor rapamycin pretreatment abrogated phosphorylation of Akt and p70S6K1 stimulated by LPA in CGTH-W3 and TPC-1 cells. Stimulating CGTH-W3 cells transfected with pEGFPC1-Grp1-PH fusion protein with LPA resulted in the generation of phosphatidylinositol (3,4,5)-triphosphate, which indicates that PI3K was activated by LPA directly. The p110ß-siRNA instead of p110α-siRNA transfection abrogated the increase of levels of phosphorylated Akt and S6K1 stimulated by LPA. Furthermore, immunoprecipitation assay confirmed an interaction between LPAR5 and p110ß. Overall, we provide new insights that the downregulation of LPAR5 decreased the proliferation and migration phenotype via the PI3K/Akt pathway. Inhibition of LPAR5 or the PI3K/Akt signal may be a novel therapeutic strategy for treating thyroid cancer.


Assuntos
Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Classe Ia de Fosfatidilinositol 3-Quinase/metabolismo , Receptores de Ácidos Lisofosfatídicos/metabolismo , Neoplasias da Glândula Tireoide/metabolismo , Neoplasias da Glândula Tireoide/patologia , Animais , Domínio Catalítico/fisiologia , Linhagem Celular Tumoral , Regulação para Baixo/fisiologia , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Transdução de Sinais/fisiologia , Câncer Papilífero da Tireoide/metabolismo , Câncer Papilífero da Tireoide/patologia
2.
Int J Mol Sci ; 22(1)2020 Dec 22.
Artigo em Inglês | MEDLINE | ID: mdl-33375029

RESUMO

The transcription factor Forkhead box E1 (FOXE1) is a key player in thyroid development and function and has been identified by genome-wide association studies as a susceptibility gene for papillary thyroid cancer. Several cancer-associated polymorphisms fall into gene regulatory regions and are likely to affect FOXE1 expression levels. However, the possibility that changes in FOXE1 expression modulate thyroid cancer development has not been investigated. Here, we describe the effects of FOXE1 gene dosage reduction on cancer phenotype in vivo. Mice heterozygous for FOXE1 null allele (FOXE1+/-) were crossed with a BRAFV600E-inducible cancer model to develop thyroid cancer in either a FOXE1+/+ or FOXE1+/- genetic background. In FOXE1+/+ mice, cancer histological features are quite similar to that of human high-grade papillary thyroid carcinomas, while cancers developed with reduced FOXE1 gene dosage maintain morphological features resembling less malignant thyroid cancers, showing reduced proliferation index and increased apoptosis as well. Such cancers, however, appear severely undifferentiated, indicating that FOXE1 levels affect thyroid differentiation during neoplastic transformation. These results show that FOXE1 dosage exerts pleiotropic effects on thyroid cancer phenotype by affecting histology and regulating key markers of tumor differentiation and progression, thus suggesting the possibility that FOXE1 could behave as lineage-specific oncogene in follicular cell-derived thyroid cancer.


Assuntos
Fatores de Transcrição Forkhead/genética , Regulação Neoplásica da Expressão Gênica , Câncer Papilífero da Tireoide/genética , Glândula Tireoide/metabolismo , Neoplasias da Glândula Tireoide/genética , Animais , Apoptose/genética , Diferenciação Celular/genética , Proliferação de Células/genética , Transformação Celular Neoplásica/genética , Fatores de Transcrição Forkhead/metabolismo , Pleiotropia Genética , Humanos , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/metabolismo , Câncer Papilífero da Tireoide/metabolismo , Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/metabolismo
3.
Int J Mol Sci ; 21(24)2020 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-33333840

RESUMO

Thyroid cancer incidence has increased worldwide; however, investigations of thyroid cancer-related factors as potential prognosis markers remain insufficient. Secreted proteins from the cancer secretome are regulators of several molecular mechanisms and are, thereby, ideal candidates for potential markers. We aimed to identify a specific factor for thyroid cancer by analyzing the secretome from normal thyroid cells, papillary thyroid cancer (PTC) cells, and anaplastic thyroid cancer cells using mass spectrometry (MS). Cathepsin B (CTSB) showed highest expression in PTC cells compared to other cell lines, and CTSB levels in tumor samples were higher than that seen in normal tissue. Further, among thyroid cancer patients, increased CTSB expression was related to higher risk of lymph node metastasis (LNM) and advanced N stage. Overexpression of CTSB in thyroid cancer cell lines activated cell migration by increasing the expression of vimentin and Snail, while its siRNA-mediated silencing inhibited cell migration by decreasing vimentin and Snail expression. Mechanistically, CTSB-associated enhanced cell migration and upregulation of vimentin and Snail occurred via increased phosphorylation of p38. As our results suggest that elevated CTSB in thyroid cancer induces the expression of metastatic proteins and thereby leads to LNM, CTSB may be a good and clinically relevant prognostic marker.


