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1.
Gene ; 716: 144031, 2019 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-31377314

RESUMO

Circular RNAs (circRNAs), a novel class of widespread and diverse endogenous RNAs, have been identified as critical regulators of various cancers, including hepatocellular carcinoma (HCC). However, the specific roles of circRNAs in HCC are largely unknown. In this study, we identified a novel circRNA, circ-IGF1R, in HCC tumour tissues and cell lines. Circ-IGF1R levels were found to be significantly upregulated in HCC tissues compared with levels in paired peritumoural tissues. The high expression levels of circ-IGF1R in HCC were associated with tumour size. Moreover, knocking down circ-IGF1R with siRNA significantly attenuated cell proliferation and induced cell apoptosis and cell cycle arrest in vitro. Further investigation revealed that PI3K/AKT signalling pathway activation was involved in the oncogenic functions of circ-IGF1R in HCC. Our study suggests that circ-IGF1R may be a potential target for the prevention and treatment of HCC.


Assuntos
Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , RNA/metabolismo , Apoptose , Carcinoma Hepatocelular/enzimologia , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Ciclo Celular , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Humanos , Neoplasias Hepáticas/enzimologia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Fosfatidilinositol 3-Quinase/antagonistas & inibidores , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Regulação para Cima
2.
Medicine (Baltimore) ; 98(26): e16084, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31261522

RESUMO

Heme oxygenase-1 (HO-1) is an important catalytic enzyme in heme degradation, which increases during stressful conditions. It plays a major role in antioxidative and antiapoptotic processes and is associated with tumor growth and metastasis.This study aimed to evaluate the degree of HO-1 expressions in hepatocellular carcinoma (HCC) surgical specimens and the correlation between HO-1 expression and patient prognosis. Formalin-fixed, paraffin-embedded HCC tissue samples (n = 96) were included in the analysis, and the expression of HO-1 was evaluated by immunohistochemical staining. We reviewed clinical features of patients and evaluated the prognostic role of HO-1 in patient survival and recurrence.Positive HO-1 expression was identified in 43 cases (44.8%) and was frequently found in patients with advanced histology (Edmondson-Steiner [E-S] grade 2, 3, 4), α-fetoprotein (AFP) level of more than 200 IU/mL, and the presence of microvascular and capsular invasion (P < .05). In the univariate analysis, the overall survival (OS) and disease-free survival (DFS) of patients with HO-1-positive HCC were not statistically different from those with HO-1-negative HCC. Moreover, HO-1 expression was not associated with patient survival and recurrence based on the multivariate analysis. In the subgroup analysis of patients without preoperative transarterial chemoembolization (TACE) (n = 61), HO-1 was not also associated with tumor recurrence (P = .681).The clinical implication of HO-1 activity is controversial in various malignancies. However, HO-1 expression did not seem to influence the prognosis of HCC patients.


Assuntos
Carcinoma Hepatocelular/enzimologia , Heme Oxigenase-1/metabolismo , Neoplasias Hepáticas/enzimologia , Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/terapia , Feminino , Expressão Gênica , Humanos , Imuno-Histoquímica , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/terapia , Masculino , Pessoa de Meia-Idade , Prognóstico , Recidiva , Estudos Retrospectivos , Análise de Sobrevida
3.
Cancer Treat Rev ; 77: 20-28, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31195212

RESUMO

Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer. Sorafenib, regorafenib, lenvatinib and cabozantinib are tyrosine kinase inhibitors (TKIs) that target, in part, vascular endothelial growth factor receptors, and are approved in various regions of the world for the treatment of advanced HCC. All these agents are associated with a range of adverse events (AEs) that can have a substantial impact on patients' health-related quality of life. Fatigue, diarrhoea, hand-foot skin reaction, nausea, vomiting, decreased appetite, hypertension and weight loss are among the most common AEs experienced with these four TKIs. In this review, we discuss strategies for the management of these AEs in patients with advanced HCC, with the aim of maximizing treatment benefits and minimizing the need for TKI treatment discontinuation. We also consider potential TKI-drug interactions and discuss the use of TKIs in patients with liver dysfunction or who have experienced tumour recurrence after liver transplantation. Use of appropriate AE management strategies and avoidance of contraindicated drugs should help patients with advanced HCC to achieve optimal outcomes with TKIs.


Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/terapia , Neoplasias Hepáticas/tratamento farmacológico , Inibidores de Proteínas Quinases/efeitos adversos , Carcinoma Hepatocelular/enzimologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/prevenção & controle , Humanos , Neoplasias Hepáticas/enzimologia , Inibidores de Proteínas Quinases/administração & dosagem
4.
Toxicol Lett ; 313: 108-119, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31251971

RESUMO

Polychlorinated biphenyls (PCBs) are classic persistent organic pollutants (POPs) and are associated with the progression of many cancers, including liver cancer. The present study investigated the effect of 2,3'4,4',5-pentachlorobiphenyl (PCB118) on hepatocellular carcinoma cell proliferation and its underlying mechanisms. The results indicated that PCB118 exposure promotes the proliferation and glycolysis of hepatocellular carcinoma SMMC-7721 cells. Moreover, PCB118 exposure increased the expression level of pyruvate kinase M2 (PKM2) and its nuclear translocation, whereas treatment with PKM2 shRNA suppressed the induction of cell proliferation and glycolysis by PCB118. PCB118 stimulated reactive oxygen species (ROS) production by activating nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. Treatment with the antioxidants N-acetyl-L-cysteine (NAC) and superoxide dismutase (SOD) prevented PCB118-induced effects on PKM2, cell proliferation and glycolysis. Furthermore, we found that PCB118 activated NADPH oxidase through the aryl hydrocarbon receptor (AhR) in SMMC-7721 cells. Consistently, treatment with AhR shRNA suppressed PCB118-induced effects on PKM2, cell proliferation and glycolysis. Overall, these results indicated that PCB118 promotes HCC cell proliferation via PKM2-dependent upregulation of glycolysis, which is mediated by AhR/NADPH oxidase-induced ROS production.


Assuntos
Carcinógenos Ambientais/toxicidade , Carcinoma Hepatocelular/enzimologia , Proteínas de Transporte/metabolismo , Proliferação de Células/efeitos dos fármacos , Glicólise/efeitos dos fármacos , Neoplasias Hepáticas/enzimologia , Proteínas de Membrana/metabolismo , Bifenilos Policlorados/toxicidade , Hormônios Tireóideos/metabolismo , Transporte Ativo do Núcleo Celular , Fatores de Transcrição Hélice-Alça-Hélice Básicos/agonistas , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Proteínas de Transporte/genética , Linhagem Celular Tumoral , Humanos , Neoplasias Hepáticas/patologia , Proteínas de Membrana/genética , NADPH Oxidases/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Receptores de Hidrocarboneto Arílico/agonistas , Receptores de Hidrocarboneto Arílico/genética , Receptores de Hidrocarboneto Arílico/metabolismo , Transdução de Sinais/efeitos dos fármacos , Hormônios Tireóideos/genética
5.
Cell Mol Biol (Noisy-le-grand) ; 65(4): 23-28, 2019 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-31078148

RESUMO

In recent years, most related studies have found that chronic hepatitis B virus infection is the main cause of hepatocellular carcinoma (HCC), but the specific pathogenesis is still unclear. To investigate the function of HDAC in hepatocellular carcinoma (HCC), this study used qRT-PCR to determine the expression levels of miR-376a and HDAC9 mNRA in HCC and para-cancerous tissues. The clinical significance of HDAC9 in HCC was assessed in a study cohort containing 37 patients with HCC using immunohistochemistry. The expression level of miR-376a in liver cancer tissues was significantly lower than that in para-cancerous tissues, while the expression level of HDAC9 mRNA in liver cancer tissue was significantly higher than that in para-cancerous tissues. The expression of HDAC9 occurred mainly in the nucleus. There was a significant correlation between tumor differentiation and HDAC9. Survival analysis showed that HCC patients with higher HDAC9 expression had poorer prognosis, and subsequent multivariate analysis showed that HDAC9 expression level was an independent predictor. There was a definite correlation between HDAC9 and the expressions of AFP and Ki67. These results suggest that the expression level of HDAC9 in HCC is abnormally high while the expression level of miR-376a is significantly decreased, indicating that HDAC9 may be a potential prognostic indicator of HCC.


Assuntos
Carcinoma Hepatocelular/enzimologia , Histona Desacetilases/metabolismo , Neoplasias Hepáticas/enzimologia , Proteínas Repressoras/metabolismo , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Histona Desacetilases/genética , Humanos , Antígeno Ki-67/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Masculino , MicroRNAs/genética , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Análise Multivariada , Prognóstico , Proteínas Repressoras/genética , Análise de Sobrevida , alfa-Fetoproteínas/metabolismo
6.
J Clin Pathol ; 72(9): 588-596, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31126975

RESUMO

AIMS: To investigate molecular alteration and expression of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) gene in hepatocellular carcinoma (HCC), and to evaluate the correlation between PTEN and cancer stem cell (CSC) markers and the prognostic value of these markers. METHODS: We evaluated changes of PTEN and CSC markers (CD133, epithelial cell adhesion molecule (EpCAM) and CK19) in 183 resection specimens by immunohistochemistry (IHC) and detected PTEN and phosphoinositide-3-kinase catalytic-alpha (PIK3CA) gene by fluorescence in situ hybridisation (FISH) in some specimens. RESULTS: PTEN and CD133, EpCAM and CK19 in 183 resection specimens were studied by IHC, and PTEN and PIK3CA genes were detected by FISH. PTEN expression was reduced in 92 HCC tissues (50.3%). There were 16 HCCs with PTEN deletion (51.6%). Comparison between PTEN IHC and FISH showed that the analysis was highly concordant (54/59, 91.5%). There were 19 HCCs with PIK3CA amplification. Deletion of PTEN was positively correlated with amplification of PIK3CA. Positive expression of CD133, EpCAM and CK19 was correlated with steatosis, moderate to poor differentiation, and so on. Reduction of PTEN expression was negatively correlated with positive expression of CD133, EpCAM and CK19. Reduced expression of PTEN (p=0.028) was an independent predictor for HCC recurrence and overall survival in HCC. PTEN-/CD133+ group had shorter OS and RFS time. CONCLUSIONS: PTEN plays a key role in hepatocarcinogenesis and reduction of PTEN expression is related to increased expression of CD133, EpCAM and CK19, which is a useful tool to evaluate HCC prognosis and recurrence.


Assuntos
Biomarcadores Tumorais , Carcinoma Hepatocelular , Amplificação de Genes , Neoplasias Hepáticas , Células-Tronco Neoplásicas , PTEN Fosfo-Hidrolase , Antígeno AC133/análise , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/enzimologia , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/cirurgia , Classe I de Fosfatidilinositol 3-Quinases/genética , Regulação para Baixo , Molécula de Adesão da Célula Epitelial/análise , Feminino , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Queratina-19/análise , Neoplasias Hepáticas/enzimologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/cirurgia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Células-Tronco Neoplásicas/enzimologia , Células-Tronco Neoplásicas/patologia , PTEN Fosfo-Hidrolase/análise , PTEN Fosfo-Hidrolase/genética , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento
7.
Int J Exp Pathol ; 100(2): 133-138, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-31058377

RESUMO

Carboxypeptidase A4 (CPA4), a member of the metallo-carboxypeptidase family, is overexpressed in liver cancer and is associated with cancer progression. The role of CPA4 in hepatocellular carcinoma (HCC) remains unclear. In this study, we aimed to evaluate the relevance of CPA4 to the proliferation and expression of stem cell characteristics of hepatocellular carcinoma cells. Western blot analysis showed high CPA4 expression in the liver cancer cell line Bel7402 and low expression in HepG2 cells. Knock-down of CPA4 decreased cancer cell proliferation as detected by MTT and clone formation assays. The serum-free culture system revealed that downregulated CPA4 suppressed the sphere formation capacities of tumour cells. However, upregulated CPA4 increased the proliferation and sphere formation capacity. In addition, the protein expression of CD133, ALDH1 and CD44 also increased in cells with upregulated CPA4. In vivo, the overexpression of CPA4 in tumour cells that were subcutaneously injected into nude mice markedly increased the growth of the tumours. These data suggest that CPA4 expression leads to poor prognoses by regulating tumour proliferation and the expression of stem cell characteristics and may therefore serve as a potential therapeutic target of HCC.


Assuntos
Carboxipeptidases A/fisiologia , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Células-Tronco Neoplásicas/fisiologia , Animais , Carboxipeptidases A/deficiência , Carboxipeptidases A/genética , Carcinoma Hepatocelular/enzimologia , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Regulação para Baixo , Técnicas de Silenciamento de Genes/métodos , Células Hep G2 , Xenoenxertos , Humanos , Neoplasias Hepáticas/enzimologia , Masculino , Camundongos Nus , Transplante de Neoplasias , Células-Tronco Neoplásicas/patologia , Regulação para Cima
8.
Medicine (Baltimore) ; 98(19): e15603, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31083251

RESUMO

BACKGROUND: Many studies explored the prognostic and clinicopathological significance of pretreatment serum Gamma-Glutamyltransferase (GGT) level in hepatocellular carcinoma (HCC). However, there are inconsistent results in the prognostic and clinicopathological significance of pretreatment serum GGT level in HCC. Thus, we conducted this meta-analysis to comprehensively assess the prognostic and clinicopathological significance of pretreatment serum GGT level in HCC patients. METHODS: We systematically searched PubMed, EMBASE and Web of Science for relevant studies (up to June 14, 2018). The estimated hazard ratios (HRs) were used to assess the association between pretreatment serum GGT level and survival in HCC patients. The estimated odds ratios (ORs) were applied to evaluate the correlation between pretreatment serum GGT and clinicopathological features in HCC. RESULTS: Our results showed that high pretreatment serum GGT level was significantly correlated with poor overall survival (OS) (HR = 1.70, 95% CI: 1.54-1.87; P < .01) and disease-free survival/relapse-free survival (DFS/RFS) (HR = 1.56, 95% CI: 1.42-1.71; P < .01). Additionally, our results also revealed that there was a close correlation between GGT level and several clinicopathological features in HCC patients, including vascular invasion, tumor size, tumor number and Alpha-fetoprotein (AFP) level. CONCLUSIONS: This meta-analysis shows that high pretreatment serum GGT level is significantly correlated with poor survival and unfavorable clinicopathological features in HCC patients, suggesting that pretreatment serum GGT may be an economical and effective prognostic biomarker for HCC patients. However, more high-quality studies are still warranted to further validate our findings, considering there are several limitations in this meta-analysis.


