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1.
Medicine (Baltimore) ; 98(36): e16705, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31490362

RESUMO

Deregulation of miR-153 has recently been observed in several common human cancer, while miR-153 serves an oncogene or tumor suppressive role in different cancer types. Previously, miR-153 has been identified to be overexpressed in prostate cancer. miR-153 played an important role in promoting proliferation of human prostate cancer cells and presented a novel mechanism of microRNA-mediated direct suppression of phosphatase and tensin homolog (PTEN) expression in prostate cancer cells. Until now, little is known about the clinical significance of miR-153 expression in prostate cancer.The miR-153 expression in 143 pairs of prostate cancer and adjacent non-cancerous prostate tissues was measured by quantitative reverse transcription polymerase chain reaction (qRT-PCR) analysis. Student t test was conducted for intergroup comparison. Pearson correlation test was used for correlation analysis. Survival curves were carried out by the Kaplan-Meier method and evaluated using the log-rank test. Multivariable Cox proportional hazard risk regression model was performed to screen the independent factor affected the prognosis of prostate cancer patients.qRT-PCR analysis showed that the expression of miR-153 was significantly increased in the prostate cancer tissues in comparison with the adjacent noncancerous prostate tissues (P < .001). The high expression of miR-153 in prostate cancer tissues is closely correlated with aggressive clinical pathological parameters such as lymph node metastasis (P = .001); bone metastasis (P < .001); Gleason score (P < .001); and tumor-node-metastasis (TNM) stage (P < .001). Prostate cancer patients with a high expression of miR-153 had an evidently lower 5-year overall survival as compared with those with a low expression of miR-153 (P = .019). Notably, the multivariate Cox regression analysis indicated that miR-153 expression was an independent factor for predicting the 5-year overall survival of prostate cancer patients (hazard ratio [HR] = 2.481, 95% confidence interval [CI]: 1.582-10.727; P = .018).Our study demonstrated that high miR-153 expression was significantly associated with a poor overall survival independently of other factors in prostate cancer. Therefore, miR-153 may be an available biomarker for prostate cancer prognosis.


Assuntos
MicroRNAs/biossíntese , Neoplasias da Próstata/mortalidade , Neoplasias da Próstata/patologia , Idoso , Biomarcadores Tumorais , Intervalo Livre de Doença , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Metástase Neoplásica , Prognóstico , Reação em Cadeia da Polimerase Via Transcriptase Reversa
2.
Medicine (Baltimore) ; 98(32): e16470, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31393351

RESUMO

We aimed to investigate the correlation of long noncoding RNA nuclear enriched abundant transcript 1 (lnc-NEAT1), microRNA-124 (miR-124) and lnc-NEAT1/miR-124 axis with disease risk, severity, inflammatory cytokines, and survival of sepsis.Eighty-two patients with sepsis and 82 healthy controls (HCs) were consecutively enrolled. Blood samples were collected for detection of lnc-NEAT1 and miR-124 expressions (using RT-qPCR) and measurement of inflammatory cytokines expressions (by ELISA). Severity and organ failure were assessed by acute physiology and chronic health evaluation II (APACHE II) score and sequential organ failure assessment (SOFA) score, and survival was assessed.Lnc-NEAT1 expression was increased while miR-124 expression was decreased in patients with sepsis compared to HCs, and both of them were able to distinguish patients with sepsis from HCs. For disease condition, lnc-NEAT1 positively associated with APACHE II score, SOFA score, and expressions of C-reactive protein (CRP), procalcitonin, tumor necrosis factor α (TNF-α), and interleukin-1ß (IL-1ß), whereas miR-124 negatively correlated with APACHE II score, SOFA score and levels of serum creatinine (Scr), CRP, TNF-α, IL-1ß, interleukin-6 (IL-6) and interleukin-17 (IL-17). Regarding prognosis, lnc-NEAT1 was upregulated but miR-124 was downregulated in nonsurvivors compared to survivors. Additionally, lnc-NEAT1 negatively correlated with miR-124. Besides, lnc-NEAT1/miR-124 axis was increased in patients with sepsis compared to HCs, and positively associated with APACHE II score, SOFA score, and levels of Scr, CRP, TNF-α, IL-1ß, IL-6, and IL-17, while negatively correlated with survival. Most importantly, lnc-NEAT1/miR-124 axis presented numerically increased predictive value for sepsis risk and survival compared to each index alone.Lnc-NEAT1/miR-124 axis correlates with increased sepsis risk, and associates with higher inflammation, deteriorative disease condition, and decreased survival in patients with sepsis.


Assuntos
Mediadores da Inflamação/metabolismo , RNA Longo não Codificante/biossíntese , Sepse/mortalidade , Sepse/fisiopatologia , APACHE , Adulto , Idoso , Deterioração Clínica , Citocinas/metabolismo , Feminino , Humanos , Masculino , MicroRNAs/biossíntese , Pessoa de Meia-Idade , Escores de Disfunção Orgânica , Índice de Gravidade de Doença
3.
Gene ; 715: 144029, 2019 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-31376409

RESUMO

Intervertebral disc degeneration (IDD) is a major cause of lower back pain, but the specific molecular mechanisms governing its development are poorly characterized. This study sought to assess to what extent HOTAIR, a long non-coding (Lnc) RNA is expressed in IDD and regulates the apoptotic death of nucleus pulposus (NP) cells. We therefore used real-time qPCR to measure HOTAIR and microRNA(miR)-34a-5p in degenerative NP cells, and then validated their functional relevance via overexpressing them in these NP cells. We further verified the targets of these RNA constructs in 293 T cells through the use of a dual luciferase reporter assay. We further measured NP cell apoptosis via flow cytometry and Notch1 expression via western blotting. Our results indicated that IDD was linked with decreased HOTAIR expression relative to regular NP cells, and overexpressing this lncRNA was linked to reduced apoptotic NP cell death, whereas overexpressing miR-34a-5p had the opposite effect. We found that HOTAIR served as a miR-34a-5p sponge, sequestering this miRNA and thereby down regulating genes linked to apoptosis through the Notch signaling pathway. Even in naturally degenerated NP cells, HOTAIR delayed the onset of apoptosis. Together these results reveal that a HOTAIR/miR-34a-5p/Notch1 signaling pathway may regulate the development of IDD, potentially making HOTAIR a viable target for treatment of this disease.


Assuntos
Apoptose , Regulação para Baixo , Degeneração do Disco Intervertebral/metabolismo , MicroRNAs/biossíntese , RNA Longo não Codificante/biossíntese , Receptor Notch1/biossíntese , Transdução de Sinais , Adulto , Idoso , Feminino , Humanos , Degeneração do Disco Intervertebral/genética , Degeneração do Disco Intervertebral/patologia , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , Núcleo Pulposo/patologia , RNA Longo não Codificante/genética , Receptor Notch1/genética
4.
Life Sci ; 232: 116619, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31265855

RESUMO

AIMS: Clinical treatment strategies for patients with myocardial ischemia typically include coronary artery recanalization to restore myocardial blood supply. However, myocardial reperfusion insult often induces oxidative stress and inflammation, which further leads to apoptosis and necrosis of myocardial cells. Increasing evidence suggests that microRNAs (miRNAs) participate in the pathological and physiological processes associated with myocardial ischemia reperfusion. MAIN METHODS: In this study, we established a myocardial H/R H9C2 cell model and a mouse I/R model to detect molecules implicated in myocardial I/R regulation and to determine the underlying signal transduction pathways. KEY FINDINGS: Herein, we showed that the expression of miR-374a-5p decreased in a myocardial cell model (H9C2 cells) of hypoxia/reoxygenation (H/R) and mouse model of ischemia/reperfusion (I/R). Alternatively, overexpression of miR-374a-5p was found to ameliorate myocardial cell damage within both in vivo and in vitro models of ischemia. Further, mitogen-activated protein kinase 6 (MAPK6) was identified as a direct target of miR-374a-5p. Thus, by targeting MAPK6, miR-374a-5p was found to negatively regulate MAPK6 expression. However, up-regulation of MAPK6 functioned to inhibit the previously observed protective effect of miR-374a-5p in the H9C2 H/R model. SIGNIFICANCE: Taken together, our study suggests that miR-374a-5p may have protective effects against cardiac I/R injury in vivo, and H/R injury in vitro, thereby providing novel insights into the molecular mechanisms associated with ischemia/reperfusion injury and a potential novel therapeutic target.


Assuntos
MicroRNAs/biossíntese , Traumatismo por Reperfusão/metabolismo , Animais , Apoptose/efeitos dos fármacos , Hipóxia Celular/fisiologia , Hipóxia/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Proteína Quinase 6 Ativada por Mitógeno/genética , Proteína Quinase 6 Ativada por Mitógeno/metabolismo , Isquemia Miocárdica/genética , Isquemia Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/genética , Traumatismo por Reperfusão Miocárdica/metabolismo , Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Estresse Oxidativo/fisiologia , Ratos , Traumatismo por Reperfusão/genética , Transdução de Sinais
5.
Cell Physiol Biochem ; 53(1): 258-280, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31313541

RESUMO

BACKGROUND/AIMS: Although neuroblastoma is a heterogeneous cancer, a substantial portion overexpresses CD71 (transferrin receptor 1) and MYCN. This study provides a mechanistically driven rationale for a combination therapy targeting neuroblastomas that doubly overexpress or have amplified CD71 and MYCN. For this subset, CD71 was targeted by its natural ligand, gambogic acid (GA), and MYCN was targeted with an HDAC inhibitor, vorinostat. A combination of GA and vorinostat was then tested for efficacy in cancer and non-cancer cells. METHODS: Microarray analysis of cohorts of neuroblastoma patients indicated a subset of neuroblastomas overexpressing both CD71 and MYCN. The viability with proliferation changes were measured by MTT and colony formation assays in neuroblastoma cells. Transfection with CD71 or MYCN along with quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting were used to detect expression changes. For pathway analysis, gene ontology (GO) and Protein-protein interaction analyses were performed to evaluate the potential mechanisms of GA and vorinostat in treated cells. RESULTS: For both GA and vorinostat, their pathways were explored for specificity and dependence on their targets for efficacy. For GA-treated cells, the viability/proliferation loss due to GA was dependent on the expression of CD71 and involved activation of caspase-3 and degradation of EGFR. It relied on the JNK-IRE1-mTORC1 pathway. The drug vorinostat also reduced cell viability/proliferation in the treated cells and this was dependent on the presence of MYCN as MYCN siRNA transfection led to a blunting of vorinostat efficacy and conversely, MYCN overexpression improved the vorinostat potency in those cells. Vorinostat inhibition of MYCN led to an increase of the pro-apoptotic miR183 levels and this, in turn, reduced the viability/proliferation of these cells. The combination treatment with GA and vorinostat synergistically reduced cell survival in the MYCN and CD71 overexpressing tumor cells. The same treatment had no effect or minimal effect on HEK293 and HEF cells used as models of non-cancer cells. CONCLUSION: A combination therapy with GA and vorinostat may be suitable for MYCN and CD71 overexpressing neuroblastomas.


