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1.
Int J Cancer ; 146(6): 1754-1763, 2020 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-31456215

RESUMO

To explore whether plasma circular RNAs (circRNAs) can diagnose hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), microarray and qPCR were used to identify plasma circRNAs that were increased in HBV-related HCC patients compared to controls (including healthy controls, chronic hepatitis B and HBV-related liver cirrhosis). A logistic regression model was constructed using a training set (n = 313) and then validated using another two independent sets (n = 306 and 526, respectively). Area under the receiver operating characteristic curve (AUC) was used to evaluate diagnostic accuracy. We identified a plasma circRNA panel (CircPanel) containing three circRNAs (hsa_circ_0000976, hsa_circ_0007750 and hsa_circ_0139897) that could detect HCC. CircPanel showed a higher accuracy than AFP (alpha-fetoprotein) to distinguish individuals with HCC from controls in all three sets (AUC, 0.863 [95% confidence interval, CI: 0.819-0.907] vs. 0.790 [0.738-0.842], p = 0.036 in training set; 0.843 [0.796-0.890] vs. 0.747 [0.691-0.804], p = 0.011 in validation set 1 and 0.864 [0.830-0.898] vs. 0.769 [0.728-0.810], p < 0.001 in validation set 2). CircPanel also performed well in detecting Small-HCC (solitary, ≤3 cm), AFP-negative HCC and AFP-negative Small-HCC.


Assuntos
Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/etiologia , Vírus da Hepatite B , Hepatite B/complicações , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/etiologia , /sangue , Biomarcadores Tumorais , Feminino , Perfilação da Expressão Gênica , Hepatite B/virologia , Humanos , Masculino , Reação em Cadeia da Polimerase , Curva ROC , Reprodutibilidade dos Testes
2.
Mol Carcinog ; 58(10): 1897-1907, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31313392

RESUMO

The mechanism of hepatocellular carcinoma (HCC) metastasis remains poorly understood. Tropomodulin 3 (TMOD3) is a member of the pointed end capping protein family that contributes to invasion and metastasis in several types of malignancies. It has been found to be crucial for the membranous skeleton and embryonic development, although, its role in HCC progression remains largely unclear. We observed increased levels of Tmod3 in HCCs, especially in extrahepatic metastasis. High Tmod3 expression correlated with aggressive carcinoma and poor patient with HCC survival. Loss-of-function studies conducted by us determined Tmod3 as an oncogene that promoted HCC growth and metastasis. Mechanistically, Tmod3 increases transcription of matrix metalloproteinase-2, -7, and -9 which required PI3K-AKT. Interaction between Tmod3 and epidermal growth factor receptor (EGFR) that supports the activation of EGFR phosphorylation, is essential for signaling activation of PI3K-AKT viral oncogene homolog. These findings reveal that Tmod3 enhances aggressive behavior of HCC both in vitro and in vivo by interacting with EFGR and by activating the PI3K-AKT signaling pathway.


Assuntos
Carcinoma Hepatocelular/genética , Proliferação de Células/genética , Neoplasias Hepáticas/genética , Tropomodulina/genética , Animais , Carcinoma Hepatocelular/patologia , Progressão da Doença , Intervalo Livre de Doença , Transição Epitelial-Mesenquimal/genética , Receptores ErbB/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Xenoenxertos , Humanos , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Pessoa de Meia-Idade , Metástase Neoplásica , Proteína Oncogênica v-akt/genética , Fosfatidilinositol 3-Quinases/genética , Transdução de Sinais/genética
3.
Oncol Lett ; 17(2): 2317-2327, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30675297

