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1.
Environ Toxicol ; 35(9): 971-981, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32302048

RESUMO

Hepatocellular carcinoma (HCC) ranks the sixth position among various cancers worldwide. Recent research shows that natural and dietary compounds possess many therapeutic effects. Citral is a monoterpene aldehyde that contains geranial and neral. The present study was considered to study the role of citral against N-nitrosodiethylamine (NDEA)-induced HCC via modulation of antioxidants and xenobiotic-metabolizing enzymes in vivo. NDEA-alone-administered group II animals profoundly showed increased tumor incidence, reactive oxygen species, liver marker enzyme levels, serum bilirubin levels, tumor markers of carcinoembryonic antigen, α-fetoprotein, proliferative markers of argyrophilic nucleolar organizing regions, proliferating cell nuclear antigen (PCNA) expressions, phase I xenobiotic-metabolic enzymes and simultaneously decreased antioxidants, and phase II enzymes levels. Citral (100 mg/kg b.w.) treatment significantly reverted the levels in group III cancer-bearing animals when compared to group II cancer-bearing animals. In group IV animals, citral-alone administration did not produce any adverse effect during the experimental condition. Based on the results, citral significantly inhibits the hepatocellular carcinogenesis through restoring the antioxidants and phase II xenobiotic-enzyme levels; thereby, it strongly proves as an antiproliferative agent against rat HCC.


Assuntos
Monoterpenos Acíclicos/uso terapêutico , Antineoplásicos Fitogênicos/uso terapêutico , Antioxidantes/metabolismo , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas Experimentais/tratamento farmacológico , Animais , Antígeno Carcinoembrionário/análise , Carcinoma Hepatocelular/enzimologia , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Dietilnitrosamina , Humanos , Testes de Função Hepática , Neoplasias Hepáticas Experimentais/enzimologia , Neoplasias Hepáticas Experimentais/patologia , Masculino , Antígeno Nuclear de Célula em Proliferação/metabolismo , Ratos , Ratos Wistar , alfa-Fetoproteínas/análise
2.
Toxicology ; 437: 152438, 2020 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-32199159

RESUMO

Polychlorinated biphenyls (PCBs) are persistent organic pollutants with human carcinogenicity. Many lower chlorinated and non-dioxin-like PCBs have been observed to be mutagenic following activation by human CYP2E1, while activation of dioxin-like (DL-) PCBs by this enzyme has never been evidenced. In this study, each DL-PCB was analyzed by molecular docking to human CYP2E1 protein for predicting a substrate interaction. All compounds demonstrated high affinities with the active site of human CYP2E1, binding energy being -8.7 ∼ -9.7 kcal/mol. However, most compounds demonstrated ligand-heme distances as ≥ 6.8 Å, while the values for 2,3,3',4,4'- (PCB 105) and 2,3',4,4',5-pentachlorobiphenyl (PCB 118) were 5.3 and 5.4 Å, respectively (valid for electron transfer). Experimentally, both PCB 105 and 118 induced micronuclei in a V79-derived cell line engineered for expression of human CYP2E1 at low micromolar concentrations, while inactive or weakly positive in V79-Mz control cells; these effects were blocked or reduced by 1-aminobenzotriazole, a suicide CYP inhibitor. However, DL-PCBs 77, 81 and 126 were all negative in both cell lines. In a human hepatoma (C3A) cell line, PCB 105 and 118 induced micronuclei marginally, while with ethanol pretreatment (to stabilize CYP2E1) both compounds induced micronuclei efficiently, and co-exposure to trans-1,2-dichloroethylene (a selective CYP2E1 inhibitor) led to clearly negative results with both compounds. Finally, both PCB 105 and 118 induced PIG-A gene mutations in C3A cells, which was blocked by trans-1,2-dichloroethylene. In summary, in silico and experimental results consistently suggest that DL- PCBs 105 and 118 may be activated by human CYP2E1 for mutagenic activities.


