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1.
BMC Cancer ; 21(1): 715, 2021 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-34144696

RESUMO

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths in Africa. In Africa, the major causes of HCC include chronic infection with hepatitis B virus (HBV) and/or hepatitis C virus (HCV). Knowledge of the changes in the incidence of viral hepatitis-associated HCC over time and the factors responsible for such changes is key in informing policies for the prevention of viral hepatitis-associated HCC in Africa. AIM: The study aimed to systematically summarize the changes in the prevalence of viral hepatitis among HCC patients and the overall effect of the prevalence of viral hepatitis on the incidence of HCC over the past four decades in Africa (1980-2019). METHODS: A literature search was conducted in MEDLINE (PubMed), Google Scholar, Science Direct, Scopus, Web of Science, and African wide web for articles published on viral hepatitis-associated HCC in Africa from 1980 to 2019. The abstracts of the articles were screened for eligibility and those meeting the inclusion criteria were retrieved and reviewed. RESULTS: A total of 272 studies were included in the analysis. Viral hepatitis-related HCC incidence changed by 1.17% (95% confidence interval (CI): 0.63-1.71, p < 0.001), 0.82% (95% CI: 0.45-1.18, p < 0.001), and 3.34% (95% CI: 2.44-4.25, p < 0.001) for every 1% change in the prevalence of HBV, HCV, and hepatitis D virus (HDV) respectively, per decade. The incidence of HBV-related HCC decreased by - 0.50% (95% CI: - 0.74 - - 0.25, p < 0.001) over the last 40 years, while HCV-related HCC increased. CONCLUSION: Overall, the incidence of viral hepatitis-associated HCC has not declined, mainly due to no decline in the prevalence of HCV, HDV, and the high number of chronic hepatitis B carriers on the African continent. There is an urgent need for the allocation of resources for the implementation of treatment and preventive programs for HBV, HCV, HDV, and HCC in Africa. This systematic review is registered with PROSPERO®, number CRD42020169723.


Assuntos
Carcinoma Hepatocelular/etiologia , Carcinoma Hepatocelular/virologia , Hepatite B/complicações , Hepatite C/complicações , Hepatite D/complicações , Hepatite Viral Humana/complicações , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/virologia , África , Carcinoma Hepatocelular/fisiopatologia , Hepatite B/patologia , Hepatite C/patologia , Hepatite D/patologia , Hepatite Viral Humana/patologia , Humanos , Neoplasias Hepáticas/fisiopatologia
2.
Toxicol Ind Health ; 37(6): 365-376, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33973497

RESUMO

Vinyl chloride (VC) is a confirmed human carcinogen associated with hepatocellular carcinoma and angiosarcoma. However, the role of microRNAs (miRNAs) in liver cell cycle changes under VC exposure remains unclear, which prevents research on the mechanism of VC-induced carcinogenesis. In this study, male rats were injected intraperitoneally with VC (0, 5, 25, and 125 mg/kg body weight) for 6, 8, and 12 weeks. Cell cycle analysis of liver cells, miRNA-222, miRNA-199a, miRNA-195, and miRNA-125b expression in the liver and serum, and target protein expression were performed at different time points. The results showed a higher percentage of hepatocytes in the G1/G0 and S phases at the end of 6 and 12 weeks of VC exposure, respectively. MiRNA-222 expression decreased initially and then increased, whereas miRNA-199a, miRNA-195, and miRNA-125b expression increased initially and then decreased, which corresponded with changes in cell cycle distribution and related target proteins expression (p27, cyclinA, cyclinD1, and CDK6). The corresponding expression levels of miRNAs in serum did not change. Dynamic changes in miR-222, miR-199a, miR-195, and miR-125b induced by VC can lead to cell cycle deregulation by affecting cell cycle-related proteins, and these miRNAs can serve as early biomarkers for malignant transformation caused by VC.


Assuntos
Carcinoma Hepatocelular/induzido quimicamente , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/genética , Hepatócitos/efeitos dos fármacos , Neoplasias Hepáticas/induzido quimicamente , MicroRNAs/efeitos dos fármacos , MicroRNAs/genética , Cloreto de Vinil/toxicidade , Animais , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/fisiopatologia , Perfilação da Expressão Gênica , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/fisiopatologia , Modelos Animais , Ratos
3.
DNA Repair (Amst) ; 103: 103117, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33990030

RESUMO

INTRODUCTION: Hepatocellular carcinoma (HCC) remains one of the most predominant types of digestive system malignancies worldwide. TNF-related apoptosis-inducing ligand (TRAIL) is a biological cytokine with the mentioned specificity, but some tumor cells' resistance limits its use as a therapeutic approach. The present study aimed to investigate thymoquinone (TQ) and TRAIL's combined effect and the potential mechanisms in human hepatic HepG2 carcinoma cells. METHODS: Cell viability and IC50 dose for TQ and TRAIL, alone and in combination, were determined using the MTT method. ELISA evaluated the expression levels of 8-Hydroxy-2'-deoxyguanosine. The apoptosis rate was assessed by flow cytometry, ELISA cell death assay, and caspase 8 activity assays. The mRNA and protein evaluation of candidate genes, including survivin, Bcl-2, XIAP, c-IAP1, c-IAP2, and c-FLIP, were accomplished before and after the treatment using qRT-PCR and Western blot analysis, respectively. RESULTS: Our results showed that TQ synergistically increased TRAIL's cell toxic effects as follows: TQ plus TRAIL > TRAIL > TQ. TQ could sensitize the HepG2 cells against the TRAIL-induced apoptosis and amplify the caspase 8 activity. This outcome is achieved by decreasing the mRNA and protein expression levels of anti-apoptotic genes. CONCLUSIONS: Our findings suggest that TQ can sensitize the human HCC cell line HepG2 against TRAIL by inducing the death receptor pathway. Moreover, these agents' combinational therapy might promise a therapeutic regimen for improving the clinical efficacy of TRAIL-induced apoptosis in patients with HCC.


Assuntos
Apoptose , Benzoquinonas/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Dano ao DNA , Neoplasias Hepáticas/tratamento farmacológico , Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Benzoquinonas/uso terapêutico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/fisiopatologia , DNA/efeitos dos fármacos , Células Hep G2 , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/fisiopatologia , Estresse Oxidativo
4.
Mol Biol Rep ; 48(4): 3463-3474, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33907947

RESUMO

Hepatocellular carcinoma is one of the most common types of cancer in the world with high mortality rate and new therapies that control of fatty acid metabolism may limit the proliferation of cancer cells. In the last two decades, the non-coding RNAs have been considered as promising molecular tools to treat diseases, because they are able to modulate gene expression and the metabolic routes; however, deep investigation of their mechanistic behavior in pathologies must be performed. Thus, our aim was to evaluate the modulatory effect of the miR-1914-5p in controlling lipid metabolism in HepG2, a widely used human hepatocarcinoma cell line. The molecular and cellular analyses demonstrated that the functional inhibition of the investigated microRNA completely changed the cellular metabolism and behavior, compared to control groups. The in vitro inhibition of the miR-1914-5p increased the energy expenditure pointed in different analyses, decreasing cell doubling time and migration rate verified in wound healing and in the classical transwell chambers invasion assays, which makes the miR-1914-5p a candidate for further translational and preclinical studies to validate its function in controlling metastasis in liver cancer or even treat those diseases.


Assuntos
Carcinoma Hepatocelular/metabolismo , Movimento Celular , Metabolismo dos Lipídeos , Neoplasias Hepáticas/metabolismo , MicroRNAs/metabolismo , Carcinoma Hepatocelular/fisiopatologia , Células Hep G2 , Humanos , Neoplasias Hepáticas/fisiopatologia
5.
J Biomed Sci ; 28(1): 29, 2021 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-33888099

RESUMO

BACKGROUND: Due to the difficulties in early diagnosing and treating hepatocellular carcinoma (HCC), prognoses for patients remained poor in the past decade. In this study, we established a screening model to discover novel prognostic biomarkers in HCC patients. METHODS: Candidate biomarkers were screened by liquid chromatography with tandem mass spectrometry (LC-MS/MS) analyses of five HCC normal (N)/tumor (T) paired tissues and preliminarily verified them through several in silico database analyses. Expression levels and functional roles of candidate biomarkers were respectively evaluated by immunohistochemical staining in N/T paired tissue (n = 120) and MTS, colony formation, and transwell migration/invasion assays in HCC cell lines. Associations of clinicopathological features and prognoses with candidate biomarkers in HCC patients were analyzed from GEO and TCGA datasets and our recruited cohort. RESULTS: We found that the transmembrane P24 trafficking protein 9 (TMED9) protein was elevated in HCC tissues according to a global proteomic analysis. Higher messenger (m)RNA and protein levels of TMED9 were observed in HCC tissues compared to normal liver tissues or pre-neoplastic lesions. The TMED9 mRNA expression level was significantly associated with an advanced stage and a poor prognosis of overall survival (OS, p = 0.00084) in HCC patients. Moreover, the TMED9 protein expression level was positively correlated with vascular invasion (p = 0.026), OS (p = 0.044), and disease-free survival (p = 0.015) in our recruited Taiwanese cohort. In vitro, manipulation of TMED9 expression in HCC cells significantly affected cell migratory, invasive, proliferative, and colony-forming abilities. CONCLUSIONS: Ours is the first work to identify an oncogenic role of TMED9 in HCC cells and may provide insights into the application of TMED9 as a novel predictor of clinical outcomes and a potential therapeutic target in patients with HCC.


Assuntos
Carcinoma Hepatocelular/fisiopatologia , Expressão Gênica , Neoplasias Hepáticas/fisiopatologia , RNA Mensageiro/metabolismo , Proteínas de Transporte Vesicular/análise , Idoso , Carcinoma Hepatocelular/diagnóstico , Cromatografia Líquida , Feminino , Humanos , Neoplasias Hepáticas/diagnóstico , Masculino , Pessoa de Meia-Idade , Prognóstico , Proteômica , Espectrometria de Massas em Tandem
6.
J Tradit Chin Med ; 41(2): 194-202, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33825398

RESUMO

OBJECTIVE: To investigate the efficacy of an herbal formula of Bushen Jianpi ( BSJP) combined with sorafenib on hepatocellular carcinoma (HCC) in vitro and in vivo, and to study the underlying mechanisms of action. METHODS: BSJP, a mixture of 12 raw herbs, was extracted in 70% alcohol/30% water and freeze-dried into a powder. The in vitro effects of BSJP alone, sorafenib alone, and their combination on cell survival, apoptosis, and cell cycle distribution were evaluated in HCC cell lines HCCLM3, HepG2, and SMMC-7721. The expression of B-cell lymphoma-2 (Bcl-2), caspase-3, and caspase-9 in HCCLM3 cells was measured using Western blots after drug administration. The in vivo effects of BSJP and sorafenib were evaluated in a tumor surgical resection model using 4-week old male athymic BALB/c nude mice injected with HCCLM3 cells. Immunohistochemical analysis of tumor tissues was performed to evaluate the effects of BSJP alone, sorafenib alone, and their combination on the expression of caspase-3, caspase-9, and Bcl-2. RESULTS: BSJP decreased the survival rate of HCC cell lines, and the combination of BSJP and sorafenib further decreased the survival rate. BSJP significantly promoted cell apoptosis and blocked cell-cycle progression in HCCLM3, HepG2, and SMMC-7721 cells in a dose-dependent manner. Furthermore, the administration of BSJP and sorafenib inhibited the growth of HCCLM3 cell xenografts in nude mice, with no reduction in body weight. In vivo and in vitro experiments showed that BSJP combined with sorafenib could significantly decrease the expression of Bcl-2. CONCLUSION: Our findings suggest that the herbal formula of BSJP is a potential HCC antitumor agent.


Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/fisiopatologia , Medicamentos de Ervas Chinesas/administração & dosagem , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/fisiopatologia , Sorafenibe/administração & dosagem , Animais , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Quimioterapia Combinada , Humanos , Masculino , Camundongos Endogâmicos BALB C
8.
Cells ; 10(3)2021 03 10.
Artigo em Inglês | MEDLINE | ID: mdl-33802077

RESUMO

Previous studies support the role of natural killer (NK) cells in controlling hepatocellular carcinoma (HCC) progression. However, ambiguity remains about the multiplicity and the role of different NK cell subsets, as a pro-oncogenic function has been suggested. We performed phenotypic and functional characterization of NK cells infiltrating HCC, with the corresponding nontumorous tissue and liver from patients undergoing liver resection for colorectal liver metastasis used as controls. We identified a reduced number of NK cells in tumors with higher frequency of CD56BRIGHTCD16- NK cells associated with higher expression of NKG2A, NKp44, and NKp30 and downregulation of NKG2D. Liver-resident (CXCR6+) NK cells were reduced in the tumors where T-bethiEomeslo expression was predominant. HCCs showed higher expression of CD49a with particular enrichment in CD49a+Eomes+ NK cells, a subset typically represented in the decidua and playing a proangiogenic function. Functional analysis showed reduced TNF-α production along with impaired cytotoxic capacity that was inversely related to CXCR6-, T-bethiEomeslo, and CD49a+Eomes+ NK cells. In conclusion, we identified a subset of NK cells infiltrating HCC, including non-liver-resident cells that coexpressed CD49a and Eomes and showed reduced cytotoxic potential. This NK cell subset likely plays a regulatory role in proangiogenic function.


Assuntos
Carcinoma Hepatocelular/fisiopatologia , Células Matadoras Naturais/metabolismo , Neoplasias Hepáticas/fisiopatologia , Oncogenes/genética , Idoso , Feminino , Humanos , Masculino
9.
Anticancer Res ; 41(4): 2025-2032, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33813409

RESUMO

BACKGROUND: The age of patients with advanced hepatocellular carcinoma (HCC) eligible for molecular-targeted drug treatment is increasing. We assessed liver function after lenvatinib administration according to age in patients with advanced HCC. PATIENTS AND METHODS: In this retrospective, multicenter, observational study, we reviewed the records of patients with HCC who received lenvatinib treatment (March 2018-March 2020). Liver function was measured using the Albumin-Bilirubin Index (ALBI). RESULTS: Of 119 patients, with a median age of 72.0 years, median overall survival was 15.3 months. Overall survival was significantly better in the group which maintained liver function (p=0.02). Older age (≥72 years) was associated with liver-function deterioration within 8 weeks (odds ratio=2.47, 95% confidence interval=1.06-5.75, p=0.035). The ALBI score was significantly higher in the older group at 4 and 8 weeks after lenvatinib administration. CONCLUSION: Lenvatinib administration was more likely to adversely affect liver function in older patients; dose adjustment should be considered in such patients.


Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Fígado/efeitos dos fármacos , Fígado/fisiopatologia , Compostos de Fenilureia/uso terapêutico , Quinolinas/uso terapêutico , Fatores Etários , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Carcinoma Hepatocelular/epidemiologia , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/fisiopatologia , Feminino , Humanos , Fígado/patologia , Testes de Função Hepática , Neoplasias Hepáticas/epidemiologia , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/fisiopatologia , Masculino , Compostos de Fenilureia/farmacologia , Quinolinas/farmacologia , Estudos Retrospectivos
10.
Int J Mol Sci ; 22(9)2021 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-33925827

RESUMO

Liver disease is the spectrum of liver damage ranging from simple steatosis called as nonalcoholic fatty liver disease (NAFLD) to hepatocellular carcinoma (HCC). Clinically, NAFLD and type 2 diabetes coexist. Type 2 diabetes contributes to biological processes driving the severity of NAFLD, the primary cause for development of chronic liver diseases. In the last 20 years, the rate of non-viral NAFLD/NASH-derived HCC has been increasing rapidly. As there are currently no suitable drugs for treatment of NAFLD and NASH, a class of thiazolidinediones (TZDs) drugs for the treatment of type 2 diabetes is sometimes used to improve liver failure despite the risk of side effects. Therefore, diagnosis, prevention, and treatment of the development and progression of NAFLD and NASH are important issues. In this review, we will discuss the pathogenesis of NAFLD/NASH and NAFLD/NASH-derived HCC and the current promising pharmacological therapies of NAFLD/NASH. Further, we will provide insights into "adipose-derived adipokines" and "liver-derived hepatokines" as diagnostic and therapeutic targets from NAFLD to HCC.


Assuntos
Diabetes Mellitus Tipo 2/complicações , Fígado/patologia , Hepatopatia Gordurosa não Alcoólica , Obesidade/complicações , Adipocinas/metabolismo , Carcinoma Hepatocelular/fisiopatologia , Diabetes Mellitus Tipo 2/metabolismo , Progressão da Doença , Humanos , Fígado/metabolismo , Cirrose Hepática/fisiopatologia , Falência Hepática , Neoplasias Hepáticas/fisiopatologia , Síndrome Metabólica/fisiopatologia , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Obesidade/metabolismo
11.
Medicine (Baltimore) ; 100(3): e23957, 2021 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-33545975

RESUMO

BACKGROUND: This meta-analysis aimed to systematically review current available literature to assess the impact of regulatory T cells (Tregs) on the prognosis of hepatocellular carcinoma (HCC). METHODS: We will browse the online databases of PubMed and Cochrane Library. The summary hazard ratio (HR) and their 95% confidence intervals (CIs) will be combined to present the value reported in the study. CONCLUSION: Our meta-analysis will provide useful guidance in treatment of HCC based on the reported evidences regarding the impact of Tregs on the prognosis of HCC. OSF REGISTRATION NUMBER: 10.17605/OSF.IO/3Q8PW.


Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Protocolos Clínicos , Linfócitos T Reguladores/transplante , Carcinoma Hepatocelular/fisiopatologia , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/fisiopatologia , Metanálise como Assunto , Prognóstico , Revisões Sistemáticas como Assunto
12.
PLoS Comput Biol ; 17(2): e1008696, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33561121

RESUMO

Hepatocellular carcinoma (HCC) is a significant health problem worldwide with poor prognosis. Drug repositioning represents a profitable strategy to accelerate drug discovery in the treatment of HCC. In this study, we developed a new approach for predicting therapeutic drugs for HCC based on tissue-specific pathways and identified three newly predicted drugs that are likely to be therapeutic drugs for the treatment of HCC. We validated these predicted drugs by analyzing their overlapping drug indications reported in PubMed literature. By using the cancer cell line data in the database, we constructed a Connectivity Map (CMap) profile similarity analysis and KEGG enrichment analysis on their related genes. By experimental validation, we found securinine and ajmaline significantly inhibited cell viability of HCC cells and induced apoptosis. Among them, securinine has lower toxicity to normal liver cell line, which is worthy of further research. Our results suggested that the proposed approach was effective and accurate for discovering novel therapeutic options for HCC. This method also could be used to indicate unmarked drug-disease associations in the Comparative Toxicogenomics Database. Meanwhile, our method could also be applied to predict the potential drugs for other types of tumors by changing the database.


Assuntos
Antineoplásicos/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/fisiopatologia , Biologia Computacional/métodos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/fisiopatologia , Apoptose , Linhagem Celular Tumoral , Sobrevivência Celular , Bases de Dados Factuais , Descoberta de Drogas , Reposicionamento de Medicamentos/métodos , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Células Hep G2 , Humanos , