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1.
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
2.
Toxicol Lett ; 319: 155-159, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31706005

RESUMO

Novel HepG2 cell clones 1A2 C2 and 1A2 C7 were independently generated by lentiviral transduction to functionally overexpress cytochrome P450 1A2 (CYP1A2). We found similar and stable CYP1A2 transcript and protein levels in both cell clones leading to specific enzyme activities of about 370 pmol paracetamol x min-1 x mg-1 protein analyzed by phenacetin conversion. Both clones showed dramatically increased sensitivity to the hepatotoxic compound aflatoxin B1 (EC50 < 100 nM) when compared to parental HepG2 cells (EC50∼5 µM). Thus, newly established cell lines are an appropriate tool to study metabolism and toxicity of substances depending on conversion by CYP1A2.


Assuntos
Citocromo P-450 CYP1A2/genética , Vetores Genéticos/genética , Hepatoblastoma/enzimologia , Hepatoblastoma/genética , Lentivirus/genética , Neoplasias Hepáticas/enzimologia , Neoplasias Hepáticas/genética , Aflatoxina B1/toxicidade , Linhagem Celular Tumoral , Citocromo P-450 CYP1A2/biossíntese , Impressões Digitais de DNA/métodos , Humanos , Fígado/metabolismo , Mycoplasma/química , Fenacetina/farmacocinética , Plasmídeos/genética
3.
Genes Dev ; 34(1-2): 53-71, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31857346

RESUMO

Hippo signaling controls organ size and tumor progression through a conserved pathway leading to nuclear translocation of the transcriptional effector Yki/Yap/Taz. Most of our understanding of Hippo signaling pertains to its cytoplasmic regulation, but how the pathway is controlled in the nucleus remains poorly understood. Here we uncover an evolutionarily conserved mechanism by which CDK7 promotes Yki/Yap/Taz stabilization in the nucleus to sustain Hippo pathway outputs. We found that a modular E3 ubiquitin ligase complex CRL4DCAF12 binds and targets Yki/Yap/Taz for ubiquitination and degradation, whereas CDK7 phosphorylates Yki/Yap/Taz at S169/S128/S90 to inhibit CRL4DCAF12 recruitment, leading to Yki/Yap/Taz stabilization. As a consequence, inactivation of CDK7 reduced organ size and inhibited tumor growth, which could be reversed by restoring Yki/Yap activity. Our study identifies an unanticipated layer of Hippo pathway regulation, defines a novel mechanism by which CDK7 regulates tissue growth, and implies CDK7 as a drug target for Yap/Taz-driven cancer.


Assuntos
Carcinogênese/genética , Quinases Ciclina-Dependentes/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/enzimologia , Drosophila melanogaster/metabolismo , Proteínas Nucleares/metabolismo , Transativadores/metabolismo , Animais , Antineoplásicos/farmacologia , Carcinogênese/efeitos dos fármacos , Linhagem Celular , Linhagem Celular Tumoral , Núcleo Celular/metabolismo , Quinases Ciclina-Dependentes/genética , Drosophila melanogaster/genética , Ativação Enzimática , Regulação Neoplásica da Expressão Gênica/genética , Técnicas de Silenciamento de Genes , Humanos , Neoplasias Hepáticas/enzimologia , Neoplasias Hepáticas/fisiopatologia , Camundongos , Tamanho do Órgão/genética , Fenilenodiaminas/farmacologia , Proteólise , Pirimidinas/farmacologia
4.
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
5.
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
6.
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
7.
Zhonghua Gan Zang Bing Za Zhi ; 27(9): 687-692, 2019 Sep 20.
Artigo em Chinês | MEDLINE | ID: mdl-31594093

RESUMO

Objective: To construct the recombinant adenoviral containing fructose 1, 6-biphosphatase 1 (FBP1), and to investigate whether FBP1 has effect on autophagy and proliferation in liver cancer cells (HepG2). Methods: FBP1 cDNA sequence was amplified by PCR and cloned in adenovirus vector pAdTrack-TO4, and then recombinant adenovirus plasmid pAdTrack-FBP1 was constructed. The recombinant adenovirus plasmid was transfected into HEK293 cells by Lipofectamine 3000. High-titer of recombinant adenovirus AdFBP1 was obtained by packaging and amplification. HepG2 cells were infected with recombinant adenovirus AdFBP1, and the Mock and AdGFP group were set at the same time. Western blot and confocal laser scanning microscopy were used to observe the effect of FBP1 on the level of autophagy in hepatocellular carcinoma cells, and the effect of FBP1on the proliferation was observed by MTS and colony formation assay. A t-test and one-way ANOVA were used to compare the mean between group. Results: A high-titer recombinant adenovirus FBP1 was successfully constructed. Western blot and confocal laser scanning microscopy showed that the level of autophagy in AdFBP1 group was significantly lower than that in AdGFP group. Western blot results showed that LC3-II protein expression level in AdGFP was 1.10 ± 0.10 and 0.30 ± 0.01 in AdFBP1 group, F = 90.36, P < 0.01. Confocal laser scanning microscopy analysis showed that the average number of autophages in AdGFP was 28.33 ± 1.53 and 12.33 ± 1.53 in AdFBP1group, F = 97.40, P < 0.01. In addition, the results of colony formation assay and MTS assay showed that the proliferation of liver cancer cells in the AdFBP1 group was significantly inhibited compared with the AdGFP group. The results of colony formation showed that the cell clones in the AdGFP group was 65.66 ± 2.57 and 34.00 ± 2.00 in AdFBP1 group, F = 141.50, P < 0.01. MTS results showed that the absorbance of AdGFP group at 96h was 39.13 ± 2.21 and 30.61 ± 3.33 in AdFBP1 group, F = 7.80, P < 0.05. Conclusion: FBP1 inhibited the autophagy and proliferation in liver cancer cells (HepG2).


Assuntos
Autofagia , Proliferação de Células , Frutose-Bifosfatase/metabolismo , Neoplasias Hepáticas/patologia , Adenoviridae , Vetores Genéticos , Células HEK293 , Células Hep G2 , Humanos , Neoplasias Hepáticas/enzimologia , Transfecção
8.
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 , 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
9.
Med Sci Monit ; 25: 6711-6718, 2019 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-31492830

RESUMO

BACKGROUND Liver cancer is one of the most common malignancies around the world and one of the major causes of cancer related mortality. The objective of this study was to evaluate the anticancer effect of the natural compound psilostachyin-A on 5-fluorouracil-resistant human liver carcinoma cells and its effects on autophagy, cell cycle, caspase activation, and the ERK/MAPK signaling pathway. MATERIAL AND METHODS Cell Counting Kit 8 (CCK-8) assay was used to evaluate the effects on HepG2 cell viability at different doses of psilostachyin-A. Cell cycle analysis was performed using flow cytometry, and Transwell assay was used to check effects on cell invasion. Transmission electron microscopic studies were done to evaluate autophagy induced by psilostachyin-A, and the western blot method was carried out to evaluate the effects on autophagy and the ERK/MAPK signaling pathway. RESULTS CCK-8 assay revealed that the psilostachyin-A reduced the cell viability of HepG2 cancer cells in a dose dependent manner. Psilostachyin-A also reduced the colony forming potential of HepG2 cells, concentration dependently. The IC50 of psilostachyin was found to be 25 µM. The anticancer effects of psilostachyin-A were due to the induction of autophagy which was accompanied by enhancement of LC3B II expression. Psilostachyin also caused cell cycle arrest by enhancing the accumulation of HepG2 cells in the G2/M phase. Transwell assay showed that psilostachyin-A suppressed the invasion of HepG2 cells. The results also showed that psilostachyin-A could block the ERK/MAPK pathway, indicative of the cytotoxic effects of psilostachyin-A on liver cancer. CONCLUSIONS These preliminary observations suggested that psilostachyin-A might prove beneficial in the treatment of liver cancer.


