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1.
Exp Cell Res ; 412(2): 113023, 2022 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-35033555

RESUMO

Enhancer RNAs (eRNAs) can serve as an independent prognostic factor for poor outcomes of cancer patients. The purpose of this study was to identify a vital eRNA signature that has prognostic value for thyroid cancer based on GTEx and TCGA screening. We downloaded gene expression data and clinical data of thyroid cancer included in the GTEx and TCGA databases and conducted data consolidation. eRNA expression data were extracted, and subjected to differential analysis and cluster analysis. Univariate Cox regression was used to screen the prognostic factors of thyroid cancer. Multivariate Cox regression was applied for prognostic risk assessment model construction, with the efficacy evaluated by receiver operating characteristic (ROC) curve. Downstream regulatory genes of candidate eRNAs were determined using correlation analysis. There were 79 differentially expressed eRNAs associated with thyroid cancer. These differentially expressed eRNAs could assign all thyroid cancer samples into three molecular subtypes, which showed a strong link to lymph node metastasis (N stage) of thyroid cancer patients. Additionally, four key eRNAs AC141930.1, NBDY, MEG3 and AP002358.1 closely related to the prognosis of thyroid cancer patients. The risk model based on the four eRNAs predicted the prognosis of thyroid cancer patients effectively. TPO, MGST2, THBS2 and SLC25A47P1 were potential downstream regulators of the four eRNAs involved in the development of thyroid cancer. Collectively, our data suggest that a four-eRNA signature consisting of AC141930.1, NBDY, MEG3 and AP002358.1 can accurately predict the prognosis of thyroid cancer patients.


Assuntos
Elementos Facilitadores Genéticos/genética , RNA/genética , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/patologia , Biomarcadores Tumorais/genética , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Prognóstico , Curva ROC , Transcriptoma/genética
2.
Front Oncol ; 11: 681736, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34222000

RESUMO

The pathogenesis of papillary thyroid cancer (PTC), the most common type of thyroid cancer, is not yet fully understood. This limits the therapeutic options for approximately 7% of invasive PTC patients. The critical role of AUF1 in the progression of thyroid cancer was first reported in 2009, however, its molecular mechanism remained unclear. Our study used CRISPR/Cas 9 system to knockdown AUF1 in IHH4 and TPC1 cells. We noticed that the expression of TRIM58 and ZBTB2 were increased in the AUF1 knockdown IHH4 and TPC1 cells. When TRIM58 and ZBTB2 were inhibited by small hairpin RNAs (shRNAs) against TRIM58 (shTRIM58) and ZBTB2 (shZBTB2), respectively, the proliferation, migration, and invasion ability of the AUF1-knockdown IHH4 and TPC1 cells were increased. In addition, two ZBTB2 binding sites (-719~-709 and -677~-668) on TRIM58 promoter and two AUF1 binding sites (1250-1256 and 1258-1265) on ZBTB2 3'-UTR were identified. These results suggested that AUF1 affecting thyroid cancer cells via regulating the expression of ZBTB2 and TRIM58.

3.
J Cell Mol Med ; 25(10): 4814-4825, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33792181

RESUMO

HYOU1 is upregulated in many kinds of cancer cells, and its high expression is associated with tumour invasiveness and poor prognosis. However, the role of HYOU1 in papillary thyroid cancer (PTC) development and progression remains to be elucidated. Here, we reported that HYOU1 was highly expressed in human PTC and associated with poor prognosis. HYOU1 silencing suppressed the proliferation, migration and invasion of PTC cells. Mechanistic analyses showed that HYOU1 silencing promoted oxidative phosphorylation while inhibited aerobic glycolysis via downregulating LDHB at the posttranscriptional level. We further confirmed that the 3'UTR of LDHB mRNA is the indirect target of HYOU1 silencing and HYOU1 silencing increased miR-375-3p levels. While LDHB overexpression significantly suppressed the inhibitory effects of HYOU1 silencing on aerobic glycolysis, proliferation, migration and invasion in PTC cells. Taken together, our findings suggest that HYOU1 promotes glycolysis and malignant progression in PTC cells via upregulating LDHB expression, providing a potential target for developing novel anticancer agents.


Assuntos
Regulação Neoplásica da Expressão Gênica , Glicólise , Proteínas de Choque Térmico HSP70/metabolismo , Lactato Desidrogenases/metabolismo , Estabilidade de RNA , RNA Mensageiro/química , Neoplasias da Glândula Tireoide/patologia , Apoptose , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Movimento Celular , Proliferação de Células , Proteínas de Choque Térmico HSP70/genética , Humanos , Lactato Desidrogenases/genética , Invasividade Neoplásica , RNA Mensageiro/genética , RNA Mensageiro/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 , Células Tumorais Cultivadas
4.
Cell Death Dis ; 11(9): 813, 2020 09 29.
Artigo em Inglês | MEDLINE | ID: mdl-32994394

RESUMO

Papillary thyroid cancer (PTC) is the most common endocrine tumor with an increasing incidence, has a strong propensity for neck lymph node metastasis. Limited treatment options are available for patients with advanced or recurrent metastatic disease, resulting in a poor prognosis. Tripartite motif protein 29 (TRIM29) is dysregulated in various cancer and functions as oncogene or tumor suppressor in discrete cancers. In this study, we found that both TRIM29 and fibronectin 1 (FN1) were upregulated with positive correlation in PTC tissues. Neither overexpression nor downregulation of TRIM29 altered the proliferation of PTC cells significantly. Overexpression of TRIM29 significantly promotes, while knockdown of TRIM29 significantly decreases migration and invasion by regulating FN1 expression in PTC cells. In terms of mechanism, we found that TRIM29 altered the stability of FN1 mRNA via regulation of miR-873-5p expression. The current study also demonstrated that long non-coding RNA (LncRNA) CYTOR suppressed maturation of miR-873-5p via interaction with premiR-873, and TRIM29 decreased miR-873-5p via upregulation of CYTOR. This study suggests that involvement of TRIM29 in migration and invasion in PTC cells may reveal potential metastatic mechanism of PTC and represent a novel therapeutic target and strategy.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Fibronectinas/metabolismo , MicroRNAs/metabolismo , RNA Longo não Codificante/metabolismo , Câncer Papilífero da Tireoide/metabolismo , Neoplasias da Glândula Tireoide/metabolismo , Fatores de Transcrição/metabolismo , Proteínas de Ligação a DNA/genética , Fibronectinas/genética , Humanos , MicroRNAs/genética , Invasividade Neoplásica , Biogênese de Organelas , Prognóstico , RNA Longo não Codificante/genética , Câncer Papilífero da Tireoide/genética , Câncer Papilífero da Tireoide/patologia , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/patologia , Fatores de Transcrição/genética , Transfecção , Microambiente Tumoral , Regulação para Cima
5.
Biochim Biophys Acta Mol Cell Res ; 1867(9): 118715, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32275930

RESUMO

Papillary thyroid cancer (PTC), the most common thyroid malignancy, has a strong propensity for neck lymph node metastasis, which will increase the risk of local recurrence and decrease the survival in some high-risk groups. Hence, it is essential to set up a reliable biomarker to predict lymph node metastasis. BAG5 is a unique member of the BAG cochaperone family because it consists of more than one BAG domain, which acts as modulator of chaperone activity. In this study, we found that expression of BAG5 was significantly increased in PTC cells and tissues. Neither overexpression nor downregulation of BAG5 altered the proliferation of PTC cells. On the contrary, overexpression of BAG5 significantly promoted, while knockdown of BAG5 significantly decreased migration and invasion of PTC cells. Along with this, fibronectin 1 (FN1) was significantly increased and decreased in cells that overexpress or downregulate BAG5, respectively. Mechanistically, we found that BAG5 modulated FN1 expression at the translational level and promoted invasion via suppression of miR-144-3p, which targeted the 3' untranslational region (UTR) of FN1 transcript. This study suggests that BAG5 is an important regulator of migration and invasion in PTC cells and may represent a novel therapeutic target for intervening in PTC progression.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Fibronectinas/genética , Regulação Neoplásica da Expressão Gênica , Câncer Papilífero da Tireoide/genética , Câncer Papilífero da Tireoide/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Expressão Ectópica do Gene , Técnicas de Silenciamento de Genes , Genes Reporter , Humanos , MicroRNAs/genética , Invasividade Neoplásica/genética , Interferência de RNA , Câncer Papilífero da Tireoide/patologia , Transcrição Genética
6.
EBioMedicine ; 53: 102689, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32114396

RESUMO

BACKGROUND: How the oncoprotein epidermal growth factor receptor (EGFR) evades proteolytic degradation and accumulates in non-small cell lung cancer (NSCLC) remains unclear, and ubiquitin pathway genes (UPGs) that are critical to NSCLC needs to be systematically identified. METHODS: A total of 696 UPGs (including E1, E2, E3, and deubiquitinases) were silenced by small interfering RNA (siRNA) library in NSCLC cells, the candidates were verified, and their significance was evaluated in patients with NSCLC. The effects of a candidate gene on EGFR were investigated in vitro and in vivo. FINDINGS: We report 31 candidates that are required for cell proliferation, with the E2 ubiquitin conjugase CDC34 as the most significant one. CDC34 is elevated in tumor tissues in 76 of 114 (66.7%) NSCLCs and inversely associated with prognosis, is higher in smoker patients than nonsmoker patients, and is induced by tobacco carcinogens in normal human lung epithelial cells. Forced expression of CDC34 promotes, whereas knockdown of CDC34 inhibits, NSCLC cell proliferation in vitro and in vivo. CDC34 competes with c-Cbl to bind Y1045 to inhibit polyubiquitination and degradation of EGFR. In EGFR-L858R and EGFR-T790M/Del (exon 19)-driven lung tumor growth in mouse models, knockdown of CDC34 significantly inhibits tumor formation. INTERPRETATION: These results demonstrate that an E2 enzyme is capable of competing with E3 ligase to stabilize substrates, and CDC34 represents an attractive therapeutic target for NSCLCs. FUNDING: National Key Research and Development Program of China, National Natural Science Foundation of China, and the CAMS Innovation Fund for Medical Sciences.


Assuntos
Carcinogênese/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Receptores ErbB/metabolismo , Neoplasias Pulmonares/metabolismo , Enzimas de Conjugação de Ubiquitina/genética , Células Epiteliais Alveolares/efeitos dos fármacos , Células Epiteliais Alveolares/metabolismo , Animais , Carcinogênese/efeitos dos fármacos , Carcinógenos/toxicidade , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Proliferação de Células , Células HEK293 , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Camundongos , Camundongos SCID , Poluição por Fumaça de Tabaco/efeitos adversos , Transcriptoma , Enzimas de Conjugação de Ubiquitina/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo
7.
Cell Death Dis ; 10(4): 284, 2019 03 25.
Artigo em Inglês | MEDLINE | ID: mdl-30910998

RESUMO

Bcl-2 associated athanogene 3 (BAG3) is an important molecule that maintains oncogenic features of cancer cells via diverse mechanisms. One of the important functions assigned to BAG3 is implicated in selective macroautophagy/autophagy, which attracts much attention recently. However, the mechanism underlying regulation of autophagy by BAG3 has not been well defined. Here, we describe that BAG3 enhances autophagy via promotion of glutamine consumption and glutaminolysis. Glutaminolysis initiates with deamination of glutamine by glutaminase (GLS), by which yields glutamate and ammonia in mitochondria. The current study demonstrates that BAG3 stabilizes GLS via prohibition its interaction with SIRT5, thereby hindering its desuccinylation at Lys158 and Lys164 sites. As an underlying molecular mechanism, we demonstrate that BAG3 interacts with GLS and decreases SIRT5 expression. The current study also demonstrates that occupation by succinyl at Lys158 and Lys164 sites prohibits its Lys48-linked ubiquitination, thereby preventing its subsequent proteasomal degradation. Collectively, the current study demonstrates that BAG3 enhances autophagy via stabilizing GLS and promoting glutaminolysis. For the first time, this study reports that succinylation competes with ubiquitination to regulate proteasomal GLS degradation.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Reguladoras de Apoptose/metabolismo , Autofagia/genética , Estabilidade Enzimática/genética , Glutaminase/metabolismo , Glutamina/metabolismo , Neoplasias/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Amônia/metabolismo , Proteínas Reguladoras de Apoptose/genética , Glutaminase/genética , Células Hep G2 , Humanos , Células MCF-7 , Mitocôndrias/metabolismo , Neoplasias/patologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteólise , Sirtuínas/metabolismo , Transfecção , Ubiquitinação
8.
Cancer Lett ; 434: 132-143, 2018 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-30031117

RESUMO

To systematically unveil transcription factors (TFs) that are critical to lung carcinogenesis, here we conducted a genome-wide lethality screening in non-small cell lung cancer (NSCLC) cells and reported that among the 1530 TFs tested, 21 genes were required for NSCLC cell proliferation and were negatively or positively associated with overall survival (OS) of patients with NSCLC. These included 11 potential tumor suppressing genes (AFF3, AhR, AR, CBFA2T3, CHD4, KANK2, NR3C2, PTEN, PRDM16, RB1, and STK11) and 10 potential oncogenic TFs (BARX1, DLX6, ELF3, EN1, ETV1, FOXE1, HOXB7, IRX4, IRX5, and SALL1). The expression levels of IRX5 were positively associated with OS of smoker and inversely associated with OS of non-smoker patients with lung adenocarcinoma. We showed that tobacco carcinogen benzo(a)pyrene (BaP) induced upregulation of IRX5 in lung epithelial cells, and Cyclin D1 was a downstream target of IRX5. Furthermore, silencing of IRX5 by lentivirus mediated transfection of short hairpin RNA significantly inhibited tumor growth in nude mice. These results indicate that tobacco smoke can modulate TFs to facilitate lung carcinogenesis, and inhibition of IRX5 may have therapeutic potentials in NSCLCs.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Regulação Neoplásica da Expressão Gênica , Estudo de Associação Genômica Ampla/métodos , Neoplasias Pulmonares/genética , Fatores de Transcrição/genética , Células A549 , Animais , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/terapia , Linhagem Celular , Linhagem Celular Tumoral , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/terapia , Camundongos Endogâmicos NOD , Camundongos SCID , Interferência de RNA , Terapêutica com RNAi/métodos , Fatores de Transcrição/metabolismo , Carga Tumoral/genética , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
9.
Huan Jing Ke Xue ; 36(11): 4189-94, 2015 Nov.
Artigo em Chinês | MEDLINE | ID: mdl-26911008

RESUMO

The effect of HCO3- on nitrogen removal efficiency in partial nitritation-ANAMMOX process was studied by using the combined process of partial nitritation and ANAMMOX has been started and achieved the stable operation of nitrogen removal. The results showed that, when the ratio of C/N decreased from 2 to 0.17 in influent, the nitrogen removal rate decreased from 1.3 kg- ( M3 x d)(-1) to 0.40 kg x (M3 x d)(-1), the decrease range arrived at 69.3%. The nitrogen conversion efficiency was limited, because of the added amount of HCO3- was decreased, which leading to the pH value declined sharply in nitritation and ANAMMOX zone. In the partial nitritation-ANAMMOX process, the effect of HCO3- limitation on activity of ammonium oxidizing bacteria, ANAMMOX bacteria and nitrifying bacteria was decreased in turn. When the C/N ratio increased to 1, the nitrogen removal rate of combined process was quickly restored to 1 kg x (m3 x d)(-1). It indicated that short HCO3- limitation on nitrogen conversion efficiency of the combined process can be fast recovery. The resulted also showed that the relationship between influent C/N ratio and nitrogen removal efficiency has obvious relativity in partial nitritation-ANAMMOX process.


Assuntos
Bactérias , Bicarbonatos/química , Desnitrificação , Nitrogênio/química , Compostos de Amônio
10.
Huan Jing Ke Xue ; 35(12): 4636-41, 2014 Dec.
Artigo em Chinês | MEDLINE | ID: mdl-25826935

RESUMO

The upflow reactor with gas-lift device was started up by inoculating ANAMMOX sludge granules of less than 0.9 mm. The effects of gas lift device system on the morphology and performance of ANAMMOX sludge were studied by using the nitrogen gas produced in ANAMMOX to drive the effluent circulation in the reactor. The results showed that, the airlift circulation function was not clear in the startup stage of the reactor, because the nitrogen gas production was very low. At the same time, the ANAMMOX granular sludge was easy to condensate. When the load rate of nitrogen removal reached 3.4 kg x (m3 x d)(-1), the function of gas lift was significant, resulting in gradually increased effluent self-circulation, and the granules were dispersed and grew gradually. After 183d of operation, the granular sludge was dominated by the granules with sizes of 1.6-2.5 mm, which accounted for 53.2% of the total sludge volume. The MLVSS content increased with the increase of sludge particle size. The gas lift device had the same function as the external reflux pump, and was helpful for sludge granulation in the ANAMMOX reactor, while reducing power consumption and the cost of the equipment.


Assuntos
Reatores Biológicos , Esgotos/química , Eliminação de Resíduos Líquidos/instrumentação , Nitrogênio/química
11.
Space Med Med Eng (Beijing) ; 15(5): 362-5, 2002 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-12449144

RESUMO

Objective. To find out the reason of "dithering" of exhalation valve plate in pressure oxygen mask under high overpressure condition. Method. Dynamic model of the exhalation valve plate in pressure oxygen mask was established. Aerodynamic force on the plate was determined by flowfield computing. The dynamic characteristic of the exhalation valve plate was analyzed by experimental measurement [correction of measurment] integrated with numerical simulation. Result. The movement of valve plate could be simulated with the method proposed, and the course of the"dithering" was found out. Conclusion. The "dithering" of the valve plate can be averted by cutting down the area of the film or increasing the diameter of the valve pedestal moderately.


Assuntos
Pressão Atmosférica , Máscaras , Oxigênio/administração & dosagem , Aviação/instrumentação , Desenho de Equipamento , Humanos , Modelos Teóricos , Voo Espacial/instrumentação
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