Assuntos
Citocromo P-450 CYP2E1/metabolismo , Proteínas de Membrana/genética , Micronúcleos com Defeito Cromossômico/induzido quimicamente , Simulação de Acoplamento Molecular , Mutação , Bifenilos Policlorados/toxicidade , Ativação Metabólica , Animais , Carcinoma Hepatocelular/enzimologia , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Domínio Catalítico , Cricetulus , Citocromo P-450 CYP2E1/química , Citocromo P-450 CYP2E1/genética , Fibroblastos/efeitos dos fármacos , Fibroblastos/enzimologia , Fibroblastos/patologia , Células Hep G2 , Humanos , Neoplasias Hepáticas/enzimologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Pulmão/efeitos dos fármacos , Pulmão/enzimologia , Pulmão/patologia , Bifenilos Policlorados/química , Bifenilos Policlorados/metabolismo , Ligação Proteica , Conformação Proteica
3.
Medicine (Baltimore) ; 99(11): e19438, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32176073

RESUMO

BACKGROUND: Numerous studies have investigated the association between pretreatment serum alkaline phosphatase (ALP) and prognosis in hepatocellular carcinoma (HCC), but conclusions remain controversial. Thus, we performed a meta-analysis to assess systematically the relationship between ALP and prognosis in HCC. METHODS: We searched the PubMed, EMBASE, and Web of Science databases for eligible studies up to October. A combined hazard ratio (HR) was determined to describe the correlation between pretreatment serum ALP level and prognosis in HCC patients. Overall survival (OS) was calculated from the date of treatment either to the end point of the follow-up period or to the date of death by any cause. Disease-free survival (DFS) and recurrence-free survival (RFS) were defined as the period from the date of treatment to the date of last follow-up or to the date of recurrence. OS was regarded as the major outcome. RESULTS: Altogether, 21 studies about OS and 6 studies about DFS/RFS were included in this meta-analysis. Our combined results showed that there was an inverse association of pretreatment serum ALP level with OS (HR=1.15, 95% CI: 1.12-1.19) and RFS (HR=1.78, 95% CI: 1.37-2.31). CONCLUSION: There was a close association between high pretreatment ALP level and poor survival in HCC patients, indicating that ALP may be used as a biomarker for prognosis. More high-quality studies are required to validate our findings further, considering the limitations of our meta-analysis.


Assuntos
Fosfatase Alcalina/sangue , Biomarcadores Tumorais/sangue , Carcinoma Hepatocelular/enzimologia , Neoplasias Hepáticas/enzimologia , Carcinoma Hepatocelular/mortalidade , Humanos , Neoplasias Hepáticas/mortalidade , Prognóstico , Análise de Sobrevida
4.
Life Sci ; 244: 117343, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31978449

RESUMO

AIMS: Epithelial-mesenchymal transition (EMT) is one of the important regulators of metastasis in advanced hepatocellular carcinoma (HCC). Blocking the Notch signaling pathway and then reversing the EMT process is a hot spot in clinical tumor research. Here, we aimed to investigate the effect and underlying mechanisms of ADAM-17 (a key cleavage enzyme of Notch pathway) inhibitor ZLDI-8 we found before on the metastasis of hepatocellular carcinoma in vitro and in vivo. MAIN METHODS: The cell viability of HCC cells was evaluated by MTT and colony formation assays. Migration and invasion were assessed respectively with wound healing and transwell assays. The expression and location of proteins were detected by western blot and immunofluorescence, respectively. The effects of ZLDI-8 on metastasis of liver cancer in vivo were investigated in a tail vein injection model. KEY FINDINGS: In the present work, ZLDI-8 significantly inhibited proliferation, migration, invasion and EMT phenotype of highly aggressive MHCC97-H and LM3 cells. Moreover, ZLDI-8 could inhibit the migration and invasion of HepG2 and Bel7402 cells induced by TGF-ß1. ZLDI-8 suppressed the protein expression of interstitial markers and increased that of epithelial markers. Meanwhile, ZLDI-8 decreased the expression of proteins in the Notch signaling pathway. Finally, ZLDI-8 blocks metastasis in the lung metastasis model in vivo. SIGNIFICANCE: ZLDI-8 suppressed the metastasis of hepatocellular carcinoma, which was associated with reversing the EMT process and regulating Notch signaling pathway. The study laid the foundation for the discovery of drugs that reverse EMT to inhibit advanced HCC metastasis.