Assuntos
Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/patologia , gama-Glutamiltransferase/sangue , Biomarcadores Tumorais/sangue , Carcinoma Hepatocelular/enzimologia , Humanos , Neoplasias Hepáticas/enzimologia , Prognóstico
9.
Ann Clin Lab Sci ; 49(2): 189-192, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31028063

RESUMO

OBJECTIVES: Histone deacetylase 4 (HDAC4) is involved in the development of multiple types of cancers. In this study, we aimed to investigate the expression and clinical significance of HDAC4 in hepatocellular carcinoma (HCC). METHODS: 49 patients with stage B HCC who underwent surgical resection were enrolled in this study. All patients were followed up with an observation time of 4.8 to 7 years. Immunohistochemistry was applied to investigate the expression level of HDAC4. RESULTS: HDAC4 protein is over-expressed in HCC tissues compared with matched adjacent non-cancer tissues. Kaplan-Meier analysis shows that the positive expression of HDAC4 is associated with poor survival in these patients. CONCLUSIONS: Our study shows that HDAC4 over-expression is important for the development of advanced HCC, which may serve as a useful prognostic biomarker and therapeutic target for this malignancy.


Assuntos
Carcinoma Hepatocelular/enzimologia , Carcinoma Hepatocelular/patologia , Histona Desacetilases/metabolismo , Neoplasias Hepáticas/enzimologia , Neoplasias Hepáticas/patologia , Proteínas Repressoras/metabolismo , Linhagem Celular Tumoral , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Análise de Sobrevida
10.
Asian Pac J Cancer Prev ; 20(4): 1119-1125, 2019 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-31030484

RESUMO

Background: DNA demethylating agents and histone deacetylase inhibitors can affect reactivation of gene expression and apoptosis induction by DNA acetylation and demethylation. The aim of the present study was to analyze the effects of DNA demethylating agent genistein (GE) and histone deacetylase inhibitor valproic acid VPA), alone and combined, on hepatocellular carcinoma Hep G2 cell line. Methods: The cells were treated with various doses of genistein and valproic acid (alone and combined) and the MTT assay and flow cytometry were used to determine cell viability and apoptosis. Results: Genistein and valproic acid inhibited the growth of HepG 2 cells significantly. Result of flow cytometry demonstrated that genistein and valproic acid (alone and combined) induce apoptosis significantly in a time­dependent manner. Conclusions: Genistein and valproic acid can significantly inhibit proliferation and induce apoptosis in HepG2 cell line. The apoptotic effects of GE in combination with VPA were more significant that of each compound alone.


Assuntos
Carcinoma Hepatocelular/patologia , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Genisteína/farmacologia , Inibidores de Histona Desacetilases/farmacologia , Ácido Valproico/farmacologia , Anticarcinógenos/farmacologia , Apoptose , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/enzimologia , Proliferação de Células , Metilases de Modificação do DNA/antagonistas & inibidores , Combinação de Medicamentos , Sinergismo Farmacológico , Inibidores Enzimáticos/farmacologia , Células Hep G2 , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/enzimologia , Neoplasias Hepáticas/patologia
11.
Anticancer Res ; 39(4): 1785-1793, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30952718

RESUMO

BACKGROUND/AIM: Efficient delivery of antisense oligonucleotide (ASO) by nanoparticle vectors is critical for its clinical application. The aim of this study was to design and evaluate a novel ASO vector TPSH-LP consisting of a reduction-sensitive cationic polymer PEI-SS-HA (PSH), lipids and transferrin (Tf) as a targeting ligand. MATERIALS AND METHODS: PSH was synthesized based on PEI 25 kDa. Nanoparticles containing PSH and Tf (TPSH-LP) were prepared and used to deliver an ASO LOR-2501 targeting ribonucleotide reductase R1. The physical and chemical properties of TPSH-LP and cellular uptake in HepG2 cells were studied. RESULTS: TPSH-LP formed a complex with LOR-2501 (L-TPSH-LP) which showed suitable particle size (267.77±16.20 nm) and zeta potential (4.87±0.52 mV). TPSH-LP showed lower cytotoxicity and higher transfection efficiency than PEI 25 kDa in HepG2 cells. The addition of Tf enhanced the targeting and delivery efficiency of PSH-LP. TPSH-LP transported LOR-2501 and down-regulated the levels of R1 protein efficiently by 64.15%. CONCLUSION: Data demonstrated the potential utility of TPSH-LP for oligonucleotide delivery in cancer therapy.


Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Portadores de Fármacos , Lipídeos/química , Neoplasias Hepáticas/tratamento farmacológico , Nanopartículas , Oligonucleotídeos Antissenso/farmacologia , Polietilenoimina/química , Transferrina/metabolismo , Proteínas Supressoras de Tumor/genética , Carcinoma Hepatocelular/enzimologia , Carcinoma Hepatocelular/genética , Regulação para Baixo , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células Hep G2 , Humanos , Neoplasias Hepáticas/enzimologia , Neoplasias Hepáticas/genética , Oligonucleotídeos Antissenso/química , Oligonucleotídeos Antissenso/genética , Oligonucleotídeos Antissenso/metabolismo , Transferrina/química , Proteínas Supressoras de Tumor/metabolismo
12.
Medicine (Baltimore) ; 98(17): e15414, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31027143

RESUMO

Alpha-fetoprotein (AFP), as the most widely used biomarker of hepatocellular carcinoma (HCC), was correlated with ongoing liver damage. The aim of this study was to evaluate the ability of inflammatory correction-based AFP to identify HCC from other liver diseases.From March 2012 to March 2017, among 926 participants, a total of 501 patients whose transaminases were higher than the upper limit of normal range, including 166 treatment-naïve HCC patients were enrolled in our retrospective study. The liver function, white blood cell (WBC) count and serum AFP level of all patients were collected at the initial stage of admission. The area under the receiver-operating curve (AUROC) of AFP, AFP/(Aspartate aminotransferase*Alanine aminotransferase) [AFP/(AST*ALT)] and AFP/WBC were compared between the HCC group and the control groups for the quantifying diagnostic efficacy.AUROCs of our novel index AFP/(AST*ALT) were up to 0.853 (95% confidence interval, CI 0.818-0.887, P < .001) and 0.825 (95% CI 0.782-0.868, P < .001), respectively, when differentiating HCC from non-HCC patients and from cirrhosis patients, which was superior to AFP and AFP/WBC. Diagnostic performance of AFP/(AST*ALT) could be verified in hepatitis B virus (HBV)- or hepatitis C virus (HCV)-associated HCC patients as well. What's more, AFP/(AST*ALT) had a significant positive and moderate correlation with tumor diameter and presence of cancerous emboli or not (Spearman correlation coefficients were 0.323 and 0.305, respectively; both P < .001). For predicting HCC, the optimal cut-off value of AFP/(AST*ALT) is 1.603, and the sensitivity and specificity were 82.8% and 72.7%, respectively, which were significantly higher than the AFP and AFP/WBC.The serum AFP levels based on correction of liver inflammation can effectively improve the diagnostic performance of HCC, providing a new indicator that is simple, economical and pervasive for clinic.


Assuntos
Carcinoma Hepatocelular/sangue , Neoplasias Hepáticas/sangue , Transaminases/sangue , alfa-Fetoproteínas/metabolismo , Adulto , Área Sob a Curva , Biomarcadores Tumorais/sangue , Carcinoma Hepatocelular/enzimologia , Carcinoma Hepatocelular/imunologia , Feminino , Humanos , Inflamação/sangue , Inflamação/enzimologia , Inflamação/imunologia , Contagem de Leucócitos , Fígado/enzimologia , Fígado/imunologia , Neoplasias Hepáticas/enzimologia , Neoplasias Hepáticas/imunologia , Masculino , Pessoa de Meia-Idade , Curva ROC , Estudos Retrospectivos
13.
Gene ; 702: 66-74, 2019 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-30930224

RESUMO

Hepatocellular carcinoma (HCC) is the most common primary cancer of the liver with high mortality and frequent recurrence. Although various therapies provide potential cure for HCC patients, unfortunately the five-year survival rate of advanced HCC remains dismal. It is critical to explore the pathogenesis of HCC and identify novel biomarkers for early HCC diagnosis. PSMD4 is a major receptor of the 26S proteasome involved in ubiquitindependent and proteasome-mediated protein degradation. In our study, PSMD4 was overexpressed in HCC tissues and cell lines determined by Northern blot, western blot and immunohistochemistry. The silencing of PSMD4 blocked cell proliferation and tumor growth, induced cell apoptosis and inhibited the proteasome activity. Western blot results showed that the knockdown of PSMD4 blocked the expression of cyclooxygenase 2 (COX2), phosphorylated Sarcoma tyrosine kinase (P-SRC) and Bcl-2, but improved the levels of p53 and Bax in HCC, lung cancer, colorectal cancer, breast cancer and endometrial cancer cell lines. Taken together, these findings indicated that the subunit of 26S proteasome PSMD4 exerts as an oncogene in HCC and other cancers via regulating the expression p53, Bcl-2 and Bax. These findings enriched the pathogenesis of HCC, and provided a new biomarker for cancers diagnosis and a new target for cancers therapy.


Assuntos
Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , Complexo de Endopeptidases do Proteassoma/fisiologia , Animais , Apoptose , Carcinogênese , Carcinoma Hepatocelular/enzimologia , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Linhagem Celular , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hepáticas/enzimologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Camundongos Nus , Complexo de Endopeptidases do Proteassoma/biossíntese , Complexo de Endopeptidases do Proteassoma/genética , Complexo de Endopeptidases do Proteassoma/metabolismo , Interferência de RNA
14.
Acta Biochim Biophys Sin (Shanghai) ; 51(3): 263-276, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30883650

RESUMO

Metastasis is the main reason for high recurrence and poor survival of hepatocellular carcinoma (HCC). The molecular mechanism underlying HCC metastasis remains unclear. In this study, we found that argininosuccinate synthase 1 (ASS1) expression was significantly decreased and down-regulation of ASS1 was closely correlated with poor prognosis in HCC patients. DNA methylation led to the down-regulation of ASS1 in HCC. Stable silencing of ASS1 promoted migration and invasion of HCC cells, whereas overexpression of ASS1-inhibited metastasis of HCC cells in vivo and in vitro. We also revealed that ASS1-knockdown increased the phosphorylation level of S727STAT3, which contributed to HCC metastasis by up-regulation of inhibitor of differentiation 1 (ID1). These findings indicate that ASS1 inhibits HCC metastasis and may serve as a target for HCC diagnosis and treatment.