Assuntos
Biomarcadores Tumorais/metabolismo , Catepsina B/metabolismo , Transição Epitelial-Mesenquimal/genética , Câncer Papilífero da Tireoide/metabolismo , Neoplasias da Glândula Tireoide/metabolismo , Catepsina B/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Feminino , Humanos , Metástase Linfática , Masculino , Espectrometria de Massas , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Fosforilação , Prognóstico , Fatores de Risco , Transdução de Sinais/genética , Fatores de Transcrição da Família Snail/metabolismo , Câncer Papilífero da Tireoide/patologia , Neoplasias da Glândula Tireoide/patologia , Regulação para Cima , Vimentina/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
5.
Life Sci ; 259: 118374, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32891613

RESUMO

OBJECTIVE: Dipeptidyl peptidase IV (DPP4) has been indicated as a possible prognostic biomarker in papillary thyroid cancer (PTC). However, the mechanism of DPP4 during metastasis of PTC remains unclear. In this study, we investigated whether lysine acetyltransferase 5 (KAT5) and FBJ murine osteosarcoma viral oncogene homolog B (FosB) synergistically regulate high DPP4 expression in PTC. METHODS: PTC tissues and matched paracancerous tissues were harvested, followed by the establishment of IHH-4 and TPC-1 cells with downregulation of DPP4. The relevance of DPP4 on the metastasis of PTC cells was assessed. Subsequently, the effect of KAT5 on the transcription of DPP4 was verified. The binding relationship between FosB and DPP4 was predicted by a bioinformatics website. Functional rescue experiments were performed to evaluate cell activities after overexpression of KAT5 or FosB in cells with DPP4 knockdown. RESULTS: DPP4 was overexpressed in PTC tissues and cell lines, which was correlated with higher risks for metastases and poorer survival. DPP4 downregulation curtailed cell growth and metastasis. Moreover, KAT5 acetylated DPP4 promoter histone, which promoted transcription activation of DPP4. Subsequently, FosB recruited KAT5 at the DPP4 promoter, thereby enhancing DPP4 transcriptional activation. Further overexpression of KAT5 or FosB in cells with low expression of DPP4 promoted cell activity. Finally, DPP4 expedited p62 nuclear translocation to elevate Keap1/Nrf2 expression, thus facilitating the growth and metastasis of PTC cells. CONCLUSION: FosB enhanced the growth and metastasis of PTC cells by recruiting histone acetyltransferases KAT5 to increase DPP4 transcription and activate the p62/Keap1/Nrf2 signaling.


Assuntos
Dipeptidil Peptidase 4/metabolismo , Lisina Acetiltransferase 5/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Câncer Papilífero da Tireoide/patologia , Neoplasias da Glândula Tireoide/patologia , Animais , Western Blotting , Linhagem Celular Tumoral , Feminino , Imunofluorescência , Humanos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Transplante de Neoplasias , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Câncer Papilífero da Tireoide/metabolismo , Neoplasias da Glândula Tireoide/metabolismo
6.
Medicine (Baltimore) ; 99(35): e21996, 2020 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-32871952

RESUMO

It is of significance to evaluate central lymph node status in patients with papillary thyroid carcinoma (PTC), because it can decrease postoperative complications resulting from unnecessary prophylactic central lymph node dissection (CLND). Due to the low sensitivity and specificity of neck ultrasonography in the evaluation of central lymph node metastasis (CLNM), it is urgently required to find alternative biomarkers to predict CLNM in PTC patients, which is the main purpose of this study.RNA-sequencing datasets and clinical data of 506 patients with thyroid carcinoma from the Cancer Genome Atlas (TCGA) database were downloaded and analyzed to identify differentially expressed miRNAs (DEMs), which can independently predict CLNM in PTC. A nomogram predictive of CLNM was developed based on clinical characteristics and the identified miRNAs. Receiver operating characteristics curves were drawn to evaluate the predictive performance of the nomogram. Bioinformatics analyses, including target genes identification, functional enrichment analysis, and protein-protein interaction network, were performed to explore the potential roles of the identified DEMs related to CLNM in PTC.A total of 316 PTC patients were included to identify DEMs. Two hundred thirty-seven (75%) PTC patients were randomly selected from the 316 patients as a training set, while the remaining 79 (25%) patients were regarded as a testing set for validation. Two DEMs, miRNA-146b-3p (HR: 1.327, 95% CI = 1.135-1.551, P = .000) and miRNA-363-3p (HR: 0.714, 95% CI = 0.528-0.966, P = .029), were significantly associated with CLNM. A risk score based on these 2 DEMs and calculating from multivariate logistic regression analysis, was significantly lower in N0 group over N1a group in both training (N0 vs N1a: 2.04 ±â€Š1.01 vs 2.73 ±â€Š0.61, P = .000) and testing (N0 vs N1a: 2.20 ±â€Š0.93 vs 2.79 ±â€Š0.68, P = .003) sets. The nomogram including risk score, age, and extrathyroidal extension (ETE) was constructed in the training set and was then validated in the testing set, which showed better prediction value than the other three predictors (risk score, age, and ETE) in terms of CLNM identification. Bioinformatics analyses revealed that 5 hub genes, SLC6A1, SYT1, COL19A1, RIMS2, and COL1A2, might involve in pathways including extracellular matrix organization, ion transmembrane transporter activity, axon guidance, and ABC transporters.On the basis of this study, the nomogram including risk score, age, and ETE showed good prediction of CLNM in PTC, which has a potential to facilitate individualized decision for surgical plans.