RESUMO

MicroRNAs (miRNAs) serve an important regulatory role in carcinogenesis and cancer progression. Aberrant expression of miR-197-3p has been reported in various human malignancies. However, the role of miR-197-3p in the progression and prognosis of hepatocellular carcinoma (HCC) remains unknown. The present study demonstrated that miR-197-3p was downregulated in HCC tissues and that the low level of miR-197-3p expression in HCC tumours correlated with aggressive clinicopathological characteristics; thus, miR-197-3p may serve as a predictor for poor prognosis in patients with HCC. Additionally, miR-197-3p markedly inhibited the metastasis of HCC cells in vitro and in vivo. Bioinformatics analysis further identified zinc finger protein interacted with K protein 1 (ZIK1) as a novel target of miR-197-3p in HCC cells. These findings suggest that miR-197-3p may regulate the survival of HCC cells, partially through the downregulation of ZIK1. Therefore, the miR-197-3p/ZIK1 axis may serve as a novel therapeutic target in patients with HCC.

4.
Oncol Rep ; 41(1): 257-269, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30542726

RESUMO

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide, and current treatments exhibit limited efficacy against advanced HCC. The majority of cancer-related deaths are caused by metastasis from the primary tumor, which indicates the importance of identifying clinical biomarkers for predicting metastasis and indicating prognosis. Patient-derived cells (PDCs) may be effective models for biomarker identification. In the present study, a wound healing assay was used to obtain 10 fast-migrated and 10 slow-migrated PDC cultures from 36 HCC samples. MicroRNA (miRNA) signatures in PDCs and PDC-derived exosomes were profiled by microRNA-sequencing. Differentially expressed miRNAs between the low- and fast-migrated groups were identified and further validated in 372 HCC profiles from The Cancer Genome Atlas (TCGA). Six exosomal miRNAs were identified to be differentially expressed between the two groups. In the fast-migrated group, five miRNAs (miR-140-3p, miR-30d-5p, miR-29b-3p, miR-130b-3p and miR-330-5p) were downregulated, and one miRNA (miR-296-3p) was upregulated compared with the slow-migrated group. Pathway analysis demonstrated that the target genes of the differentially expressed miRNAs were significantly enriched in the 'focal adhesion' pathway, which is consistent with the roles of these miRNAs in tumor metastasis. Three miRNAs, miR-30d, miR-140 and miR-29b, were significantly associated with patient survival. These findings indicated that these exosomal miRNAs may be candidate biomarkers for predicting HCC cell migration and prognosis and may guide the treatment of advanced HCC.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/genética , Exossomos/metabolismo , Neoplasias Hepáticas/genética , MicroRNAs/metabolismo , Adulto , Idoso , Carcinoma Hepatocelular/patologia , Movimento Celular/genética , Células Cultivadas , Regulação para Baixo , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Fígado/citologia , Fígado/patologia , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Cultura Primária de Células , Prognóstico , Análise de Sobrevida
5.
Sci Rep ; 8(1): 10461, 2018 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-29992971

RESUMO

Recent studies have shown that miR-494-3p is oncogene and has a central role in many solid tumors; however, the role of miR-494-3p in the progression and prognosis of hepatocellular carcinoma (HCC) remains unknown. In this study, it was found that miR-494-3p was up-regulated in HCC tissues. The high level of miR-494-3p in HCC tumors was correlated with aggressive clinicopathological characteristics and predicted poor prognosis in HCC patients. Functional study demonstrated that miR-494-3p significantly promoted HCC cell metastasis in vitro and vivo. Since phosphoinositide 3-kinase/protein kinase-B (PI3K/AKT) signaling is a basic oncogenic driver in HCC, a potential role of miR-494-3p was explored as well as its target genes in PI3K/AKT activation. Of all the predicted target genes of miR-494-3p, the tumor-suppressor phosphatase and tensin homolog (PTEN) were identified. In conclusion, the data we collected could define an original mechanism of PI3K/AKT hyperactivation and sketch the regulatory role of miR-494-3p in suppressing the expression of PTEN. Therefore, targeting miR-494-3p could provide an effective therapeutic method for the treatment of the disease.