Assuntos
Antineoplásicos/uso terapêutico , Autofagia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Fluoruracila/uso terapêutico , Lactonas/uso terapêutico , Neoplasias Hepáticas/tratamento farmacológico , Pontos de Checagem da Fase M do Ciclo Celular , Sistema de Sinalização das MAP Quinases , Sesquiterpenos/uso terapêutico , Antineoplásicos/química , Antineoplásicos/farmacologia , Autofagia/efeitos dos fármacos , Proteína Beclina-1/metabolismo , Proliferação de Células/efeitos dos fármacos , Fluoruracila/farmacologia , Células Hep G2 , Humanos , Lactonas/química , Lactonas/farmacologia , Neoplasias Hepáticas/enzimologia , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/ultraestrutura , Pontos de Checagem da Fase M do Ciclo Celular/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Proteínas Associadas aos Microtúbulos/metabolismo , Invasividade Neoplásica , Fosforilação/efeitos dos fármacos , Sesquiterpenos/química , Sesquiterpenos/farmacologia , Ensaio Tumoral de Célula-Tronco , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
10.
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 , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Regulação para Cima
11.
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
12.
BMC Cancer ; 19(1): 629, 2019 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-31238895

RESUMO

BACKGROUND: This study aimed to evaluate the value of chitinase activity in prognosticating the occurrence of metastasis in and prognosis of patients with colorectal cancer (CRC). METHODS: The chitinase activity in four different groups, namely 335 CRC patients without distant metastasis at their first visit (Group 1), 51 patients with CRC having synchronous liver metastasis (Group 2), 100 healthy age-matched controls (Group 3) and 40 patients with liver cancer (Group 4), were assayed using an enzyme-linked immunosorbent assay. The Cox proportional hazards ratio model and Kaplan-Meier curve were used to identify the association between chitinase activity and the clinical outcome of CRC patients without metastasis in the training set and testing set at their first visit. An in vitro Transwell experiment was performed to evaluate the migration of colon cancer cells. RESULTS: Patients with high chitinase activity had a significantly higher metastasis risk than those with low chitinase activity in the training and testing sets during follow-up, both at stage I/II and stage III. Further, multivariate analysis revealed that chitinase activity was an independent risk factor prognosticating liver metastases (P = 0.001). The combination of chitinase activity and lymph node metastasis status increased the accuracy of the prognosis of liver metastases after radical resection (P = 0.454E-011). In addition, chitinase promoted CRC cell migration in vitro. CONCLUSIONS: Chitinase activity can prognosticate the occurrence of metastasis in patients with CRC. Moreover, the combination of chitinase activity and N stage increased the power of prognosticating the occurrence of metastasis. Inhibiting chitinase activity may serve as a new strategy to treat metastases of CRC.


Assuntos
Quitinases/sangue , Neoplasias do Colo/enzimologia , Neoplasias do Colo/patologia , Neoplasias Hepáticas/secundário , Neoplasias Retais/enzimologia , Neoplasias Retais/patologia , Biomarcadores Tumorais/sangue , Estudos de Casos e Controles , Linhagem Celular Tumoral , Movimento Celular , Neoplasias do Colo/mortalidade , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/enzimologia , Neoplasias Hepáticas/mortalidade , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Estadiamento de Neoplasias , Prognóstico , Modelos de Riscos Proporcionais , Neoplasias Retais/mortalidade , Estudos Retrospectivos
13.
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
14.
Biomed Pharmacother ; 117: 109051, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31177062

RESUMO

The inhibitory roles of limonin have been revealed in various tumors. However, the roles and related mechanism of limonin in hepatocellular carcinoma (HCC) progression are still confused. Here, we collected non-adherent spheroids formed by HCC cells and found that the proportion of spheroids in G0 phase was remarkably higher than that in HCC cells. Additionally, limonin increased EdU incorporation without affecting apoptosis in spheroids. Notably, upon limonin treatment, the proportion of spheroids in G0 was decreased and S/G2/M increased. Furthermore, we found that limonin attenuated the stemness of HCC cells, characterized as the decreased ALDH1 activity, stemness marker expression and spheroid formation ability. Moreover, an integrated transcriptional analysis based on RNA-sequencing data was employed to gain mechanistic insight into limonin functioning, and we found that the most significant pathways identified centered on PI3K/Akt signaling. qRT-PCR and western blot obtained the consistent results. Overall, these data suggest that limonin attenuates the stemness of HCC cells by reducing cellular quiescence through activating PI3K/Akt signaling.


Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Ciclo Celular , Limoninas/uso terapêutico , Neoplasias Hepáticas/tratamento farmacológico , Células-Tronco Neoplásicas/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Carcinoma Hepatocelular/enzimologia , Carcinoma Hepatocelular/patologia , Ciclo Celular/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Células Hep G2 , Humanos , Limoninas/farmacologia , Neoplasias Hepáticas/enzimologia , Neoplasias Hepáticas/patologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Esferoides Celulares/efeitos dos fármacos , Esferoides Celulares/metabolismo , Esferoides Celulares/patologia
15.
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
16.
Toxicol Lett ; 313: 1-10, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31170421

RESUMO

The constitutive androstane receptor(CAR) activation is connected with mitogenic effects leading to liver hyperplasia and tumorigenesis in rodents. CAR activators, including phenobarbital, are considered rodent non-genotoxic carcinogens. Recently, trans-3,4,5,4´-tetramethoxystilbene(TMS), a potential anticancer drug (DMU-212), have been shown to alleviate N-nitrosodiethylamine/phenobarbital-induced liver carcinogenesis. We studied whether TMS inhibits mouse Car to protect from the PB-induced tumorigenesis. Unexpectedly, we identified TMS as a murine CAR agonist in reporter gene experiments, in mouse hepatocytes, and in C57BL/6 mice in vivo. TMS up-regulated Car target genes Cyp2b10, Cyp2c29 and Cyp2c55 mRNAs, but down-regulated expression of genes involved in gluconeogenesis and lipogenesis. TMS did not change or down-regulate genes involved in liver proliferation or apoptosis such as Mki67, Foxm1, Myc, Mcl1, Pcna, Bcl2, or Mdm2, which were up-regulated by another Car ligand TCPOBOP. TMS did not increase liver weight and had no significant effect on Ki67 and Pcna labeling indices in mouse liver in vivo. In murine hepatic AML12 cells, we confirmed a Car-independent proapoptotic effect of TMS. We conclude that TMS is a Car ligand with limited effects on hepatocyte proliferation, likely due to promoting apoptosis in mouse hepatic cells, while controlling Car target genes involved in xenobiotic and endobiotic metabolism.


Assuntos
Anticarcinógenos/farmacologia , Proliferação de Células/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Neoplasias Hepáticas/prevenção & controle , Fígado/efeitos dos fármacos , Receptores Citoplasmáticos e Nucleares/agonistas , Estilbenos/farmacologia , Animais , Anticarcinógenos/metabolismo , Apoptose/efeitos dos fármacos , Hidrocarboneto de Aril Hidroxilases/genética , Hidrocarboneto de Aril Hidroxilases/metabolismo , Sítios de Ligação , Família 2 do Citocromo P450/genética , Família 2 do Citocromo P450/metabolismo , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Gluconeogênese/efeitos dos fármacos , Gluconeogênese/genética , Células Hep G2 , Hepatócitos/metabolismo , Hepatócitos/patologia , Humanos , Lipogênese/efeitos dos fármacos , Lipogênese/genética , Fígado/metabolismo , Neoplasias Hepáticas/enzimologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Masculino , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Ligação Proteica , Piridinas/farmacologia , Receptores Citoplasmáticos e Nucleares/genética , Receptores Citoplasmáticos e Nucleares/metabolismo , Transdução de Sinais/efeitos dos fármacos , Esteroide Hidroxilases/genética , Esteroide Hidroxilases/metabolismo , Estilbenos/metabolismo
17.
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
18.
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
19.
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
20.
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
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