Assuntos
Proteína ADAM17/antagonistas & inibidores , Carcinoma Hepatocelular/tratamento farmacológico , Inibidores Enzimáticos/farmacologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Animais , Apoptose , Carcinoma Hepatocelular/enzimologia , Carcinoma Hepatocelular/patologia , Proliferação de Células , Humanos , Técnicas In Vitro , Neoplasias Hepáticas/enzimologia , Neoplasias Hepáticas/patologia , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/secundário , Camundongos , Camundongos Nus , Transdução de Sinais , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Oncology ; 98(3): 186-194, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31846974

RESUMO

BACKGROUND: The clinical course of hepatocellular carcinoma (HCC) is complicated, because it often recurs and shows multiple lesions, some of which progress to a more malignant form, shortening the life of the patient. The hepatocyte growth factor receptor c-Met has been shown to play an important role in the pathogenesis of HCC, but the influence of c-Met expression on the clinical course of HCC remains to be fully elucidated. METHODS: We randomly selected and included 600 tumor specimens obtained from the primary and recurrent lesions of 319 HCC cases between 1995 and 2007. The expression of c-Met was determined by immunohistochemistry using archived formalin-fixed paraffin-embedded samples. We analyzed the correlation between c-Met expression and clinical parameters, including survival. In addition, we examined c-Met expression in the malignant transition of HCC in all cases including recurrent lesions. RESULTS: Survival analysis using the multivariate Cox proportional-regression model revealed that the prognosis was significantly better in the primary cases with high c-Met expression than in those with low c-Met expression (hazard ratio 0.159, 95% confidence interval 0.065-0.391; p < 0.001). During the course of recurrence, some cases with high c-Met expression returned to low c-Met expression. Among 40 cases with high c-Met expression, 29 survived more than 2 years after detecting the high c-Met expression. CONCLUSION: High expression of c-Met may be a prognostic factor for a good, rather than a poor, HCC prognosis. The involvement of c-Met expression in the malignant transition of recurrent HCC is obscure.


Assuntos
Biomarcadores Tumorais/análise , Carcinoma Hepatocelular/enzimologia , Neoplasias Hepáticas/enzimologia , Recidiva Local de Neoplasia , Proteínas Proto-Oncogênicas c-met/análise , Idoso , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/terapia , Progressão da Doença , Feminino , Humanos , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/terapia , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Regulação para Cima
6.
J Pharm Pharmacol ; 72(1): 29-43, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31617221

RESUMO

OBJECTIVES: Arctigenin (ARG) has been proved to inhibit the viability of hepatocellular carcinoma (HCC) via inducing apoptosis. However, the precise mechanism remains unknown. The present study was aimed to further investigate the mechanism of ARG against HCC in vitro and in vivo. METHODS: Arctigenin was applied in vitro and in vivo. Western blotting, immunohistochemistry, etc., were used to investigate the mechanisms. KEY FINDINGS: The time-dependent enhancement of Bax/Bcl-2 ratio, cytochrome c release, Fas and FasL levels, caspase cascade activation and the loss in the mitochondrial out membrane potential indicated that both intrinsic and extrinsic apoptotic pathways were triggered by ARG. Moreover, Jun NH2-terminal kinase (JNK) and p38 phosphorylated time-dependently. And inhibition of the phosphorylation of either p38 or JNK led to a significant reduction in HepG2 apoptosis, owing to the crucial roles of p38 and JNK played in regulating the apoptosis pathways. In addition, ARG increased the generation of reactive oxygen species (ROS) in HepG2 cells, while the antioxidant N-acetyl cysteine almost reversed ARG-induced JNK and p38 activation, and dramatically decreased cell apoptosis. In vivo, ARG increased the cell apoptosis in tumour tissues, and p-p38, p-JNK and Bax were significantly upregulated. CONCLUSIONS: Our findings demonstrated that ARG induced apoptosis in HCC via ROS-mediated mitogen-activated protein kinases apoptosis pathway.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/tratamento farmacológico , Furanos/farmacologia , Lignanas/farmacologia , Neoplasias Hepáticas/tratamento farmacológico , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Carcinoma Hepatocelular/enzimologia , Carcinoma Hepatocelular/patologia , Ativação Enzimática , Células Hep G2 , Humanos , Neoplasias Hepáticas/enzimologia , Neoplasias Hepáticas/patologia , Camundongos Endogâmicos BALB C , Camundongos Nus , Transdução de Sinais , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Environ Int ; 134: 105313, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31731000

RESUMO

Exposure to environmental pollutant organochlorine pesticides (OCPs) and the role of tumour suppressor GSTs gene polymorphisms as well as epigenetic alterations have all been well reported in hepatocarcinogenesis. However, the interplay between environmental risk factors and polymorphic tumour suppressor genes or epigenetic factors in hepatocellular carcinoma (HCC) development remains ambiguous. Herein, we investigated the relationship of three GSTs polymorphisms (GSTT1 deletion, GSTM1 deletion, GSTP1 rs1695) as well as GSTP1 promoter region DNA methylation and HCC risk with a particular focus on the interaction with OCPs exposure among 90 HCC cases and 99 controls in a Chinese population. Serum samples were analysed for OCPs exposure employing gas chromatography coupled with mass selective detector (GC-MS). GSTs polymorphisms and epigenetic alterations were determined using high-resolution melting PCR (HRM PCR) and DNA sequencing. After adjusting for confounders (HBV infection, smoking, alcohol consumption, BMI, age, gender), OCPs exposure and GSTP1 methylation is significantly associated with elevated risk of HCC, while no significance is observed for GSTs polymorphisms. Moreover, the effects of OCPs exposure on HCC risk are more pronounced amongst GSTP1 (Ile/Val + Val/Val) and GSTP1 promoter methylation subjects than those who were GSTP1 (Ile/Ile) and unmethylated subjects. The interactions between OCPs exposure and GSTP1 genotype as well as GSTP1 epigenetic status are statistically significant. The current study demonstrates the importance of gene-environment interactions in the multifactorial development of HCC.


Assuntos
Carcinoma Hepatocelular/genética , Exposição Ambiental/efeitos adversos , Epigênese Genética , Interação Gene-Ambiente , Neoplasias Hepáticas/genética , Praguicidas/efeitos adversos , Grupo com Ancestrais do Continente Asiático , Carcinoma Hepatocelular/enzimologia , Estudos de Casos e Controles , China , Genótipo , Glutationa Transferase/genética , Humanos , Neoplasias Hepáticas/enzimologia
8.
Dis Markers ; 2019: 2046825, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31814857

RESUMO

Background and Aim: Aspartate aminotransferase-to-platelet ratio index (APRI) is widely used in the assessment of fibrosis and cirrhosis, especially in patients with chronic hepatitis. However, the prognostic value of APRI in patients with chronic hepatitis with regard to the prediction of hepatocellular carcinoma (HCC) occurrence remains controversial. The objective of this meta-analysis is to investigate the association between APRI and HCC risk on the basis of cohort studies. Methods: We systematically reviewed PubMed, EMBASE, Web of Science, and Chinese National Knowledge Infrastructure databases for relevant cohort studies up to May 1, 2019. Pooled hazard ratios (HRs) with 95% confidence intervals (CIs) for total and subgroup analyses were calculated with Stata 12.0 software for the assessment of the relationship between APRI and HCC risk. Results: A total of 13 studies, involving 8897 patients, were included in the meta-analysis, of which 11 explored the association between pretreatment APRI and HCC risk and four reported the relationship between posttreatment APRI and HCC risk. Pooled results showed that an elevated level of pretreatment APRI was associated with increased HCC risk (HR = 2.56, 95% CI: 1.78-3.68). When stratified by hepatitis type, high pretreatment APRI predicted HCC development in patients with chronic hepatitis B (CHB) and C (CHC) but not in alcoholic liver cirrhosis (ALC). In the subgroup analyses of study region, cut-off value, sample size, and analysis method, the relationship between high pretreatment APRI and increased HCC risk was significant. Meanwhile, patients with a high level of posttreatment APRI suffered from high HCC risk (HR = 3.69, 95% CI: 2.52-5.42). Conclusion: Results revealed a significant association between elevated APRI and HCC development in patients with chronic hepatitis, suggesting that APRI might serve as a valuable predictor for HCC risk in patients with chronic hepatitis.


Assuntos
Aspartato Aminotransferases/metabolismo , Plaquetas/patologia , Carcinoma Hepatocelular/patologia , Hepatite B Crônica/complicações , Hepatite C Crônica/complicações , Neoplasias Hepáticas/patologia , Carcinoma Hepatocelular/enzimologia , Carcinoma Hepatocelular/etiologia , Estudos de Coortes , Hepacivirus/isolamento & purificação , Vírus da Hepatite B/isolamento & purificação , Hepatite B Crônica/virologia , Hepatite C Crônica/virologia , Humanos , Neoplasias Hepáticas/enzimologia , Neoplasias Hepáticas/etiologia , Prognóstico
9.
World J Gastroenterol ; 25(43): 6386-6403, 2019 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-31798276

RESUMO

BACKGROUND: Hepatocellular carcinoma (HCC) is now the most common primary liver malignancy worldwide, and multiple risk factors attribute to the occurrence and development of HCC. Recently, increasing studies suggest that ubiquitin-conjugating enzyme E2T (UBE2T) serves as a promising prognostic factor in human cancers, although the molecular mechanism of UBE2T in HCC remains unclear. AIM: To investigate the clinical relevance and role of UBE2T in HCC development. METHODS: UBE2T expression in HCC tissues from the TCGA database and its association with patient survival were analyzed. A lentivirus-mediated strategy was used to knock down UBE2T in HCC cells. qRT-PCR and Western blot assays were performed to check the effect of UBE2T silencing in HCC cells. Cell growth in vitro and in vivo was analyzed by multiparametric high-content screening and the xenograft tumorigenicity assay, respectively. Cell cycle distribution and apoptosis were determined by flow cytometry. The genes regulated by UBE2T were profiled by microarray assay. RESULTS: UBE2T was overexpressed in HCC tissues compared with paired and non-paired normal tissues. High expression of UBE2T predicted a poor overall survival in HCC patients. In vitro, lentivirus-mediated UBE2T knockdown significantly reduced the viability of both SMMC-7721 and BEL-7404 cells. In vivo, the xenograft tumorigenesis of SMMC-7721 cells was largely attenuated by UBE2T silencing. The cell cycle was arrested at G1/S phase in SMMC-7721 and BEL-7404 cells with UBE2T knockdown. Furthermore, apoptosis was increased by UBE2T knockdown. At the molecular level, numerous genes were dysregulated after UBE2T silencing, including IL-1B, FOSL1, PTGS2, and BMP6. CONCLUSION: UBE2T plays an important role in cell cycle progression, apoptosis, and HCC development.


Assuntos
Carcinogênese , Carcinoma Hepatocelular/enzimologia , Neoplasias Hepáticas/enzimologia , Oncogenes , Enzimas de Conjugação de Ubiquitina/metabolismo , Apoptose , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/mortalidade , Ciclo Celular , Linhagem Celular Tumoral , Técnicas de Silenciamento de Genes , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/mortalidade , Enzimas de Conjugação de Ubiquitina/genética
10.
Anal Cell Pathol (Amst) ; 2019: 9423907, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31886121

RESUMO

The epithelial-mesenchymal transition (EMT) is a transformation process mandatory for the local and distant progression of many malignant tumors, including hepatocellular carcinoma (HCC). Matrix metalloproteinases (MMPs) play significant roles in cellular regeneration, programmed death, angiogenesis, and many other essential tissular functions, involved in the normal development and also in pathological processes, such as the EMT. This paper reviews the roles of MMPs in the EMT involved in HCC invasion, as well as the ancillary roles that MMP cross-activation and tissue inhibitors play in modulating this process. While gelatinases MMP-2 and MMP-9 are the MMPs commonly cited in the EMT of HCC, MMPs belonging to other classes have been proven to be involved in this process, favoring not only invasion and metastasis (MMP-1, MMP-3, MMP-7, MMP-10, MMP-11, MMP-13, MMP-14, MMP-16, MMP-26, and MMP-28) but also angiogenesis (MMP-8 and MMP-10). There is also data suggesting that other MMPs with a suspected or demonstrated role in the EMT of other cancers may also have some degree of involvement in HCC. The auto- and cross-activation of MMPs may complicate this issue, as pinpointing the extent of implication of each MMP may be extremely difficult. The homeostasis between MMPs and their tissue inhibitors is essential in preventing tumor progression, and the disturbance of this stability is another entailed factor in the EMT of HCC, which is addressed herein.


Assuntos
Carcinoma Hepatocelular/enzimologia , Carcinoma Hepatocelular/patologia , Transição Epitelial-Mesenquimal , Neoplasias Hepáticas/enzimologia , Neoplasias Hepáticas/patologia , Metaloproteinases da Matriz/metabolismo , Carcinogênese/patologia , Humanos , Modelos Biológicos
11.
Zhonghua Gan Zang Bing Za Zhi ; 27(10): 760-765, 2019 Oct 20.
Artigo em Chinês | MEDLINE | ID: mdl-31734989