Assuntos
Metástase Linfática , MicroRNAs/metabolismo , Nomogramas , Câncer Papilífero da Tireoide/metabolismo , Mineração de Dados , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mapas de Interação de Proteínas , Câncer Papilífero da Tireoide/genética , Câncer Papilífero da Tireoide/patologia
7.
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
8.
Zhonghua Zhong Liu Za Zhi ; 42(6): 463-468, 2020 Jun 23.
Artigo em Chinês | MEDLINE | ID: mdl-32575941

RESUMO

Objective: To explore the differential protein expressions in papillary thyroid carcinoma (PTC) with or without Hashimoto's thyroiditis (HT). Methods: Tissue microarray was prepared and the protein expression levels of v-Raf murine sarcoma viral oncogene homolog B1 (BRAF), vascular endothelial growth factor (VEGF), cyclinD1, mesothelial cell (MC) , CD56 and Galectin3 in the PTC tissues with or without HT were detected by immunohistochemical staining. Results: The positive expression rates of BRAF protein in the PTC tissues with or without HT groups were 55.4% (36/65) and 63.6% (42/66), respectively, without significant difference (P=0.336). The positive expression rates of VEGF protein in the PTC tissues with or without HT groups were 25.7% (19/74) and 25.8%(17/66), respectively, without significant difference (P=0.991). The positive expression rates of cyclin D1 protein in the PTC tissues with or without HT groups were 93.4% (71/76) and 97.6% (80/82), without significant difference (P=0.206). The positive expression rates of MC protein in the PTC tissues with or without HT groups were 86.1% (62/72) and 83.5%(71/85), without significant difference (P=0.654). The positive expression rates of Galectin3 protein in the PTC tissues with or without HT groups were 98.7% (76/77) and 97.5% (78/80), without significant difference (P=0.583). The positive expression rates of CD56 in the PTC tissues and adjacent thyroid follicular epithelial cells were 27.4% (32/117) and 65.0% (76/117), respectively, and the difference was statistically significant (P=0.001). The positive expression rates of CD56 in PTC tissues with or without HT were 35.5% (24/68) and 16.5% (13/79), respectively, and the difference was statistically significant (P=0.009). Conclusions: There are no significant differences in the expressions of BRAF, VEGF, CyclinD1, MC and Galectin3 between the PTC tissues with or without HT. However, the significantly differential expression of CD56 between the two group suggests that CD56 may be related to the pathogenesis of PTC with HT. CD56 may be used as a potential molecular marker in PTC diagnosis.


Assuntos
Adenocarcinoma Papilar/genética , Antígeno CD56/metabolismo , Carcinoma Papilar/patologia , Doença de Hashimoto/genética , Proteínas Proto-Oncogênicas B-raf/genética , Câncer Papilífero da Tireoide/genética , Neoplasias da Glândula Tireoide/patologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Adenocarcinoma Papilar/metabolismo , Adenocarcinoma Papilar/patologia , Animais , Biomarcadores/análise , Carcinoma Papilar/metabolismo , Ciclina D1/genética , Galectinas , Doença de Hashimoto/metabolismo , Doença de Hashimoto/patologia , Humanos , Camundongos , Valor Preditivo dos Testes , Proteínas Proto-Oncogênicas B-raf/metabolismo , Câncer Papilífero da Tireoide/metabolismo , Câncer Papilífero da Tireoide/patologia , Glândula Tireoide/metabolismo , Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/metabolismo , Análise Serial de Tecidos , Fator A de Crescimento do Endotélio Vascular/genética
9.
Medicine (Baltimore) ; 99(26): e20644, 2020 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-32590739

RESUMO

The present study aimed to investigate the correlation between ultrasonographic features, basic fibroblast growth factor (bFGF), and the local invasiveness of papillary thyroid carcinoma (PTC).A total of 350 samples of thyroid nodules were collected. Routine ultrasonography was performed before the operation and routine pathological diagnosis and bFGF detection were performed after the operation.'These 350 samples of thyroid nodules included 90 samples of nodular goiter, 36 samples of focal thyroiditis, and 224 samples of PTC. A total of 326 thyroid nodules were examined for bFGF. The results revealed that the difference in the expression of bFGF between the benign and malignant groups was statistically significant (P < .05) and the difference in the positive expression of bFGF between the invasive and non-invasive PTC groups was statistically significant (P < .05).Whether the shape of PTC is regular or not and whether there is micro-calcification in PTC and other ultrasonographic features, the size and location of the lesions and the age of the patient help make a preliminary prediction of local invasiveness before the operation. Postoperative detection of bFGF is helpful for further risk assessments of PTC.


Assuntos
Fator 2 de Crescimento de Fibroblastos/metabolismo , Câncer Papilífero da Tireoide/diagnóstico por imagem , Câncer Papilífero da Tireoide/metabolismo , Neoplasias da Glândula Tireoide/diagnóstico por imagem , Neoplasias da Glândula Tireoide/metabolismo , Adulto , Fatores Etários , Idoso , Biomarcadores Tumorais/metabolismo , Feminino , Bócio/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Estudos Prospectivos , Câncer Papilífero da Tireoide/patologia , Neoplasias da Glândula Tireoide/patologia , Nódulo da Glândula Tireoide/metabolismo , Tireoidite/metabolismo , Ultrassonografia , Adulto Jovem
10.
Arch Biochem Biophys ; 689: 108461, 2020 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-32531316

RESUMO

The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway plays an important role in the development of papillary thyroid cancer. While rapamycin has been shown to exhibit anti-tumor effects, it may also activate AKT, resulting in increased cell survival and drug resistance, thereby limiting its anti-tumor effects. Resveratrol can also inhibit tumor growth by regulating the PI3K/AKT/mTOR signaling pathway. The present study investigated the anti-tumor effects of the combined use of rapamycin and resveratrol in papillary thyroid cancer. We first treated two human papillary thyroid cancer cell lines (KTC-1 and TPC-1) with single or combined administration, and examined the effects on proliferation, the cell cycle, apoptosis, and invasion/migration of papillary thyroid cancer cells. A mouse xenograft model was induced with KTC-1 and TPC-1 cells followed by treatment with single or combined administration. Body weight and tumor size were monitored to assess the toxicity of each compound. The phosphorylation of AKT and the mTORC1 target p70S6 kinase (p70S6K) in tumors was also examined. Both rapamycin and resveratrol inhibited proliferation, altered the cell cycle, and induced apoptosis of papillary thyroid cancer cells. Invasion and migration were also reduced, as was the tumor growth rate in the xenograft model. Co-administration significantly enhanced the anti-tumor effects than use of any one drug, and significantly reduced the phosphorylation of AKT and p70S6K compared to treatment with rapamycin alone. Overall, compared to single use of rapamycin or resveratrol, co-administration had a synergistic effect in inhibiting proliferation and invasion/migration of papillary thyroid cancer cells and inducing apoptosis. Resveratrol is sensitizing the anti-tumor effects of rapamycin and the PI3K/AKT/mTOR signaling is involved. Although further animal and clinical studies are needed to clarify the mechanism and assess drug safety, the present study suggests that the combination of rapamycin and resveratrol may be a promising strategy for the treatment of papillary thyroid cancer.


Assuntos
Antineoplásicos/uso terapêutico , Resveratrol/uso terapêutico , Sirolimo/uso terapêutico , Câncer Papilífero da Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/tratamento farmacológico , Animais , Antineoplásicos/farmacologia , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sinergismo Farmacológico , Humanos , Camundongos Endogâmicos BALB C , Camundongos Nus , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Resveratrol/farmacologia , Transdução de Sinais/efeitos dos fármacos , Sirolimo/farmacologia , Serina-Treonina Quinases TOR/metabolismo , Câncer Papilífero da Tireoide/metabolismo , Neoplasias da Glândula Tireoide/metabolismo
11.
Arch Biochem Biophys ; 685: 108353, 2020 05 30.
Artigo em Inglês | MEDLINE | ID: mdl-32234499

RESUMO

OBJECTIVE: Despite of previous report regarding the aberrant overexpression of hsa_circ_0011290 in thyroid cancer, the regulatory mechanism and mechanistic involvements of which were still elusive currently in papillary thyroid cancer (PTC). Here we set out to characterize expression status and functional contributions of hsa_circ_0011290 in this disease especially through mode-of-action of sponging RNA. METHODS: Relative expression of hsa_circ_0011290, microRNA (miR)-1252 and FSTL1 was quantified by real-time polymerase chain reaction. Glucose metabolism was determined by examination of glucose uptake, lactate production and ATP contents. The regulatory effects of miR-1252 on both hsa_circ_0011290 and Follistatin Like 1 (FSTL1) were interrogated by luciferase reporter assay. Direct binding between miR-1252 with hsa_circ_0011290 and FSTL1 transcripts were analyzed by RNA pulldown assay. Protein levels of FSTL1 was examined by Western blots. RESULTS: Aberrant over-expression of hsa_circ_0011290 was associated with advanced stage and unfavorable prognosis of PTC. Knockdown of hsa_circ_0011290 greatly inhibited cell viability, proliferation and stimulated cell apoptosis in PTC cells. Meanwhile, glucose metabolism was significantly switched with decreased glucose uptake and lactate production, and increased ATP contents. We identified miR-1252 as target miR of hsa_circ_0011290, and miR-1252 evidently inhibited expressions of both luciferase reporter and endogenous hsa_circ_0011290, and miR-1252 was negatively regulated by hsa_circ_0011290 vice versa. We further suggested that FSTL1 as direct target of miR-1252, and provided direct evidences in support of binding between miR-1252 with both hsa_circ_0011290 and FSTL1. Through sponging miR-1252, hsa_circ_0011290 was capable of positively modulate FSTL1 expression. Notably, inhibition of miR-1252 completely reversed phenotypic effects of hsa_circ_0011290 knockdown including cell viability, proliferation, apoptosis and glucose metabolisms. CONCLUSION: Our study uncovered the oncogenic contributions of hsa_circ_0011290-miR-1252-FSTL1 in PTCs.


Assuntos
Apoptose/fisiologia , Proliferação de Células/fisiologia , RNA Circular/metabolismo , Transdução de Sinais/fisiologia , Câncer Papilífero da Tireoide/metabolismo , Apoptose/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Proteínas Relacionadas à Folistatina/metabolismo , Técnicas de Silenciamento de Genes , Glicólise/fisiologia , Humanos , MicroRNAs/metabolismo , Prognóstico , RNA Circular/análise , RNA Circular/genética , Transdução de Sinais/genética , Câncer Papilífero da Tireoide/diagnóstico
12.
Life Sci ; 250: 117519, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32147429

RESUMO

OBJECTIVE: Papillary thyroid cancer (PTC) is the most ordinary type of thyroid cancer. Studies pivoting on the mechanisms of microRNAs (miRNAs) are adequately explored but not much on miR-448 in PTC. Thus, this study is proposed to bring forward the uncovered mechanisms of miR-448 in PTC. METHODS: Lysine specific demethylase 5B (KDM5B), miR-448 and transforming growth factor ß-induced factor 1 (TGIF1) expression in PTC tissues and cell lines were detected. The connection between miR-448 expression and clinicopathological characteristics of PTC patients was determined. PTC cell lines TPC-1 and K-1 were transfected with sh-KDM5B, si-TGIF1 or miR-448 mimic to explore their roles in PTC cell progression. Tumor xenografts in nude mice was performed to detect tumor volume and weight. RESULTS: KDM5B and TGIF1 were increased and miR-448 was declined in PTC tissues and cell lines. MiR-448 expression was connected with N stage, lymph node metastasis and advanced tumor node metastasis stage of PTC patients. KDM5B knockdown or TGIF1 reduction or miR-448 elevation undermined PTC cell progression and inhibited tumor growth of nude mice. Down-regulation of miR-448 followed by KDM5B knockdown reversed the effect of decreased KDM5B on the proliferation inhibition and apoptosis promotion of PTC cells. CONCLUSION: Our study elaborates that KDM5B-mediated miR-448 up-regulation restrains PTC cell progression and slows down tumor growth via TGIF1 repression, which provides a novel reference for treatment of PTC.


Assuntos
Carcinoma Papilar/metabolismo , Proteínas de Homeodomínio/metabolismo , Histona Desmetilases com o Domínio Jumonji/metabolismo , MicroRNAs/genética , Proteínas Nucleares/metabolismo , Proteínas Repressoras/metabolismo , Câncer Papilífero da Tireoide/metabolismo , Neoplasias da Glândula Tireoide/metabolismo , Idoso , Animais , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Humanos , Histona Desmetilases com o Domínio Jumonji/genética , Metástase Linfática , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Metástase Neoplásica , Transplante de Neoplasias , Proteínas Nucleares/genética , Proteínas Repressoras/genética , Fator de Crescimento Transformador beta1/metabolismo , Regulação para Cima
13.
Biomed Res Int ; 2020: 8954513, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32047817

RESUMO

PBX3 (Pre-B-cell leukemia homeobox 3) had been considered to be a multifunctional oncogene which involved in tumor growth, invasion, and metastasis in leukemia and some solid tumors. However, the contribution of PBX3 to papillary thyroid carcinoma (PTC) remains unclear. In this study, we found that PBX3 expression was significantly upregulated in PTC tissues compared to adjacent normal tissues, and high levels of PBX3 were correlated with tumor size, lymphatic metastasis, TMN stage, and poor prognosis of PTC patients. Overexpression of PBX3 in PTC cell lines promoted cell proliferation. Consistently, knockdown of PBX3 by shRNA induced cell cycle arrest at G0/G1 phase, and inhibited angiogenesis and tumor growth in vitro and in vivo. Furthermore, PBX3 promoted PTC cell proliferation and angiogenesis through activation of AT1R/VEGFR2 pathway while overexpression of AT1R and treatment with VEGFA reversed PBX3-shRNA-induced decreased phosphorylation of VEGFR2 and its downstream (ERK1/2, AKT and Src). It demonstrated that PBX3 could be used as a potential prognostic biomarker and therapeutic target for PTC.