Assuntos
Argininossuccinato Sintase/fisiologia , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Fator de Transcrição STAT3/antagonistas & inibidores , Animais , Argininossuccinato Sintase/antagonistas & inibidores , Argininossuccinato Sintase/genética , Carcinoma Hepatocelular/enzimologia , Linhagem Celular Tumoral , Movimento Celular , Metilação de DNA , Humanos , Proteína 1 Inibidora de Diferenciação/genética , Neoplasias Hepáticas/enzimologia , Camundongos , Invasividade Neoplásica , Metástase Neoplásica/prevenção & controle , Fator de Transcrição STAT3/fisiologia , Transdução de Sinais/fisiologia
15.
Cancer Sci ; 110(6): 2033-2043, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30919528

RESUMO

Hepatocellular carcinoma (HCC) has high recurrence rates even after curative hepatectomy. Drug therapy for recurrence of HCC is still limited; therefore, identifying new therapeutic targets is urgently needed. We searched for genes that would predict HCC recurrence from intrahepatic metastasis in an exhaustive DNA microarray database by searching genes associated with high early recurrence rate and having higher expression in the tumor area compared to background liver. We detected lysyl oxidase (LOX) and validated the clinical significance of LOX in 358 patients who underwent hepatectomy. Expression of LOX was evaluated by qRT- PCR, and immunohistochemical (IHC) staining. High LOX expression group had a significantly higher recurrence rate than the low LOX expression group (2-year recurrence rate was 64.0% vs 24.2%, P < .0001 for IHC) and poorer survival rate (5-year rate was 60.1% vs 86.2%, P < .0001 for IHC). Multivariate analysis showed that high LOX expression was an independent risk factor for early recurrence (IHC: HR, 2.52; P < .0001). Bioinformatic analysis showed that LOX expression was associated with hypoxia-inducible factor-1α (HIF-1α) and the hypoxia cascade, suggesting that HIF-1α or hypoxia regulates LOX expression and induces epithelial-mesenchymal transition (EMT). In vitro, LOX and HIF-1α were involved in migration and invasion capability. High LOX expression is associated with EMT markers and predicts early recurrence and poor survival in patients with HCC. These findings indicate that lysyl oxidase could be a potential therapeutic target for early recurrence of HCC.


Assuntos
Carcinoma Hepatocelular/genética , Transição Epitelial-Mesenquimal/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Hepáticas/genética , Proteína-Lisina 6-Oxidase/genética , Idoso , Carcinoma Hepatocelular/enzimologia , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Feminino , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neoplasias Hepáticas/enzimologia , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Recidiva Local de Neoplasia , Prognóstico , Proteína-Lisina 6-Oxidase/metabolismo
16.
Expert Rev Gastroenterol Hepatol ; 13(3): 247-256, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30791763

RESUMO

INTRODUCTION: Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer, currently ranking as one of the highest neoplastic-related mortalities in the world. Due to the difficulty in early diagnosis and lack of effective treatment options, the 5-year survival rate of HCC remains extremely low. Histone deacetylation is one of the most important epigenetic mechanisms, regulating cellular events such as differentiation, proliferation and cell cycle. Histone deacetylases (HDACs), the chief mediators of this epigenetic mechanism, are often aberrantly expressed in various tumours including HCC. Areas covered: This review focuses on the most up-to-date findings of HDACs and their associated molecular mechanisms in HCC onset and progression. In addition, a potential network between HDACs and non-coding RNAs including microRNAs and long noncoding RNAs underlying hepatocarcinogenesis is considered. Expert opinion: Unmasking the role of HDACs and their association with HCC pathogenesis could have implications for future personalized therapeutic and diagnostic targeting.