RESUMO

Objective: To study the expression level of monoacylglycerol lipase (MAGL) in liver tissues of patients with hepatocellular carcinoma (HCC), and its clinical correlation. Methods: Immunohistochemistry was employed to detect MAGL protein in 353 cases with hepatocellular carcinoma (HCC) and tissue microarray (TMA) for paracancerous liver tissues. The expression levels of MAGL in TMA were quantitatively analyzed using Image-Pro plus 6.0. The difference in MAGL expression between liver cancer tissues and paracancerous liver tissues was compared. Combined with the clinical follow-up data of TMA patients, the correlation between the expression of MAGL in TMA and the degree of HCC tumors differentiation and the survival rate of 1-year and 3-year were analyzed using Logistic regression analysis. The survival curves of patients with different levels of MAGL protein was plotted and analyzed using Kaplan-Meier method. The expression of MAGL protein was analyzed by multiple linear regression analysis. COX regression was used to analyze the correlation between MAGL protein expression level and the risk of HCC death in the included patients. Results: The expression of MAGL in HCC tissues was significantly higher than paracancerous liver tissues. The expression level of MAGL was correlated to the degrees of HCC tumors differentiation (P < 0.001) and 1-year survival rate (P = 0.01), but not with 3-year survival rate (P = 0.91). Survival curve showed that the expression level of MAGL was negatively correlated with prognosis and survival of HCC patients (P = 0.001). Multiple linear regressions showed a negative correlation between MAGL expression level and overall survival time of HCC patients (P=0.010, R2=0.166, Durbin-Watson value: 1.989). COX regression showed that the expression of MAGL was a risk factor for death of patients with HCC [P = 0.004, Exp (B) = 1.000]. Conclusion: The expression level of MAGL has positive correlation with the malignant degree in HCC patients, and negative correlation with its prognosis. Therefore, MAGL may serve as a new prognostic indicator for HCC patients.


Assuntos
Carcinoma Hepatocelular/diagnóstico , Neoplasias Hepáticas/diagnóstico , Monoacilglicerol Lipases/metabolismo , Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/enzimologia , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/enzimologia , Prognóstico
12.
Pathol Res Pract ; 215(12): 152702, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31704152

RESUMO

The ETFDH (electron transfer flavoprotein dehydrogenase) gene mutations are reported to be a major cause of riboflavin-responsive multiple acyl-coenzyme A dehydrogenation deficiency (MADD). However, the role of ETFDH in the prognosis of hepatocellular carcinoma (HCC) remains unclear. The aim of this study was to investigate the expression of ETFDH in HCC. Immunohistochemical staining of the 207 HCC tissue microarray showed that expression of ETFDH was significantly decreased in HCC compared with the matching noncancerous hepatic tissues (P < 0.001). Moreover, ETFDH expression levels were found to be correlated with AFP levels (P = 0.011). Intriguingly, ETFDH expression levels were significantly lower in poorly differentiated or undifferentiated HCCs as compared to the well or moderately differentiated cases (P = 0.001). Kaplan-Meier analysis revealed that low tumor expression of ETFDH was associated with a poorer overall survival in patients with HCC (P = 0.024). Furthermore, multivariate analysis showed that ETFDH (P = 0.047) was an independent predictor of overall survival. Our findings may shed new light on the identification of new prognostic marker for HCC.


Assuntos
Biomarcadores Tumorais/análise , Carcinoma Hepatocelular/enzimologia , Flavoproteínas Transferidoras de Elétrons/análise , Proteínas com Ferro-Enxofre/análise , Neoplasias Hepáticas/enzimologia , Oxirredutases atuantes sobre Doadores de Grupo CH-NH/análise , Adulto , Idoso , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/terapia , Diferenciação Celular , Feminino , Humanos , Imuno-Histoquímica , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/terapia , Masculino , Pessoa de Meia-Idade , Prognóstico , Fatores de Risco , Análise Serial de Tecidos , alfa-Fetoproteínas/análise
13.
Pathol Res Pract ; 215(12): 152674, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31732382

RESUMO

Hepatocellular carcinoma (HCC) is among the most frequently observed forms of cancer. MicroRNAs (miRNAs) are increasingly thought to play a key role in regulating the onset and progression of a wide range of cancer types. In the present report, we found that miR-455-5p expression was significantly decreased in both HCC patient tumor tissues and cell lines, and that this reduction in expression was linked to poorer patient outcomes. When we overexpressed miR-455-5p in HCC cell lines (Huh7 and HepG2), this was linked with impaired proliferation, colony formation, migration, and invasion. We further found that this miRNA was able to directly bind the insulin growth factor receptor (IGF-1R) 3'-untranslated region, thereby suppressing IGF-1R expression in HCC cells. Consistent with this, miR-455-5p overexpression was associated with reduced glucose transporter (GLUT) 1 expression, which in turn inhibited HCC cell uptake of glucose, production of lactate, and generation of ATP. Together these results thus indicate that mIR-455-5p is able to suppress tumor functionality via impairing glycolysis in HCC cells, highlighting this miRNA as a potential target for anti-cancer therapeutic interventions.


Assuntos
Carcinoma Hepatocelular/enzimologia , Proliferação de Células , Transportador de Glucose Tipo 1/metabolismo , Neoplasias Hepáticas/enzimologia , MicroRNAs/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor IGF Tipo 1/metabolismo , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Movimento Celular , Feminino , Regulação Neoplásica da Expressão Gênica , Transportador de Glucose Tipo 1/genética , Glicólise , Células Hep G2 , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , Invasividade Neoplásica , Receptor IGF Tipo 1/genética , Transdução de Sinais
14.
Metabolism ; 101: 153993, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31672442

RESUMO

BACKGROUND: Therapies targeting altered activity of pyruvate dehydrogenase (PDH) and pyruvate carboxylase (PC) have been proposed for hepatomas. However, the activities of these pathways in hepatomas in vivo have not been distinguished. Here we examined pyruvate entry into the tricarboxylic acid (TCA) cycle through PDH versus PC in vivo using hepatoma-bearing rats. METHODS: Hepatoma-bearing rats were generated by intrahepatic injection of H4IIE cells. Metabolism of 13C-labeled glycerol, a physiological substrate for both gluconeogenesis and energy production, was measured with 13C NMR analysis. The concentration of key metabolites and the expression of relevant enzymes were measured in hepatoma, surrounding liver, and normal liver. RESULTS: In orthotopic hepatomas, pyruvate entry into the TCA cycle occurred exclusively through PDH and the excess PDH activity compared to normal liver was attributed to downregulated pyruvate dehydrogenase kinase (PDK) 2/4. However, pyruvate carboxylation via PC and gluconeogenesis were minimal, which was linked to downregulated forkhead box O1 (FoxO1) by Akt activity. In contrast to many studies of cancer metabolism, lactate production in hepatomas was not increased which corresponded to reduced expression of lactate dehydrogenase. The production of serine and glycine in hepatomas was enhanced, but glycine decarboxylase was downregulated. CONCLUSIONS: The combination of [U-13C3]glycerol and NMR analysis enabled investigation of multiple biochemical processes in hepatomas and surrounding liver. We demonstrated active PDH and other related metabolic alterations in orthotopic hepatomas that differed substantially not only from the host organ but also from many earlier studies with cancer cells.


Assuntos
Carcinoma Hepatocelular/metabolismo , Gluconeogênese , Neoplasias Hepáticas/metabolismo , Complexo Piruvato Desidrogenase/metabolismo , Animais , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13/métodos , Carcinoma Hepatocelular/enzimologia , Ciclo do Ácido Cítrico , Glicerol/metabolismo , Fígado/enzimologia , Neoplasias Hepáticas/enzimologia , Ratos
15.
Biomed Pharmacother ; 120: 109532, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31605953

RESUMO

PURPOSE: Reactive oxygen species (ROS) are implicated in carcinogenesis, and cellular antioxidant systems are important for detoxifying ROS and reversing oxidant-mediated modifications. Glutathione S-transferase mu (GSTM) belongs to a family of phase II detoxification enzymes that catalyze the conjugation of reduced glutathione (GSH) to a wide range of endogenous and exogenous electrophilic compounds. The genotype of GSTM1 was associated with the risk and prognosis of cancer in several meta-analyses. This study explored the function of GSTM1 in hepatocellular carcinoma (HCC). METHODS: Polymerase chain reaction (PCR) and western blotting (WB) were used to detect the levels of gene and protein expression. MTS assays, Transwell assays, and flow cytometry were used to explore the function of GSTM1 in vitro. The xenograft assay and tail vein injection model were used to explore the function of GSTM1 in vivo. RESULTS: The mRNA and protein expression of GSTM1 was downregulated in HCC, but the expression levels of GSTM1 were not correlated with patient survival time. In vitro, Transwell and doxorubicin (DOX)-induced apoptosis assays revealed that GSTM1 showed opposite functions in different HCC cell lines with varied TP53 genotype statuses. The overexpression of GSTM1 in the above cell lines led to a significant decrease in ROS and an increase in GSH concentration and TP53 levels, suggesting that the controversial role of GSTM1 resulted from the TP53 genotype of HCC cells. The overexpression of GSTM1 promoted cell migration and inhibited apoptosis in the MHCC-97H cell line (TP53, R249S), but inhibited cell migration and increased apoptosis in the SMMC-7721 cell line (TP53 wildtype). CONCLUSION: GSTM1 down-regulation may partially account for ROS-mediated oxidative damage and HCC carcinogenesis. GSTM1 also regulates tumor progression by disrupting the ROS-TP53 axis in HCC cells with different genetic backgrounds.