Assuntos
Proteínas de Homeodomínio/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Câncer Papilífero da Tireoide/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Pontos de Checagem do Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Proteínas de Homeodomínio/genética , Humanos , Metástase Linfática , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Prognóstico , Proteínas Proto-Oncogênicas/genética , Câncer Papilífero da Tireoide/genética , Câncer Papilífero da Tireoide/patologia , Regulação para Cima , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética
14.
J Clin Ultrasound ; 48(4): 227-230, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32045024

RESUMO

Metastases to the submandibular gland are extremely rare; a literature search retuned only three previously reported cases from a thyroid gland primary site. Herein, we report two cases of metastatic thyroid carcinoma to the submandibular gland in a 64-year-old woman with PTC and a 70-year-old-woman with medullary thyroid carcinoma (MTC). The metastases were identified on CT and PET/CT in one case and on CT in the other case, but both were diagnosed with ultrasound-guided fine-needle aspiration. Our cases highlight that while rare, both PTC and MTC can metastasize to the submandibular gland.


Assuntos
Carcinoma Neuroendócrino/secundário , Neoplasias da Glândula Submandibular/secundário , Câncer Papilífero da Tireoide/secundário , Neoplasias da Glândula Tireoide/patologia , Idoso , Biópsia por Agulha Fina , Calcitonina/metabolismo , Carcinoma Neuroendócrino/diagnóstico por imagem , Carcinoma Neuroendócrino/metabolismo , Feminino , Humanos , Pessoa de Meia-Idade , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Neoplasias da Glândula Submandibular/diagnóstico por imagem , Câncer Papilífero da Tireoide/diagnóstico por imagem , Câncer Papilífero da Tireoide/metabolismo , Neoplasias da Glândula Tireoide/diagnóstico por imagem , Neoplasias da Glândula Tireoide/metabolismo , Neoplasias da Glândula Tireoide/secundário , Tireoidectomia , Tomografia Computadorizada por Raios X , Ultrassonografia
15.
Sci Rep ; 10(1): 1539, 2020 01 30.
Artigo em Inglês | MEDLINE | ID: mdl-32001748

RESUMO

Nerves are emerging regulators of cancer progression and in several malignancies innervation of the tumour microenvironment is associated with tumour aggressiveness. However, the innervation of thyroid cancer is unclear. Here, we investigated the presence of nerves in thyroid cancers and the potential associations with clinicopathological parameters. Nerves were detected by immunohistochemistry using the pan-neuronal marker PGP9.5 in whole-slide sections of papillary thyroid cancer (PTC) (n = 75), compared to follicular thyroid cancer (FTC) (n = 13), and benign thyroid tissues (n = 26). Nerves were detected in most normal thyroid tissues and thyroid cancers, but nerve density was increased in PTC (12 nerves/cm2 [IQR 7-21]) compared to benign thyroid (6 nerves/cm2 [IQR: 3-10]) (p = 0.001). In contrast, no increase in nerve density was observed in FTC. In multivariate analysis, nerve density correlated positively with extrathyroidal invasion (p < 0.001), and inversely with tumour size (p < 0.001). The majority of nerves were adrenergic, although cholinergic and peptidergic innervation was detected. Perineural invasion was present in 35% of PTC, and was independently associated with extrathyroidal invasion (p = 0.008). This is the first report of infiltration of nerves into the tumour microenvironment of thyroid cancer and its association with tumour aggressiveness. The role of nerves in thyroid cancer pathogenesis should be further investigated.


Assuntos
Metástase Neoplásica/patologia , Neurônios/metabolismo , Câncer Papilífero da Tireoide/metabolismo , Adulto , Idoso , Carcinoma/patologia , Feminino , Humanos , Imuno-Histoquímica/métodos , Masculino , Pessoa de Meia-Idade , Neurônios/patologia , Câncer Papilífero da Tireoide/patologia , Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/patologia , Microambiente Tumoral/fisiologia
16.
Med Sci Monit ; 26: e919820, 2020 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-31902939

RESUMO

BACKGROUND Thyroid cancer is the most common endocrine system malignancy. Scientists have done considerable research into the molecular mechanisms involved, but many mechanisms remain undiscovered. MATERIAL AND METHODS We performed a comprehensive analysis of the whole-transcriptome resequencing derived from thyroid tissues and paired papillary thyroid cancer (PTC) and showed that lysophosphatidic acid receptor 5 (LPAR5) is strongly overexpressed in thyroid carcinoma. Then, we used TPC-1 and KTC-1 to explore the effect of LPAR5 knockdown on colony formation, migration, proliferation, invasion, and apoptosis of PTC cell line cells. AKT activator was used for the recovery test. Finally, we designed proteomic experiments to explore the role of LPAR5 in the AKT pathway and the EMT process. RESULTS Cell function experiments showed that LPAR5 knockdown can significantly induce apoptosis of KTC-1 and TPC-1 cells. Furthermore, LPAR5 can promote PTC metastasis and tumorigenesis by activating the PI3K/AKT pathway and decreasing its cancer-promoting effect when using AKT agonist. We also found that LPAR5 can regulate the expression of EMT-related proteins, which affect invasion and migration. CONCLUSIONS In summary, downregulation of LPAR5 expression can inhibit the physiological process of PTC, and this phenomenon is related to the PI3K/AKT pathway and EMT.


Assuntos
Fosfatidilinositol 3-Quinase/metabolismo , Receptores de Ácidos Lisofosfatídicos/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Câncer Papilífero da Tireoide/metabolismo , Neoplasias da Glândula Tireoide/metabolismo , Adulto , Idoso , Apoptose/fisiologia , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteômica/métodos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Glândula Tireoide/metabolismo , Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/patologia
17.
Life Sci ; 244: 117298, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31953163

RESUMO

Long non-coding RNA (lncRNA) is emerging as an essential player in cancer progression. However, its biological function and clinical implication in papillary thyroid carcinoma (PTC) remain poorly understood. In the current study, we found that a novel lncRNA, ASMTL antisense RNA 1 (ASMTL-AS1), was significantly downregulated in PTC. And its downregulation was positively linked to larger tumor size, advanced clinical stage and unfavorable outcome. Overexpression of ASMTL-AS1 evidently inhibited PTC cell proliferation and glycolysis, while knockdown of ASMTL-AS1 resulted in the opposite effect. Regarding the mechanism, ASMTL-AS1 was capable of sponging miR-93-3p and miR-660 to elevate FOXO1 expression, leading to repressing glycolysis and tumorigenesis. In turn, FOXO1 could also increase ASMTL-AS1 expression via directly binding to ASMTL-AS1 promoter, which formed a positive feedback regulation loop. Importantly, the regulatory axis of ASMTL-AS1/miR-93-3p/miR-660/FOXO1 was also identified in vivo. Collectively, our data clearly indicate that ASMTL-AS1 functions as a novel tumor suppressor in PTC through regulation of miR-93-3p/miR-660/FOXO1 pathway. Targeting ASMTL-AS1 and its downstream pathway may be an effective therapeutic approach for patients with PTC.


Assuntos
Proteína Forkhead Box O1/metabolismo , Regulação Neoplásica da Expressão Gênica , Glicólise , MicroRNAs/genética , RNA Longo não Codificante/genética , Câncer Papilífero da Tireoide/patologia , Animais , Apoptose , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Estudos de Casos e Controles , Proliferação de Células , Feminino , Seguimentos , Proteína Forkhead Box O1/genética , Humanos , Masculino , Metiltransferases/antagonistas & inibidores , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Prognóstico , RNA Antissenso/genética , Taxa de Sobrevida , Câncer Papilífero da Tireoide/genética , Câncer Papilífero da Tireoide/metabolismo , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/metabolismo , Neoplasias da Glândula Tireoide/patologia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Int J Mol Sci ; 21(2)2020 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-31936675

RESUMO

The constitutive activation of Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) signal transduction is well elucidated in STAT3-mediated oncogenesis related to thyroid cancer and is considered to be a plausible therapeutic target. Hence, we investigated whether curcumin, a natural compound, can target the JAK/STAT3 signaling pathway to induce cytotoxic effects in papillary thyroid cancer (PTC) cell lines (BCPAP and TPC-1) and derived thyroid cancer stem-like cells (thyrospheres). Curcumin suppressed PTC cell survival in a dose-dependent manner via the induction of caspase-mediated apoptosis and caused the attenuation of constitutively active STAT3 (the dephosphorylation of Tyr705-STAT3) without affecting STAT3. Gene silencing with STAT3-specific siRNA showed the modulation of genes associated with cell growth and proliferation. The cotreatment of PTC cell lines with curcumin and cisplatin synergistically potentiated cytotoxic effects via the suppression of JAK/STAT3 activity along with the inhibition of antiapoptotic genes and the induction of proapoptotic genes, and it also suppressed the migration of PTC cells by downregulating matrix metalloproteinases and the inhibition of colony formation. Finally, thyrospheres treated with curcumin and cisplatin showed suppressed STAT3 phosphorylation, a reduced formation of thyrospheres, and the downregulated expression of stemness markers, in addition to apoptosis. The current study's findings suggest that curcumin synergistically enhances the anticancer activity of cisplatin in PTC cells as well as in cancer stem-like cells by targeting STAT3, which suggests that curcumin combined with chemotherapeutic agents may provide better therapeutic outcomes.