Assuntos
Carcinoma Hepatocelular/enzimologia , Histona Desacetilases/metabolismo , Histonas/metabolismo , Neoplasias Hepáticas/enzimologia , Acetilação , Animais , Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Inibidores de Histona Desacetilases/uso terapêutico , Histona Desacetilases/genética , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Processamento de Proteína Pós-Traducional , RNA não Traduzido/genética , RNA não Traduzido/metabolismo , Transdução de Sinais
17.
Virology ; 529: 226-233, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30738360

RESUMO

Hepatitis C virus (HCV) was shown to activate protein kinase R (PKR), which inhibits expression of interferon (IFN) and IFN-stimulated genes by controlling the translation of newly transcribed mRNAs. However, it is unknown exactly how HCV activates PKR. To address the molecular mechanism(s) of PKR activation mediated by HCV infection, we examined the effects of viral proteins on PKR activation. Here, we show that expression of HCV NS5B strongly induced PKR and eIF2α phosphorylation, and attenuated MHC class I expression. In contrast, expression of Japanese encephalitis virus RNA-dependent RNA polymerase did not induce phosphorylation of PKR. Co-immunoprecipitation analyses showed that HCV NS5B interacted with PKR. Furthermore, expression of NS5B with polymerase activity-deficient mutation failed to phosphorylate PKR, suggesting that RNA polymerase activity is required for PKR activation. These results suggest that HCV activates PKR by association with NS5B, resulting in translational suppression of MHC class I to establish chronic infection.


Assuntos
Hepacivirus/enzimologia , RNA Replicase/metabolismo , eIF-2 Quinase/metabolismo , Carcinoma Hepatocelular/enzimologia , Carcinoma Hepatocelular/virologia , Linhagem Celular Tumoral , Ativação Enzimática , Regulação Neoplásica da Expressão Gênica , Regulação Viral da Expressão Gênica , Humanos , Neoplasias Hepáticas , Plasmídeos , RNA Replicase/genética , RNA Viral/genética , eIF-2 Quinase/genética
18.
Gastroenterology ; 156(6): 1849-1861.e13, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30711629

RESUMO

BACKGROUND & AIMS: Inhibitors of MET have not produced satisfactory outcomes in trials of patients with liver cancer. We investigated the mechanisms of liver tumor resistance to MET inhibitors in mice. METHODS: We tested the effects of MET inhibitors tivantinib and capmatinib in the mouse hepatocellular carcinoma (HCC) cell line HCA-1 and in immune-competent and immunodeficient mice with subcutaneous tumors grown from this cell line. Tumors were collected from mice and tumor cells were analyzed by time-of-flight mass cytometry. We used short hairpin RNAs to weaken expression of MET in Hep3B, SK-HEP-1, HA59T, and HA22T liver cancer cell lines and analyzed cells by immunoblot, immunofluorescence, and immunoprecipitation assays. Mass spectrometry was used to assess interactions between MET and glycogen synthase kinase 3ß (GSK3B), and GSK3B phosphorylation, in liver cancer cell lines. C57/BL6 mice with orthotopic tumors grown from Hep1-6 cells were given combinations of capmatinib or tivantinib and antibodies against programmed cell death 1 (PDCD1; also called PD1); tumors were collected and analyzed by immunofluorescence. We analyzed 268 HCCsamples in a tissue microarray by immunohistochemistry. RESULTS: Exposure of liver cancer cell lines to MET inhibitors increased their expression of PD ligand 1 (PDL1) and inactivated cocultured T cells. MET phosphorylated and activated GSK3B at tyrosine 56, which decreased the expression of PDL1 by liver cancer cells. In orthotopic tumors grown in immune-competent mice, MET inhibitors decreased the antitumor activity of T cells. However, addition of anti-PD1 decreased orthotopic tumor growth and prolonged survival of mice compared with anti-PD1 or MET inhibitors alone. Tissue microarray analysis of HCC samples showed an inverse correlation between levels of MET and PDL1 and a positive correlation between levels of MET and phosphorylated GSK3B. CONCLUSIONS: In studies of liver cancer cell lines and mice with orthotopic tumors, MET mediated phosphorylation and activated GSK3B, leading to decreased expression of PDL1. Combined with a MET inhibitor, anti-PD1 and anti-PDL1 produced additive effect to slow growth of HCCs in mice.


Assuntos
Antígeno B7-H1/metabolismo , Carcinoma Hepatocelular/enzimologia , Glicogênio Sintase Quinase 3 beta/metabolismo , Neoplasias Hepáticas/enzimologia , Proteínas Proto-Oncogênicas c-met/metabolismo , Fator 6 Associado a Receptor de TNF/metabolismo , Evasão Tumoral/efeitos dos fármacos , Animais , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/imunologia , Linhagem Celular Tumoral , Regulação para Baixo , Granzimas/metabolismo , Imidazóis/farmacologia , Imidazóis/uso terapêutico , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/imunologia , Masculino , Camundongos , Fosforilação , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Pirrolidinonas/farmacologia , Pirrolidinonas/uso terapêutico , Quinolinas/farmacologia , Quinolinas/uso terapêutico , Fator 6 Associado a Receptor de TNF/imunologia , Triazinas/farmacologia , Triazinas/uso terapêutico , Ubiquitinação
19.
J Exp Clin Cancer Res ; 38(1): 88, 2019 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-30777103