Assuntos
Carcinogênese/metabolismo , Carcinogênese/patologia , Carcinoma Hepatocelular/enzimologia , Carcinoma Hepatocelular/patologia , Glutationa Transferase/metabolismo , Neoplasias Hepáticas/enzimologia , Animais , Apoptose , Carcinoma Hepatocelular/genética , Linhagem Celular Tumoral , Proliferação de Células , Progressão da Doença , Regulação para Baixo/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Masculino , Camundongos Nus , Pessoa de Meia-Idade , Metástase Neoplásica , Fenótipo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Proteína Supressora de Tumor p53/metabolismo
16.
Food Chem Toxicol ; 134: 110830, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31562948

RESUMO

Hepatocellular carcinoma (HCC) is a prevalent malignancy and a leading cause of cancer-related mortality. α-Humulene (HML) is a natural 11-membered monocyclic terpene with three E-configured double bonds isolated from Eupatorium odoratum L. We recently showed that HML has significant anti-HCC activity in vitro and in vivo. We found that HML was cytotoxic to HCC cells and induced mitochondrial apoptosis of HCC cells, promoting caspase-3 activation and PARP cleavage. HCC cells show abnormal Akt signaling to resist apoptosis. Mechanistically, HML was found to inhibit Akt activation, subsequently decreasing GSK-3 and Bad phosphorylation, promoting apoptotic induction. HML also inhibited cell proliferation and enhanced apoptosis in HCC tumor xenografts further highlighting its activity in vivo. Although HML showed minimal cytotoxicity to normal hepatocytes, weight loss was observed in mice administered HML. Taken together, these data provide important and novel insights into the anti-HCC effects of HML through its ability to inhibit Akt, reduced HCC cell proliferation, and enhanced HCC cell apoptotic induction in vitro and in vivo.


Assuntos
Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/patologia , Proliferação de Células/efeitos dos fármacos , Neoplasias Hepáticas/patologia , Sesquiterpenos Monocíclicos/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Carcinoma Hepatocelular/enzimologia , Células Hep G2 , Xenoenxertos , Humanos , Neoplasias Hepáticas/enzimologia , Camundongos , Camundongos Nus
17.
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/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Circular , Transdução de Sinais , Regulação para Cima
18.
Biochem J ; 476(16): 2355-2369, 2019 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-31395734

RESUMO

Hepsin is a transmembrane serine protease implicated in many biological processes, including hepatocyte growth, urinary protein secretion, auditory nerve development, and cancer metastasis. Zymogen activation is critical for hepsin function. To date, how hepsin is activated and regulated in cells remains an enigma. In this study, we conducted site-directed mutagenesis, cell expression, plasma membrane protein labeling, trypsin digestion, Western blotting, and flow cytometry experiments in human hepatoma HepG2 cells, where hepsin was originally discovered, and SMMC-7721 cells. Our results show that hepsin is activated by autocatalysis on the cell surface but not intracellularly. Moreover, we show that hepsin undergoes ectodomain shedding. In the conditioned medium from HepG2 and SMMC-7721 cells, we detected a soluble fragment comprising nearly the entire extracellular region of hepsin. By testing protease inhibitors, gene knockdown, and site-directed mutagenesis, we identified calpain-1 as a primary protease that acted extracellularly to cleave Tyr52 in the juxtamembrane space of hepsin. These results provide new insights into the biochemical and cellular mechanisms that regulate hepsin expression and activity.


Assuntos
Calpaína/metabolismo , Carcinoma Hepatocelular/enzimologia , Membrana Celular/enzimologia , Neoplasias Hepáticas/enzimologia , Proteínas de Neoplasias/metabolismo , Serina Endopeptidases/biossíntese , Calpaína/genética , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Membrana Celular/genética , Membrana Celular/patologia , Ativação Enzimática , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Células Hep G2 , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Proteínas de Neoplasias/genética , Domínios Proteicos , Serina Endopeptidases/genética
19.
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
20.
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
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