Assuntos
Apoptose/efeitos dos fármacos , Curcumina/farmacologia , Janus Quinases/metabolismo , Células-Tronco Neoplásicas/patologia , Fator de Transcrição STAT3/metabolismo , Câncer Papilífero da Tireoide/metabolismo , Câncer Papilífero da Tireoide/patologia , Neoplasias da Glândula Tireoide/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cisplatino/farmacologia , Sinergismo Farmacológico , Humanos , Interleucina-6/metabolismo , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Neoplasias da Glândula Tireoide/metabolismo , Regulação para Cima/efeitos dos fármacos
19.
Biomed Res Int ; 2020: 4983420, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31998791

RESUMO

Background: Growing evidence shows that dysregulation of miRNAs plays a significant role in papillary thyroid cancer (PTC) tumorigenesis and development. The abnormal expression of miR-384 has been acknowledged in the proliferation or metastasis of some cancers. However, the function and the underlying mechanism of miR-384 in PTC progression remain largely unknown. Methods: Real-time PCR was conducted to detect miR-384 expression in 58 cases of PTC and their adjacent noncancerous tissues. MTT, soft agar assay Transwell assay, and wound-healing assay were carried out to explore the biological function of miR-384 in PTC cell lines of BCPAP and K1. Bioinformatics analysis, dual-luciferase reporter assay, western blot, and functional complementation analysis were conducted to explore the target gene of miR-384. Moreover, Spearman's correlation analysis was conducted to reveal the correlation between miR-384 and PRKACB mRNA in PTC. Results: The expression of miR-384 decreased obviously in PTC, especially in the tumors with lymph node metastasis or larger tumor size. The ectopic upregulation of miR-384 significantly suppressed PTC progression, and the inhibition of miR-384 had the opposite effects. Moreover, PRKACB gene was confirmed as the target of miR-384. Conclusion: The study suggests that miR-384 serves as a tumor suppressor in PTC progression by directly targeting the 3'-UTR of PRKACB gene.


Assuntos
Subunidades Catalíticas da Proteína Quinase Dependente de AMP Cíclico/metabolismo , Genes Supressores de Tumor , MicroRNAs/metabolismo , Proteínas de Neoplasias/metabolismo , RNA Neoplásico/metabolismo , Câncer Papilífero da Tireoide/metabolismo , Neoplasias da Glândula Tireoide/metabolismo , Animais , Linhagem Celular Tumoral , Subunidades Catalíticas da Proteína Quinase Dependente de AMP Cíclico/genética , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , MicroRNAs/genética , Proteínas de Neoplasias/genética , RNA Neoplásico/genética , Câncer Papilífero da Tireoide/genética , Neoplasias da Glândula Tireoide/genética
20.
Artif Cells Nanomed Biotechnol ; 48(1): 326-335, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31878795

RESUMO

Thyroid cancer is a frequently happened malignancy in human endocrine system. Papillary thyroid cancer (PTC) presents 70-80% of all thyroid cancer cases. Herein, we probed the possible oncogenic function of long non-coding RNA (lncRNA) highly up-regulated in liver cancer (HULC) in PTC. First, the HULC and microRNA-106a (miR-106a) expressions in PTC tissues and cells were tested. Plasmids or miRNAs transfections were done for altering HULC and miR-106a expressions. Then, cells viability and apoptosis, along with cell proliferative, migratory and invasive abilities, were tested, respectively. The PI3K/AKT and Wnt/ß-catenin pathways activities were measured. Finally, the animal model of PTC was constructed and the tumour volumes and weights were gauged. We discovered that HULC and miR-106a had relative high expression levels in PTC tissues and cells. HULC overexpression enhanced TPC-1 cells viability and cell proliferative, migratory and invasive abilities. Silencing HULC induced TPC-1 cell apoptosis. miR-106a engaged in the oncogenic impacts of HULC. Moreover, HULC overexpression boosted PI3K/AKT and Wnt/ß-catenin pathways activities via raising miR-106a expression. Besides, HULC overexpression enhanced the volumes and weights of PTC tumours. To sum up, HULC exhibited oncogenic function on PTC in vitro and in vivo.


Assuntos
Proliferação de Células , Regulação Neoplásica da Expressão Gênica , RNA Longo não Codificante/biossíntese , RNA Neoplásico/biossíntese , Câncer Papilífero da Tireoide/metabolismo , Neoplasias da Glândula Tireoide/metabolismo , Via de Sinalização Wnt , Linhagem Celular Tumoral , Humanos , Invasividade Neoplásica , RNA Longo não Codificante/genética , RNA Neoplásico/genética , Câncer Papilífero da Tireoide/genética , Câncer Papilífero da Tireoide/patologia , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/patologia
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