Assuntos
Antígenos CD , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Sistemas de Liberação de Medicamentos , Proteína Proto-Oncogênica N-Myc , Neuroblastoma , Receptores da Transferrina , Antígenos CD/genética , Antígenos CD/metabolismo , Caspase 3/genética , Caspase 3/metabolismo , Células HEK293 , Humanos , MicroRNAs/biossíntese , MicroRNAs/genética , Proteína Proto-Oncogênica N-Myc/antagonistas & inibidores , Proteína Proto-Oncogênica N-Myc/genética , Proteína Proto-Oncogênica N-Myc/metabolismo , Neuroblastoma/tratamento farmacológico , Neuroblastoma/genética , Neuroblastoma/metabolismo , Neuroblastoma/patologia , RNA Neoplásico/biossíntese , RNA Neoplásico/genética , Receptores da Transferrina/antagonistas & inibidores , Receptores da Transferrina/genética , Receptores da Transferrina/metabolismo , Vorinostat/farmacologia , Xantonas/farmacologia
6.
Gene ; 715: 144012, 2019 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-31357021

RESUMO

Long noncoding RNAs (lncRNAs) have been shown to play an important role in tumor biogenesis and prognosis. The glioma is a grade classified cancer, however, we still lack the knowledge on their function during glioma progression. While previous studies have shown how lncRNAs regulate protein-coding gene epigenetically, it is still unclear how lncRNAs are regulated epigenetically. In this study, we firstly analyzed the RNA-seq data systematically across grades II, IV, and IV of glioma samples. We identified 60 lncRNAs that are significantly differentially expressed over disease progression (DElncRNA), including well-known PVT1, HOTAIR, H19 and rarely studied CARD8-AS, MIR4435-2HG. Secondly, by integrating HM450K methylation microarray data, we demonstrated that some of the lncRNAs are epigenetically regulated by methylation. Thirdly, we developed a DESeq2-GSEA-ceRNA-survival analysis strategy to investigate their functions. Particularly, MIR4435-2HG is highly expressed in high-grade glioma and may have an impact on EMT and TNFα signaling pathway by functioning as a miRNA sponge of miR-125a-5p and miR-125b-5p to increase the expression of CD44. Our results revealed the dynamic expression of lncRNAs in glioma progression and their epigenetic regulation mechanism.


Assuntos
Metilação de DNA , DNA de Neoplasias , Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Glioma , MicroRNAs , RNA Longo não Codificante , RNA Neoplásico , DNA de Neoplasias/genética , DNA de Neoplasias/metabolismo , Perfilação da Expressão Gênica , Glioma/genética , Glioma/metabolismo , Glioma/patologia , Humanos , MicroRNAs/biossíntese , MicroRNAs/genética , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , RNA Longo não Codificante/biossíntese , RNA Longo não Codificante/genética , RNA Neoplásico/biossíntese , RNA Neoplásico/genética
7.
Artigo em Chinês | MEDLINE | ID: mdl-31315361

RESUMO

Objective: To compare the carcinogenic abilities of CD133(+)CD44(+) laryngeal cancer stem cells and general laryngeal cancer stem cells and to identify the mechanism underlying the action of miRNAs. Methods: Solid tumor-derived laryngeal carcinoma stem cells and Hep-2-derived laryngeal carcinoma stem cells were cultured, and CD133(+)CD44(+) laryngeal cancer stem cells were sorted by flow cytometry. Boden chamber invasion assay, cell migration assay and tumor formation assay were then performed to compare the invasion, migration and tumorigenic abilities of CD133(+)CD44(+) laryngeal cancer stem cells and general laryngeal cancer stem cells. And then, miRNAs isolated from two laryngeal cancer stem cells were detected and analysed with miRNA chip. Results: (1)In Boyden chamber invasion assay, the cell invasion rate of CD133(+)CD44(+) laryngeal cancer stem cells was obviously higher (80.2%±2.3% vs. 63.9%±3.2%, t=5.011, P=0.027); (2)CD133(+)CD44(+) laryngeal cancer stem cells also had higher mobility in cell migration assay (82.9%±1.1% vs. 70.9%±0.6%, t=4.514, P=0.031); (3)In tumor formation assay, the tumor formation rate of CD133(+)CD44(+) laryngeal cancer stem cells was also higher (80% vs. 50%). What's more, we identified 15 miRNAs that were significantly upregulated in CD133(+)CD44(+) laryngeal cancer stem cells and 3 miRNAs that were significantly downregulated in CD133(+)CD44(+) laryngeal cancer stem cells, compared with normal laryngeal cancer stem cells. Conclusions: CD133(+)CD44(+) laryngeal cancer stem cells have stronger invasion, migration and tumorigenic abilities compared with normal laryngeal cancer stem cells, and the difference of miRNAs' expression is one of the possible causes.


Assuntos
Neoplasias Laríngeas/fisiopatologia , MicroRNAs/biossíntese , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Antígeno AC133/biossíntese , Carcinogênese/metabolismo , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Humanos , Receptores de Hialuronatos/biossíntese , Neoplasias Laríngeas/metabolismo , Neoplasias Laríngeas/patologia , Laringe/metabolismo , Laringe/patologia , Laringe/fisiopatologia , Invasividade Neoplásica/fisiopatologia , Processos Neoplásicos
8.
Artigo em Chinês | MEDLINE | ID: mdl-31315362

RESUMO

Objective: To investigate the diagnostic value of serum miRNAlet-7a in laryngeal carcinoma and the effect of let-7a on proliferation and apoptosis of laryngeal carcinoma cells. Methods: Real-time quantitative PCR was used to determine the expression level of serum miRNAlet-7a. The miRNA let-7a mimetic was synthesized and transiently transfected into the laryngeal carcinoma Hep-2 cell line by cationic liposome method. The effects of up-regulation of let-7a expression on laryngeal cancer Hep-2 cells were detected by FCM and MTT assays,respectively. The association of let-7a levels with laryngeal cancer and the diagnostic value for laryngeal cancer were analyzed. Measurement data were taken by t test or analysis of variance; Counting data were analyzed by χ(2) test and Fisher exact probability method. The receiver operating characteristic curve was used to analyze the diagnostic value of let-7a for laryngeal cancer. Results: The relative expression of serum let-7a in healthy subjects was significantly higher than that in patients with laryngeal cancer (0.931±0.094) vs (0.380±0.113) (t=26.507,P<0.01). The relative expressions of serum let-7a in patients with laryngeal cancer before and after surgery were (0.380±0.113) vs(0.493±0.164),with significant difference (t=3.848,P<0.01).The relative expression of serum let-7a was related to lymph node metastasis (t=2.946, P<0.01). There was a positive correlation between the relative expression of let-7a in laryngeal carcinoma and that in serum (r=0.466,P=0.003). After transfection of let-7a mimics, Hep-2 cells showed an increased significant increase in the expression of let-7a (P<0.01), proliferation (P<0.01) and apoptosis (P<0.01). ROC curve analysis showed that the best critical value for relative expression of let-7a in the diagnosis of laryngeal carcinoma was 0.557 with a sensitivity of 0.794,a specificity of 0.727,an area under curve(AUC) of 0.859,and a 95%CI of 0.773-0.926. Conclusions: miRNA let-7a can inhibit the proliferation of laryngeal carcinoma Hep-2 cells and promote apoptosis. Serum let-7a is down-regulated in patients with laryngeal cancer and the level of let-7a is related to lymph node metastasis,which would help early diagnosis and postoperative disease monitoring of laryngeal cancer,but further research is needed.


Assuntos
Neoplasias Laríngeas/diagnóstico , MicroRNAs/sangue , Apoptose/fisiologia , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Regulação Neoplásica da Expressão Gênica/fisiologia , Humanos , Neoplasias Laríngeas/sangue , Neoplasias Laríngeas/metabolismo , Neoplasias Laríngeas/cirurgia , Metástase Linfática/fisiopatologia , MicroRNAs/biossíntese
9.
Int J Oncol ; 55(1): 267-276, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31180557

RESUMO

We previously reported that cystatin B (CSTB) is a progression marker of human ovarian cancer (OC); however, the regulatory mechanism of CSTB and its function in OC remain unclear. The present study aimed to explore the mechanism underlying transforming growth factor-ß (TGF­ß) 1­mediated CSTB regulation, and to examine the function of CSTB on OC cell proliferation and apoptosis. Using the online program, miRWalk, a microRNA (miR)­143­3p was detected, which contains a homologous sequence of the potential binding site to the 3'­untranslated region (3'­UTR) of CSTB. A dual­luciferase reporter assay confirmed the interaction between miR­143­3p and CSTB 3'­UTR. Treating OC cells with miR­143­3p mimics or inhibitors resulted in a decrease or an increase of CSTB expression at mRNA and protein levels, respectively. Additionally, CSTB was significantly overexpressed, whereas miR­143­3p was downregulated in human OC tissues compared with normal ovarian tissues. A negative correlation between miR­143­3p and CSTB mRNA expression was observed in ovarian malignant tumors. The levels of primary and mature miR­143­3p expression were upregulated in OC cells after TGF­ß1 treatment; the action of TGF­ß1 was abolished in the presence of an inhibitor of TGF­ß type I receptor. These results indicated an axis between TGF­ß, miR­143­3p and CSTB in OC cells. Furthermore, high levels of CSTB expression were associated with the poor overall survival of patients with OC. Knockdown of CSTB resulted in a decrease in OC cell proliferation and arrested cells in G2/M phase. In addition, suppression of CSTB induced cell apoptosis. In conclusion, CSTB was overexpressed and miR­143­3p was downregulated in ovarian malignant tumors. Mature miR­143­3p directly bound CSTB 3'­UTR, leading to a decrease in CSTB expression in OC cells, which was regulated by TGF­ß1. Our findings suggest the potential therapeutic application of targeting the TGF­ß/miR­143­3p/CSTB axis for treating patients with OC.


Assuntos
Carcinoma Epitelial do Ovário/metabolismo , Cistatina B/metabolismo , MicroRNAs/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Regiões 3' não Traduzidas , Adulto , Idoso , Idoso de 80 Anos ou mais , Apoptose/fisiologia , Carcinoma Epitelial do Ovário/genética , Carcinoma Epitelial do Ovário/patologia , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Cistatina B/biossíntese , Cistatina B/genética , Feminino , Técnicas de Silenciamento de Genes , Humanos , MicroRNAs/biossíntese , MicroRNAs/genética , Pessoa de Meia-Idade , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transdução de Sinais , Fator de Crescimento Transformador beta1/genética , Regulação para Cima , Adulto Jovem
10.
Life Sci ; 232: 116596, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31233760

RESUMO

AIMS: The aim of the study was to identify key miRNAs related to hepatocellular carcinoma (HCC) and then to explore their potential function and clinical significance. MATERIALS AND METHODS: The miRNA expression profiles of 387 HCC and 62 normal liver tissues were obtained from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases. GEO2R tool and edgeR package in R/Bioconductor were used to screen out HCC-related miRNAs. VennDiagram package was used to identify key miRNAs related to HCC. The miRWalk tool and multiple R packages, such as pROC and survival, were used to explore potential function and clinical significance of these key miRNAs. KEY FINDINGS: A total of 17 and 300 HCC-related human miRNAs were identified in GEO dataset and TCGA, respectively. Thereinto seven miRNAs including hsa-miR-199a-3p, hsa-miR-199b-3p, hsa-miR-139-5p, hsa-miR-139-3p, hsa-miR-424-3p, hsa-miR-1269b and hsa-miR-1269a were key miRNAs related to HCC. Functional enrichment analysis showed that these key miRNAs were involved in multiple biological processes, such as telomere maintenance via telomerase, protein sumoylation, histone mRNA metabolic process and angiotensin maturation. Cox regression analysis indicated that hsa-miR-139-5p expression was associated with the prognosis of HCC patients. ROC curve analysis suggested that survival prediction model developed based on tumor stage and hsa-miR-139-5p exhibited good performance in predicting 3-year overall survival of HCC patients. SIGNIFICANCE: The present study identified several HCC-related miRNAs, which might serve as new diagnostic markers and therapeutic targets for HCC. In addition, hsa-miR-139-5p might act as a promising prognostic indicator for HCC patients.


Assuntos
Carcinoma Hepatocelular/genética , MicroRNAs/biossíntese , MicroRNAs/genética , Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/metabolismo , Bases de Dados Genéticas , Feminino , Perfilação da Expressão Gênica , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Masculino , Prognóstico , Curva ROC , Transcriptoma/genética
11.
Mol Cell Biochem ; 458(1-2): 11-26, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31165315

RESUMO

Dysregulation of microRNAs (miRNAs) has been found to disrupt the progression of oral cancer. However, which miRNAs are most effective against oral cancer and how these miRNAs should be delivered are major unanswered problems. We aimed at investigating if human bone marrow mesenchymal stem cells (hBMSCs)-derived exosomes affect oral cancer development, and the potential regulatory mechanism associated with COL10A1 and miR-101-3p. COL10A1 was upregulated, while miR-101-3p was downregulated in oral cancer, and miR-101-3p targeted COL10A1 as verified by dual-luciferase reporter gene assay. Meanwhile, exosomes derived from hBMSCs were isolated and then co-cultured with oral cancer cells to identify the role of exosomes, and the results suggested that hBMSCs-derived exosomes overexpressing miR-101-3p inhibited oral cancer progression. Furthermore, tumorigenicity assay in nude mice further confirmed the inhibitory effects of hBMSCs-derived exosomes, loaded with miR-101-3p, on oral cancer, which provides a new theoretical basis in the treatment of oral cancer.


Assuntos
Células da Medula Óssea/metabolismo , Movimento Celular , Proliferação de Células , Exossomos/transplante , Células-Tronco Mesenquimais/metabolismo , MicroRNAs/biossíntese , Neoplasias Bucais/terapia , Idoso , Animais , Exossomos/metabolismo , Feminino , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Neoplasias Bucais/metabolismo , Neoplasias Bucais/patologia , Invasividade Neoplásica , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Medicine (Baltimore) ; 98(25): e16050, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31232941

RESUMO

BACKGROUND: miR-222 is one of the most consistently overexpressed miRNAs in papillary thyroid carcinoma (PTC). Previous studies demonstrated that miR-222 overexpression conferred high-risk features in PTC patients, suggesting its value in risk-stratification. However, studies in term of miR-222's utility on stratifying PTCs are lacking. METHODS: One hundred patients including 10 with multinodular goiter and 90 with PTC were enrolled. Formalin-fixed paraffin-embedded samples were exploited for miR-222 quantitative reverse transcriptase- polymerase chain reaction (RT-PCR) analysis. Correlations between miR-222 expression and different clinicopathological features, Tumor-node-metastasis (TNM) staging and ATA risk level were analyzed. RESULTS: miR-222 expression of the PTC group was significantly higher than that of the goiter group (P < .001). Furthermore, miR-222 expression was significantly higher in PTCs with advanced features like larger tumor, capsular invasion, vascular invasion and lymph nodes metastasis. The majority of patients (61%) were in stage I group (similar to ATA low-risk) by TNM staging system. As to the ATA system, the majority (73%) were in intermediate-risk group (similar to TNM stage II and III roughly). Contrary to previous report, here we found that miR-222 expression was correlated with the ATA risk level (P < .001), but not with the TNM staging (P = .122). CONCLUSION: In the present study, we demonstrated that miR-222 overexpression was correlated with advanced features like capsular invasion, vascular invasion, larger tumor size and lymph node metastasis in PTCs. Most importantly, miR-222 expression was correlated with ATA risk levels, suggesting its potential value in PTC risk-stratification.


Assuntos
MicroRNAs/análise , Medição de Risco/métodos , Câncer Papilífero da Tireoide/classificação , Adolescente , Adulto , Idoso , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/biossíntese , Biomarcadores Tumorais/sangue , China , Feminino , Humanos , Masculino , Oncologia/organização & administração , MicroRNAs/biossíntese , MicroRNAs/sangue , Pessoa de Meia-Idade , Prognóstico , Câncer Papilífero da Tireoide/sangue
13.
Spine (Phila Pa 1976) ; 44(12): E707-E714, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-31150368

RESUMO

STUDY DESIGN: The effect of triptolide on spinal cord injury (SCI) and inflammatory response was observed by establishing SCI rat model. And in vitro experiments were conducted to determine the underlying mechanism of triptolide-mediated in murine microglial cell line BV2. OBJECTIVE: To determine the underlying mechanism of triptolide in suppressing the microglia activation to improve SCI. SUMMARY OF BACKGROUND DATA: Triptolide, as a major active ingredient of Chinese herb Tripterygium wilfordii, can promote spinal cord repair through inhibiting microglia activation, but the underlying mechanism is not clear. METHODS: Locomotion recovery was accessed by Basso, Beattie, and Bresnahan score, the number of footfalls, stride length, and angle of rotation analysis. Expressions of microRNA 96 (miR-96), microglia activation marker Iba-1, and IκB kinase (IKKß)/nuclear factor (NF)-κB-related proteins were detected by qRT-PCR or western blot. Inflammatory cytokines tumor necrosis factor-α and interleukin -1ß were measured by enzyme-linked immuno sorbent assay. The regulation of miR-96 on IKKß was confirmed by dual luciferase reporter assay. RESULTS: Triptolide promoted locomotion recovery of SCI rats, upregulated the expression of miR-96, decreased microglia activation marker Iba-1 and IKKß/NF-κB-related proteins, and inhibited inflammatory cytokines tumor necrosis factor-α and interleukin-1ß levels in spinal cord tissues and lipopolysaccharide -induced microglia. Triptolide suppressed the microglia activation and inflammatory cytokines secretion in BV2 cells through up-regulating miR-96. We confirmed the interaction between miR-96 and IKKß, and IKKß expression was negatively regulated by miR-96. Finally, we determined that triptolide suppressed the microglia activation and inflammatory cytokines secretion through miR-96/IKKß pathway. CONCLUSION: Triptolide suppressed microglia activation after SCI through miR-96/IKKß/NF-κB pathway. LEVEL OF EVIDENCE: N/A.


Assuntos
Diterpenos/uso terapêutico , Quinase I-kappa B/biossíntese , MicroRNAs/biossíntese , Microglia/metabolismo , NF-kappa B/biossíntese , Fenantrenos/uso terapêutico , Traumatismos da Medula Espinal/metabolismo , Animais , Diterpenos/farmacologia , Compostos de Epóxi/farmacologia , Compostos de Epóxi/uso terapêutico , Quinase I-kappa B/antagonistas & inibidores , Imunossupressores/farmacologia , Imunossupressores/uso terapêutico , Lipopolissacarídeos/toxicidade , Locomoção/efeitos dos fármacos , Locomoção/fisiologia , Masculino , Camundongos , Microglia/efeitos dos fármacos , NF-kappa B/antagonistas & inibidores , Fenantrenos/farmacologia , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Traumatismos da Medula Espinal/tratamento farmacológico
14.
Ann Hematol ; 98(9): 2045-2052, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31243572

RESUMO

Thalassemia has a high prevalence in Thailand. Oxidative damage to erythroid cells is known to be one of the major etiologies in thalassemia pathophysiology. Oxidative stress status of thalassemia is potentiated by the heme, nonheme iron, and free iron resulting from imbalanced globin synthesis. In addition, levels of antioxidant proteins are reduced in α-thalassemia and ß-thalassemia erythrocytes. However, the primary molecular mechanism for this phenotype remains unknown. Our study showed a high expression of miR-144 in ß- and α-thalassemia. An increased miR-144 expression leads to decreased expression of nuclear factor erythroid 2-related factor 2 (NRF2) target, especially in α-thalassemia. In α-thalassemia, miR-144 and NRF2 target are associated with glutathione level and anemia severity. To study the effect of miR-144 expression, the gain-loss of miR-144 expression was performed by miR inhibitor and mimic transfection in the erythroblastic cell line. This study reveals that miR-144 expression was upregulated, whereas NRF2 expression and glutathione levels were decreased in comparison with the untreated condition after miR mimic transfection, while the reduction of miR-144 expression contributed to the increased NRF2 expression and glutathione level compared with the untreated condition after miR inhibitor transfection. Moreover, miR-144 overexpression leads to significantly increased sensitivity to oxidative stress at indicated concentrations of hydrogen peroxide (H2O2) and rescued by miR-144 inhibitor. Taken together, our findings suggest that dysregulation of miR-144 may play a role in the reduced ability of erythrocyte to deal with oxidative stress and increased RBC hemolysis susceptibility especially in thalassemia.


Assuntos
Eritrócitos/metabolismo , MicroRNAs/biossíntese , Fator 2 Relacionado a NF-E2/biossíntese , Estresse Oxidativo , Regulação para Cima , Talassemia alfa/metabolismo , Talassemia beta/metabolismo , Eritrócitos/patologia , Feminino , Glutationa/biossíntese , Glutationa/genética , Hemólise , Humanos , Peróxido de Hidrogênio/metabolismo , Células K562 , Masculino , MicroRNAs/genética , Fator 2 Relacionado a NF-E2/genética , Talassemia alfa/genética , Talassemia alfa/patologia , Talassemia beta/genética , Talassemia beta/patologia
15.
Gen Physiol Biophys ; 38(4): 295-304, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31241046

RESUMO

Glioma is a serious malignant tumor without effective therapies till now. lncRNA PEG10 was reported to have some biological activities in cancers. Hence, we explored the effects of PEG10 on the human glioma cell line U251 cells. U251 cells were transfected with sh-PEG10 and/or miR-506 inhibitor. The expression of PEG10 and miR-506 was measured by qRT-PCR. Cell viability, cell apoptosis, cell migration and invasion were detected by CCK-8 assay, flow cytometry and Transwell chamber assay, respectively. The cell proliferation and apoptosis related p16, p53, Bcl-2, Bax, and pro-/Cleaved-Caspase-3/9, migration and invasion related-protein: matrix metalloproteinases MMP-2, MMP-9 and vimentin, and Raf/MEK/ERK and JAK1/STAT3 pathways-related proteins were accessed by Western blot. Transfection with sh-PEG10 inhibited cell viability, migration and invasion, and increased cell apoptosis. Meanwhile, PEG10 silence upregulated the expression of p16 and p53, Bax, cleaved-Caspase-3/9 expression, and downregulated Bcl-2 expression. PEG10 silence upregulated miR-506 expression. Co-transfection with sh-PEG10 and miR-506 inhibitor impaired the tumor suppressive effects. PEG10 knockdown decreased the phosphorylation of Raf/MEK/ERK and JAK1/STAT3-related proteins Raf, MEK, ERK, JAK1 and STAT3. PEG10 knockdown inhibited cell viability, migration and invasion, induced cell apoptosis through miR-506 upregulation, as well as inactivation of Raf/MEK/ERK and JAK1/STAT3 signal pathways.


Assuntos
Movimento Celular/genética , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Glioma/patologia , MicroRNAs/genética , Invasividade Neoplásica/genética , Proteínas/genética , RNA Longo não Codificante/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Glioma/genética , Humanos , MicroRNAs/biossíntese
16.
Hematology ; 24(1): 487-491, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31210592

RESUMO

OBJECTIVES: Acute myeloid leukemia (AML) is a heterogeneous and highly recurrent hematological malignancy. Studies have shown an association between microRNAs and drive genes in AMLs. However, the regulatory roles of miRNAs in AML and how they act on downstream targets and the signaling pathway has been little studied. METHODS: As to understand the mechanism of mRNA-miRNA interaction in the blood malignancy from a large scale of transcriptomic sequencing studies, we applied a comprehensive miRNA-mRNA association, co-expression gene network and ingenuity pathway analysis using TCGA AML datasets. RESULTS: Our results showed that his-mir-335 was a critical regulatory of homeobox A gene family. PBX3, KAT6A, MEIS1, and COMMD3-BMI1 were predicted as top transcription regulators in the regulatory network of the HOXA family. The most significantly enriched functions were cell growth, proliferation, and survival in the mRNA-miRNA network. CONCLUSION: Our work revealed that regulation of the HOXA gene family and its regulation played an important role in the development of AML.


Assuntos
Perfilação da Expressão Gênica , Regulação Leucêmica da Expressão Gênica , Redes Reguladoras de Genes , Leucemia Mieloide Aguda , MicroRNAs , RNA Mensageiro , RNA Neoplásico , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , MicroRNAs/biossíntese , MicroRNAs/genética , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , RNA Neoplásico/biossíntese , RNA Neoplásico/genética
17.
Invest Ophthalmol Vis Sci ; 60(6): 2064-2071, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-31081880

RESUMO

Purpose: To investigate the roles and pathways of microRNAs 143 and 145 in transforming growth factor (TGF)-ß1-induced human subconjunctival fibrosis. Methods: Human tenon's capsule fibroblasts (HTFs) were obtained from a healthy eye. After treating cultured HTFs with TGF-ß1, the expression of microRNAs 143 and 145 was evaluated using polymerase chain reaction. To identify the pathways of TGF-ß1-induced microRNA 143/145 expression, HTFs were treated with specific inhibitors of p38MAPK, PI3K/Akt, JNK, ERK, and with siRNAs for SMAD2 and SMAD4. Mutagenesis studies were performed to evaluate the role of the CArG box and SMAD-binding element (SBE). To investigate the role of microRNA 143/145 in TGF-ß1-induced myofibroblast transdifferentiation, microRNA 143/145 mimics and microRNA 143/145 inhibitors were applied to the HTFs. Results: Array analysis revealed that TGF-ß1 induced the expression of microRNA 143/145 in a dose- and time-dependent manner. When inhibitors and siRNAs for p38MAPK, PI3K/Akt, ERK, and JNK were applied, the TGF-ß1-induced expression of microRNA 143/145 was inhibited; however, SMAD2 and SMAD4 inhibition did not affect the TGF-ß1-induced expression of these microRNAs. In the mutagenesis studies, both the CArG box and SBE were associated with TGF-ß1-induced expression of microRNA 143/145. Mimics of microRNA 143/145 induced increased myofibroblast formation, whereas their inhibitors had the opposite effect. Conclusions: TGF-ß1-induced human subconjunctival fibrosis was mediated by the expression of microRNA 143/145, mainly via SMAD-independent pathways. Inhibition of TGF-ß1-induced microRNA 143/145 expression in HTFs might represent a novel strategy to prevent subconjunctival fibrosis.


Assuntos
Doenças da Túnica Conjuntiva/genética , Regulação da Expressão Gênica , MicroRNAs/genética , RNA/genética , Fator de Crescimento Transformador beta1/efeitos adversos , Western Blotting , Transdiferenciação Celular , Células Cultivadas , Doenças da Túnica Conjuntiva/metabolismo , Doenças da Túnica Conjuntiva/patologia , Fibroblastos/metabolismo , Fibroblastos/patologia , Fibrose/genética , Fibrose/metabolismo , Fibrose/patologia , Humanos , MicroRNAs/biossíntese , Reação em Cadeia da Polimerase em Tempo Real
18.
Transplant Proc ; 51(4): 1157-1161, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31101191

RESUMO

Liver transplantation (LT) is the best treatment option for hepatitis B virus (HBV)-mediated hepatocellular carcinoma (HCC). Nevertheless, recurrence is the most important issue after LT. The aims of the present study were to evaluate the relation of dysregulated expression of microRNAs (miRNAs) in recurrence formation in HBV-mediated HCC cases. A total of 42 HBV-mediated HCC patients were evaluated in this study. Among 21 miRNAs, the expression level of miR-106a and miR-21 were higher and miR-143 and miR145 were lower in patients with HCC compared with noncancerous liver tissues (P = .0388, P = .0214, P = .0321, and P = .002, respectively). Compared with nonrecurrent patients, the expression level of miR-21 was 3.54-fold higher and miR-145 was 2.42-fold lower in patients with recurrence during the 5-year follow-up (P = .004 and P = .032; respectively). In addition, according to multivariate Cox regression analysis, the overexpression of miR-21 was found to be a prognostic indicator in HBV-mediated HCC patients (P = .002). In conclusion, we show a significant association between high expression of miR-21 and recurrence in HBV-mediated HCC. Therefore, up-regulation of miR-21 could serve as a promising prognostic marker for HCC.


Assuntos
Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Transplante de Fígado , MicroRNAs/biossíntese , Recidiva Local de Neoplasia/genética , Adulto , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/cirurgia , Feminino , Hepatite B/complicações , Vírus da Hepatite B/genética , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/cirurgia , Masculino , Pessoa de Meia-Idade , Prognóstico
19.
Zhonghua Zhong Liu Za Zhi ; 41(5): 331-337, 2019 May 23.
Artigo em Chinês | MEDLINE | ID: mdl-31137165

RESUMO

Objective: To investigate the differential expression profiles of circular RNA (circRNA) in human epidermal growth factor receptor 2 (HER-2) positive breast cancer cells and normal mammary epithelial cells, and to develop novel diagnostic and therapeutic markers for HER-2 positive breast cancer. Methods: Total RNA were extracted from HER-2 positive breast cancer cell SK-BR-3 and normal mammary epithelial cell MCF10A. RNA quality was detected using NanoDrop ND-1000. Rnase R was applied to remove linear RNA and enrich circRNAs. After amplification and reverse transcription into fluorescent complementary RNA (cRNA) using random primer, the labeled cRNAs were hybridized onto the Arraystar Human circRNA Arrays. The raw data were extracted and the acquired array images were subjected to quantile normalization followed by heat map and volcano plot analysis. The expression of circRNAs with large fold change was verified by real-time quantitative polymerase chain reaction (RT-qPCR). Finally, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed in the differentially expressed circRNAs and circRNA-microRNA (miRNA) network was constructed. Results: The total RNA extracted from SK-BR-3 and MCF10A had high integrity and quality. The expression profiles of circRNA in SK-BR-3 and MCF10A cells were significantly different shown by fluorescent expression signals. Compared with MCF10A cells, there were 6 584 up-regulated circRNAs and 6254 down-regulated circRNAs in SK-BR-3 cells. There were 348 circRNAs with |log(2)FC|≥2, of which 153 were up-regulated and 195 were down-regulated. Moreover, 8 circRNAs with |log(2)FC|>5. Among them, 5 were up-regulated in SK-BR-3 cells, including hsa_circRNA_074595 (|log(2)FC|=7.84), hsa_circRNA_074598 (|log(2)FC|=6.50), hsa_circRNA_085362 (|log(2)FC|=5.86), hsa_circRNA_101379 (|log(2)FC|=5.71) and hsa_circRNA_406683 (|log(2)FC|=5.34); as well as 3 were down-regulated, including hsa_circRNA_021714 (|log(2)FC|=5.46), hsa_circRNA_100777 (|log(2)FC|=5.40), and hsa_circRNA_100796 (|log(2)FC|=5.03). The expression levels of hsa_circRNA_074595, hsa_circRNA_074598 and hsa_circRNA_100777 were further validated by RT-qPCR in consistent with the results of microarray. GO analysis showed that differentially expressed circRNAs were significantly enriched in the biological process of heart development (P<0.001), cellular component in the cell adhesion-related components (P<0.001), molecular function in protein serine/threonine kinase activity (P<0.001). KEGG analysis revealed that differentially expressed circRNAs were significantly enriched in the PI3K-Akt signaling pathway. Conclusions: The expression profile of circRNA in HER-2 positive breast cancer cells is significantly different from that in normal mammary epithelial cells. The differentially expressed circRNAs may be served as potential diagnostic or therapeutic targets for HER-2 positive breast cancer.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Mama/metabolismo , Células Epiteliais/metabolismo , RNA não Traduzido/biossíntese , Receptor ErbB-2/metabolismo , Mama/citologia , Células Epiteliais/citologia , Feminino , Perfilação da Expressão Gênica , Humanos , MicroRNAs/biossíntese , MicroRNAs/genética , RNA não Traduzido/genética , Receptor ErbB-2/genética
20.
Artigo em Inglês | MEDLINE | ID: mdl-31071453

RESUMO

An 8 week experiment was conducted to evaluate the effects of dietary fat on growth and on the accumulation of lipids and the expression of lipid metabolism-related microRNAs (miRNAs) and genes in grass carp (Ctenopharyngodon idella). Two diets (normal fat diet (NFD), 60 g/kg lipid content; high fat diet (HFD), 160 g/kg lipid content) were fed to triplicate groups of 35 fish [initial weight of (40.0 ±â€¯0.5) g]. The results showed that increased dietary fat did not lead to significant differences in the feed conversion rate (FCR) and specific growth rate (SGR) (P > .05), but the HFD significantly increased the hepatosomatic index (HSI) (P < .05). The serum high density lipoprotein-cholesterol (HDLC) level was significantly increased in the HFD group (P < .05). Oil Red O staining showed that both the size and amounts of lipid droplets in the liver of fish fed a diet with 2 g/kg lipid content increased significantly. In the liver of fish fed with 160 g/kg dietary fat, the expression of mir-33a, mir-30, mir-122 and mir-16 significantly decreased (P < .05). In contrast, the expression of sterol regulatory element-binding transcription factor 1 (SREBP1), peroxisome proliferator-activated receptor gamma (PPARγ), liver X receptor alpha (LXRα) and ATP-binding cassette transporter A1 (ABCA1) significantly increased (P < .05). In conclusion, 2 g/kg dietary fat did not influence growth but altered the expression of miRNAs and genes related to lipid metabolism in the liver of grass carp, which caused severe lipid deposition.


Assuntos
Carpas/metabolismo , Gorduras na Dieta/farmacologia , Proteínas de Peixes/biossíntese , Regulação da Expressão Gênica/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/metabolismo , MicroRNAs/biossíntese , Animais
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