Assuntos
Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , MicroRNAs/fisiologia , PTEN Fosfo-Hidrolase/antagonistas & inibidores , Biomarcadores Tumorais , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/mortalidade , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , MicroRNAs/análise , Pessoa de Meia-Idade , Metástase Neoplásica , Fosfatidilinositol 3-Quinases/metabolismo , Prognóstico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Análise de Sobrevida
6.
Ann Surg ; 268(6): 943-954, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-29521740

RESUMO

BACKGROUND: Despite antiviral treatment has been shown to reduce hepatocellular carcinoma (HCC) recurrence after curative treatment for hepatitis B virus (HBV)-related HCC in patients with high preoperative HBV-DNA levels, it is still unclear whether antiviral therapy is useful in reducing recurrence in patients with low preoperative HBV-DNA levels. METHODS: In this randomized controlled trial, 200 patients who underwent curative resection for HCC with low baseline HBV-DNA levels were randomly assigned to receive preemptive antiviral therapy or not. The primary endpoints were recurrence-free survival. This study was censored on March 31, 2015 when all surviving patients had a minimum follow-up of 60 months. The analysis was done on an intention-to-treat basis. RESULTS: The baseline clinical, laboratory, and tumor characteristics of the 2 groups were comparable. The 1-, 3-, and 5-year recurrence-free survival rates for the antiviral group and the control group were 85.9%, 55.2%, and 52.0% and 80.6%, 40.9%, and 32.3%, respectively. The corresponding overall survival rates for the 2 groups were 94.0%, 75.7%, and 64.1% and 90.0%, 62.4%, and 43.7%, respectively. The recurrence-free survival and overall survival for the antiviral group were significantly better than the control group (P = 0.016, P = 0.004, respectively). After adjusting for confounding prognostic factors in a Cox model, the relative risks of recurrence and death for antiviral treatment were 0.601 [95% confidence interval (CI), 0.409-0.884; P = 0.010] and 0.509 (95% CI, 0.333-0.778; P = 0.002), respectively. Antiviral therapy was an independent protective factor of late tumor recurrence (hazard ratio [HR] = 0.316, 95% CI 0.157-0.637; P = 0.001) but not of early tumor recurrence (HR = 0.782, 95% CI, 0.493-1.240; P = 0.296). CONCLUSIONS: In patients with low preoperative HBV-DNA levels, antiviral therapy significantly reduced HCC recurrence after R0 hepatic resection.


Assuntos
Antivirais/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/virologia , DNA Viral/sangue , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/virologia , Recidiva Local de Neoplasia/prevenção & controle , Telbivudina/uso terapêutico , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/cirurgia , Feminino , Vírus da Hepatite B/genética , Humanos , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/cirurgia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Taxa de Sobrevida
7.
Sci Rep ; 6: 37070, 2016 11 30.
Artigo em Inglês | MEDLINE | ID: mdl-27901021

RESUMO

Transmembrane p24 trafficking protein 3(TMED3) is a metastatic suppressor in colon cancer, but its function in the progression of hepatocellular carcinoma (HCC) is unknown. Here, we report that TMED3 was up-regulated in HCC and portal vein tumor thrombus. TMED3 up-regulation in HCC was significantly correlated with aggressive characteristics and predicted poor prognosis in HCC patients. TMED3 overexpression in HCC cell lines promoted cell migration and invasion. In contrast, TMED3 knockdown suppressed HCC metastasis both in vitro and in vivo. Gene microarray analysis revealed decreased IL-11 expression in TMED3-knockdown cells. We propose that TMED3 promotes HCC metastasis through IL-11/STAT3 signaling. Taken together, these findings demonstrate that TMED3 promotes HCC metastasis and is a potential prognostic biomarker in HCC.


Assuntos
Carcinoma Hepatocelular/metabolismo , Interleucina-11/metabolismo , Neoplasias Hepáticas/metabolismo , Fator de Transcrição STAT3/metabolismo , Proteínas de Transporte Vesicular/metabolismo , Animais , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/secundário , Movimento Celular , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/secundário , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Metástase Neoplásica/fisiopatologia , Regulação para Cima , Proteínas de Transporte Vesicular/genética
8.
Surg Oncol ; 25(3): 171-7, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27566019

RESUMO

The caudal-type homeobox 1 (CDX1) transcription factor is a member of the caudal-related homeobox transcription factor gene family and has been reported to be down-regulated in a variety of cancers. However, the expression status and significance of CDX1 in hepatocellular carcinoma (HCC) is still controversial, and little is known about the role of CDX1 in HCC·In our previous study, we investigated the expression and clinical significance of CDX1 in HCC samples from 313 HCC patients. We found CDX1 was strikingly down-regulated in HCC samples. CDX1 expression was associated with poor differentiation (P = 0.002), and patients with low CDX1 expression had a significantly poorer prognosis. A subgroup analysis revealed a difference in prognosis between groups with low and high CDX1 expression among patients who had tumors <5 cm in size and who were alpha-fetoprotein (AFP) negative. Moreover, low expression was more frequently observed in the early recurrence group (within 2 years, P = 0.002). In addition, multivariate Cox regression analysis indicated that the CDX1 expression level, tumor size, presence of hepatitis B e antigen (HBeAg), vascular invasion, and presence of hepatitis B surface antigen (HBsAg) were independent risk factors for HCC recurrence, and the CDX1 expression level, tumor size, tumor number, and presence of HBsAg were independent predictor of overall survival of HCC patients. In conclusion, the downregulation of CDX1 is associated with poor prognosis; and it may serve as a novel predictor of the prognosis of HCC patients after curative resection.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/patologia , Hepatectomia/efeitos adversos , Proteínas de Homeodomínio/metabolismo , Neoplasias Hepáticas/patologia , Recidiva Local de Neoplasia/patologia , Complicações Pós-Operatórias , Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/cirurgia , Feminino , Seguimentos , Proteínas de Homeodomínio/genética , Humanos , Técnicas Imunoenzimáticas , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/cirurgia , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/cirurgia , Estadiamento de Neoplasias , Prognóstico , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Taxa de Sobrevida
9.
Chemosphere ; 132: 108-13, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25835270

RESUMO

The hormesis characterized by low-concentration stimulation and high-concentration inhibition has gained significant interest over the past decades. Some organic solvents and ionic liquids (ILs) have hormetic concentration responses (HCR) to bioluminescence such as firefly luciferase and Vibrio qinghaiensis sp.-Q67. In this study, we determine the effects of 1-alkyl-3-methylimidazolium chlorine ILs ([Cnmim]Cl, n=2, 4, 6, 8, 10 and 12) to firefly luciferase in order to verify the mechanism of hormesis. The luminescence inhibition toxicity tests show that the stimulation effects of [C8mim]Cl and [C10mim]Cl are obvious, [C6mim]Cl and [C12mim]Cl are minor, and [C2mim]Cl and [C4mim]Cl are rare. The enzyme kinetics show that [C8mim]Cl and [C10mim]Cl are the competitive inhibitors with ATP while [C2mim]Cl and [C4mim]Cl are the noncompetitive ones. Molecular dynamics simulation results reveal that imidazolium rings of [C8mim] and [C10mim] locate at the entrance of luciferin pocket which is adjacent to AMP pocket, while alkyl-chains insert into the bottom of the luciferin pocket. Combining the results from inhibition test, kinetics assay and molecular simulation, we can deduce that occupying AMP pocket by imidazolium ring is responsible for hormetic stimulation.


Assuntos
Monofosfato de Adenosina/metabolismo , Hormese/efeitos dos fármacos , Imidazóis/química , Imidazóis/toxicidade , Líquidos Iônicos/química , Líquidos Iônicos/toxicidade , Luciferases de Vaga-Lume/química , Transporte Biológico/efeitos dos fármacos , Cinética , Luciferases de Vaga-Lume/metabolismo , Luminescência , Conformação Molecular , Simulação de Dinâmica Molecular , Testes de Toxicidade
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