RESUMO

BACKGROUND: Over-expression and over-activation of immunosuppressive enzyme indoleamine 2, 3 -dioxygenase 1 (IDO1) is a key mechanism of cancer immune escape. However, the regulation of IDO1 has not been fully studied. The relation between hydrogen sulfide (H2S) and IDO1 is unclear. METHODS: The influences of endogenous and exogenous H2S on the expression of IDO1, iNOS and NF-κB and STAT3 signaling proteins were investigated using qPCR or western blot, and the production of nitric oxide (NO) was analyzed by nitrate/nitrite assay in Cse-/- mice and MCF-7 and SGC-7901 cells. The effect of H2S on IDO1 activity was investigated by HPLC and in-vitro enzymatic assay. The effect of H2S on tryptophan metabolism was tested by luciferase reporter assay in MCF-7 and SGC-7901 cells. The correlation between H2S-generating enzyme CSE and IDO1 was investigated by immunostaining and heatmaps analysis in clinical specimens and tissue arrays of hepatocellular carcinoma (HCC) patients. The immunotherapeutic effects of H2S on H22 HCC-bearing mice were investigated. RESULTS: Using Cse-/- mice, we found that H2S deficiency increased IDO1 expression and activity, stimulated NF-κB and STAT3 pathways and decreased the expression of NO-generating enzyme Inos. Using IDO1-expressing MCF-7 and SGC-7901 cells, we found that exogenous H2S inhibited IDO1 expression by blocking STAT3 and NF-κB pathways, and decreased IDO1 activity via H2S/NO crosstalk, and combinedly decreased the tryptophan metabolism. The negative correlation between H2S-generating enzyme CSE and IDO1 was further validated in clinical specimens and tissue arrays of HCC patients. Additionally, H2S donors effectively restricted the tumor development in H22 HCC-bearing mice via downregulating IDO1 expression, inducing T-effector cells and inhibiting MDSCs. CONCLUSIONS: Thus, H2S, as a novel negative regulator of IDO1, shows encouraging antitumor immunotherapeutic effects and represents a novel therapeutic target in cancer therapy.


Assuntos
Carcinoma Hepatocelular/enzimologia , Sulfeto de Hidrogênio/farmacologia , Indolamina-Pirrol 2,3,-Dioxigenase/efeitos dos fármacos , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Neoplasias Hepáticas/enzimologia , Animais , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Humanos , Imunoterapia/métodos , Neoplasias Hepáticas/patologia , Camundongos , Camundongos Knockout , Células Tumorais Cultivadas
20.
Toxicol Appl Pharmacol ; 365: 51-60, 2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30625338

RESUMO

Hepatocellular carcinoma (HCC) is a lethal malignancy with few effective options for therapeutic treatment in its advanced stages. Metformin, a first-line oral agent used in the treatment of type 2 diabetes, exhibits efficacy in metabolic reprogramming fueling changes in cell growth and proliferation for multiple cancer types, including HCC. However, the molecular mechanism by which metformin delays hepatocarcinogenesis in individuals with hepatic steatosis remains rare. Here, we investigate the preventive efficacy of metformin in a rapid AKT/c-Met-triggered HCC mouse model featuring excessive levels of steatosis. Hematoxylin and eosin staining, Oil Red O staining and immunoblotting were applied for mechanistic investigations. Pharmacological and biochemical strategies were employed to illuminate molecular evidence for HCC cell lines. The results show that metformin obstructs the malignant transformation of hepatocytes in AKT/c-Met mice. Mechanistically, metformin reduces the expression of phospho-ERK (Thr202/Tyr204) and two forms of proto-oncogenes, Cyclin D1 and c-Myc, in AKT/c-Met mice. Moreover, metformin ameliorates FASN-mediated aberrant lipogenesis and HK2/PKM2-driven ATP generation in vivo. Furthermore, metformin represses the expression of FASN and HK-2 by targeting c-Myc in an AMPK-dependent manner in vitro. In addition, metformin is effective at inhibiting PKM2 expression in the presence of an AMPK inhibitor compound C, suggesting that its functioning in PKM2 is AMPK-independent. Our study experimentally validates a novel molecular mechanism by which metformin alleviates enhanced lipogenesis and high energy metabolism during hepatocarcinogenesis, indicating that metformin may serve as an agent for the prevention of HCC in patients with nonalcoholic fatty liver diseases.


Assuntos
Trifosfato de Adenosina/metabolismo , Anticarcinógenos/farmacologia , Carcinoma Hepatocelular/prevenção & controle , Transformação Celular Neoplásica/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Fígado Gorduroso/tratamento farmacológico , Lipogênese/efeitos dos fármacos , Neoplasias Hepáticas/prevenção & controle , Fígado/efeitos dos fármacos , Metformina/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-met/metabolismo , Animais , Carcinoma Hepatocelular/enzimologia , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Modelos Animais de Doenças , Ácido Graxo Sintase Tipo I/metabolismo , Fígado Gorduroso/enzimologia , Fígado Gorduroso/genética , Fígado Gorduroso/patologia , Hexoquinase/metabolismo , Humanos , Fígado/enzimologia , Fígado/patologia , Neoplasias Hepáticas/enzimologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Camundongos , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-met/genética , Piruvato Quinase/metabolismo , Transdução de Sinais/efeitos dos fármacos
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