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1.
Gene ; 707: 44-52, 2019 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-30898716

RESUMO

Long non-coding RNAs (lncRNAs) have been wildly verified to modulate multiple tumorigenesis, especially nasopharyngeal carcinoma (NPC). In present study, we aims to investigate the role and mechanism of LINC00520 in the NPC carcinogenesis. Results indicated that LINC00520 was significantly increasing in NPC tissues and cells in comparison to their corresponding controls. Moreover, the aberrant overexpression of LINC00520 indicated the poor prognosis of NPC patients. Silence of LINC00520 was able to repress NPC cell growth in vitro while overexpression of LINC00520 inversed this process. Moreover, in vivo tumor xenografts were establishing using CNE-1/SUNE-1 cells to investigate the function of LINC00520 in NPC tumorigenesis. Rescue assay was conducting to further confirm that LINC00520 contributed to NPC progression by regulating miR-26b-3p/ubiquitin-specific protease 39 (USP39) signal pathway. Taken together, our study discovered the oncogenic role of LINC00520 in clinical specimens and cellular experiments, showing the potential LINC00520/miR-26b-3p/USP39 pathway. This results and findings provide a novel insight for NPC tumorigenesis.


Assuntos
MicroRNAs/genética , Carcinoma Nasofaríngeo/genética , Neoplasias Nasofaríngeas/genética , RNA Longo não Codificante/genética , Proteases Específicas de Ubiquitina/genética , Animais , Linhagem Celular Tumoral , Proliferação de Células , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Camundongos , Carcinoma Nasofaríngeo/metabolismo , Neoplasias Nasofaríngeas/metabolismo , Transplante de Neoplasias , Prognóstico , Proteases Específicas de Ubiquitina/metabolismo , Regulação para Cima
2.
Theranostics ; 8(19): 5200-5212, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30555541

RESUMO

Cisplatin resistance significantly affects the survival rate of patients with ovarian cancer. However, the main mechanism underlying cisplatin resistance in ovarian cancer remains unclear. Methods: Immunohistochemistry was used to determine the expression of OGT, OGA and O-GlcNAc in chemoresistant and chemosensitive ovarian cancer tissues. Functional analyses (in vitro and in vivo) were performed to confirm the role of OGT in cisplatin resistance. Autophagy-related proteins were tested by western blot. Transmission electron microscopy and mRFP-GFP-LC3 adenovirus reporter were used for autophagy flux analysis. Immunoprecipitation assay was utilized to detect protein-protein interactions. Results: We found that O-GlcNAc and O-GlcNAc transferase (OGT) levels were significantly lower in chemoresistant ovarian cancer tissues than in chemosensitive tissues, whereas O-GlcNAcase (OGA) levels did not differ. The down-regulation of OGT increased cisplatin resistance in ovarian cancer cells but had no effect on the efficacy of paclitaxel. The down-regulation of OGT improved tumor resistance to cisplatin in a mouse xenograft tumor model. OGT knockdown enhanced cisplatin-induced autophagy, which reduced apoptotic cell death induced by cisplatin, and promoted autolysosome formation. A reduction in O-GlcNAcylated SNAP-29 levels caused by the down-regulation of OGT promoted the formation of the SNARE complex and autophagic flux. Conclusion: Our findings suggest that down-regulation of OGT enhances cisplatin-induced autophagy via SNAP-29, resulting in cisplatin-resistant ovarian cancer. OGT may represent a novel target for overcoming cisplatin resistance in ovarian cancer.


Assuntos
Antineoplásicos/farmacologia , Autofagia , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos , N-Acetilglucosaminiltransferases/biossíntese , Neoplasias Ovarianas/patologia , Proteínas Qb-SNARE/metabolismo , Proteínas Qc-SNARE/metabolismo , Adenoviridae/genética , Animais , Antineoplásicos/administração & dosagem , Western Blotting , Cisplatino/administração & dosagem , Modelos Animais de Doenças , Regulação para Baixo , Feminino , Genes Reporter , Vetores Genéticos , Xenoenxertos , Humanos , Imuno-Histoquímica , Imunoprecipitação , Camundongos , Microscopia Eletrônica de Transmissão , Pessoa de Meia-Idade , Transplante de Neoplasias , Neoplasias Ovarianas/tratamento farmacológico , Coloração e Rotulagem , Resultado do Tratamento
3.
Stem Cells Dev ; 27(11): 771-782, 2018 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-29644939

RESUMO

Various microenvironments influence the multiple differentiation potential of mesenchymal stromal cells. For example, inflammatory microenvironment can suppress the myogenic differentiation capability of laryngeal mucosa mesenchymal stromal cells (LM-MSCs). The present study therefore sought to identify the underlying molecular mechanisms regulating these processes. We isolated a novel population of MSCs, LM-MSCs, from the laryngeal mucosa tissues. The cells were cultured in osteogenic, adipogenic, and myogenic differentiation media in the presence or absence of interleukin-1ß and tumor necrosis factor α (to simulate inflammatory microenvironment). The expression of active ß-catenin, p-GSK3ß, and GSK3ß were detected by western blot and real-time polymerase chain reaction. The myogenic differentiation of LM-MSCs in inflammatory microenvironment and the regulation by Dickkopf-1 (DKK1) were tested both in vivo and in vitro. Inflammatory microenvironment could suppress the osteogenesis, adipogenesis, and myogenesis of LM-MSCs. The Wnt/ß-catenin signaling pathway was activated during myogenesis in inflammatory microenvironment. The suppressed myogenic differentiation capability of LM-MSCs in inflammatory microenvironment was reversed by DKK1. By regulating the Wnt/ß-catenin signaling pathway, DKK1 can improve the myogenic differentiation of LM-MSCs in inflammatory microenvironment. Thus, the results of this study may help improve the efficacy of LM-MSCs injection therapy for vocal fold regeneration.


Assuntos
Diferenciação Celular/genética , Microambiente Celular/genética , Células-Tronco Mesenquimais/metabolismo , Desenvolvimento Muscular/genética , Via de Sinalização Wnt/genética , beta Catenina/genética , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Microambiente Celular/efeitos dos fármacos , Expressão Gênica/efeitos dos fármacos , Humanos , Inflamação/genética , Inflamação/metabolismo , Mediadores da Inflamação/administração & dosagem , Mediadores da Inflamação/farmacologia , Peptídeos e Proteínas de Sinalização Intercelular/administração & dosagem , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Interleucina-1beta/administração & dosagem , Interleucina-1beta/farmacologia , Mucosa Laríngea/citologia , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Desenvolvimento Muscular/efeitos dos fármacos , Fator de Necrose Tumoral alfa/administração & dosagem , Fator de Necrose Tumoral alfa/farmacologia , beta Catenina/metabolismo
4.
Tumour Biol ; 39(6): 1010428317710225, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28639905

RESUMO

PURPOSE: The aim of this study was to explore the associations of Kruppel-like factor 4 expression with sensitivity to radiation therapy in locally advanced cervical squamous cell carcinoma patients. METHODS: The records of 117 locally advanced cervical squamous cell carcinoma patients were retrospectively reviewed, and Kruppel-like factor 4 expression in cervical carcinoma tissues was examined by immunohistochemical staining. The associations of Kruppel-like factor 4 expression with clinicopathological parameters were analyzed. Survival time was analyzed using Kaplan-Meier analysis and a Cox regression model. RESULTS: Patients being resistant to radiation therapy were associated with advanced International Federation of Gynecology and Obstetrics stage, tumor diameter (>4 cm), and poor differentiation grade. The high Kruppel-like factor 4 expression level was significantly related to resistance to radiation therapy, including radiation therapy non-response, local recurrence, and distant metastasis. The high Kruppel-like factor 4 expression level was also significantly related to the advanced International Federation of Gynecology and Obstetrics stage and poor differentiation grade. Kaplan-Meier analysis indicates that locally advanced cervical squamous cell carcinoma patients with high Kruppel-like factor 4 expression showed worse progression-free survival and overall survival. Univariate and multivariate Cox regression model analyses suggest that the high Kruppel-like factor 4 expression was one of the high-risk factors associated with poor prognosis in locally advanced cervical squamous cell carcinoma patients after radiation therapy. CONCLUSION: Our results suggest that the high Kruppel-like factor 4 expression can be used as a novel biomarker to predict radiation therapy resistance and poor prognosis for locally advanced cervical squamous cell carcinoma.


Assuntos
Biomarcadores Tumorais/biossíntese , Carcinoma de Células Escamosas/genética , Fatores de Transcrição Kruppel-Like/biossíntese , Neoplasias do Colo do Útero/genética , Adulto , Idoso , Biomarcadores Tumorais/genética , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/radioterapia , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Fatores de Transcrição Kruppel-Like/genética , Metástase Linfática , Pessoa de Meia-Idade , Prognóstico , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/radioterapia
5.
J Mol Cell Cardiol ; 101: 11-24, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27838370

RESUMO

Cinnamaldehyde (CA), a major bioactive compound extracted from the essential oil of Cortex Cinnamomi, exhibits anti-inflammatory activity on endotoxemia. Accumulating evidence indicates reactive oxygen species (ROS) and autophagy play a vital role in the cardiac dysfunction during endotoxemia. The aim of this study was to unveil the mechanism of CA on ROS production and autophagy during endotoxemia. Male Sprague-Dawley rats were stimulated by LPS (20mg/kg i.v.) with or without treatment of CA. Cardiac function and histopathological staining were preformed 4h after LPS stimulation. The levels of TNF-α, IL-1ß and IL-6 were detected by ELISA. The expression of p-JNK, p-ERK, p-p38, TLR4, NOX4, NOX2, ATG5 and LC3 proteins were determined by Western blot. The results showed that CA inhibited cardiac dysfunction, inflammatory infiltration and the levels of TNF-α, IL-1ß and IL-6 in LPS stimulated rats by blocking the TLR4, NOX4, MAPK and autophagy signalings. In order to obtain further confirmation of the mechanism of CA on endotoxemia in vitro, a limited time-course study was firstly performed by Western blot. TLR4, NOX4 and LC3 were significantly increased after 4h LPS stimulation. CA reversed the intracellular ROS production and MAPK signaling activation induced by LPS. Electron microscopy, mRFP-GFP-LC3 transfection and western blot results revealed autophagic flux were attenuated after CA treatment. The siRNA and molecular docking results suggest that CA can suppress both TLR4 and NOX4 during endotoxemia. Our data revealed that CA ameliorated LPS-induced cardiac dysfunction by inhibiting ROS production and autophagy through TLR4-NOX4 pathway.


Assuntos
Acroleína/análogos & derivados , NADPH Oxidases/metabolismo , Transdução de Sinais/efeitos dos fármacos , Receptor 4 Toll-Like/metabolismo , Disfunção Ventricular/etiologia , Disfunção Ventricular/metabolismo , Acroleína/química , Acroleína/farmacologia , Animais , Autofagia/efeitos dos fármacos , Biomarcadores , Citocinas/biossíntese , Modelos Animais de Doenças , Ecocardiografia , Mediadores da Inflamação , Lipopolissacarídeos/efeitos adversos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Miócitos Cardíacos , NADPH Oxidase 4 , NADPH Oxidases/genética , Interferência de RNA , Ratos , Espécies Reativas de Oxigênio/metabolismo , Receptor 4 Toll-Like/genética , Disfunção Ventricular/diagnóstico , Disfunção Ventricular/tratamento farmacológico
6.
Biomol Ther (Seoul) ; 24(5): 536-42, 2016 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-27582557

RESUMO

Shuangdan oral liquid (SDO) containing radix Salviae miltiorrhizae (Chinese name Danshen) and cortex moutan (Chinese name Mudanpi) is a traditional Chinese medicine using for treating vascular diseases. Danshensu (DSS) is a main effective monomer composition derived from radix Salviae miltiorrhizae and paeonol (Pae) from cortex moutan. Although the two herbs are widely used in traditional Chinese medicine, the pharmacological functions of their active compositions were not reported. Therefore, the research of DSS and Pae in mechanisms and pharmacodynamics interaction can provide scientific evidence to support clinical application. The diabetic nephropathy (DN) rats which were induced by streptozotocin (STZ) were treated with SDO, DSS, Pae, and DSS+Pae for eight weeks. The positive effects on DN animal models were investigated by detection of physiological and biochemical indexes and oxidative stress markers, within five treatments: SDO, DSS, Pae, DSS+Pae and insulin group. Compared with the model group, the DSS+Pae group improved the renal function, blood lipid metabolism and blood viscosity, increased the vitality of T-SOD or T-AOC and decreased the level of MDA or NO after the treatment. The study was successfully showed that the DSS+Pae group could delay the process of DN, especially in the renal injury part of histopathology changes. Our results suggest that the co-administration of DSS and Pae significantly may play a protective role in DN rats through decreasing the oxidative stress and improving the blood lipid metabolism mechanisms.

7.
J Steroid Biochem Mol Biol ; 159: 19-25, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26923859

RESUMO

Endometrial cancer (EC) is one of the most common gynecological malignancies in the world. Associations between fasting glucose levels (greater than 5.6mmol/L) and the risk of cancer fatality have been reported. However, the underlying link between glucose metabolic disease and EC remains unclear. In the present study, we explored the influence of elevated glucose levels on the WNT/ß-catenin pathway in EC. Previous studies have suggested that elevated concentrations of glucose can drive the hexosamine biosynthesis pathway (HBP) flux, thereby enhancing the O-GlcNAc modification of proteins. Here, we cultured EC cell lines, AN3CA and HEC-1-B, with various concentrations of glucose. Results showed that when treated with high levels of glucose, both lines showed increased expression of ß-catenin and O-GlcNAcylation levels; however, these effects could be abolished by the HBP inhibitors, Azaserine and 6-Diazo-5-oxo-l-norleucine, and be restored by glucosamine. Moreover the AN3CA and HEC-1-B cells that were cultured with or without PUGNAc, an inhibitor of the O-GlcNAcase, showed that PUGNAc increased ß-catenin levels. The results suggest that elevated glucose levels increase ß-catenin expression via the activation of the HBP in EC cells. Subcellular fractionation experiments showed that AN3CA cells had a higher expression of intranuclear ß-catenin in high glucose medium. Furthermore, TOP/FOP-Flash and RT-PCR results showed that glucose-induced increased expression of ß-catenin triggered the transcription of target genes. In conclusion, elevated glucose levels, via HBP, increase the O-GlcNAcylation level, thereby inducing the over expression of ß-catenin and subsequent transcription of the target genes in EC cells.


Assuntos
Vias Biossintéticas , Neoplasias do Endométrio/metabolismo , Glucose/fisiologia , Hexosaminas/biossíntese , Via de Sinalização Wnt , Linhagem Celular Tumoral , Feminino , Glicosilação , Humanos , Processamento de Proteína Pós-Traducional , beta Catenina/metabolismo
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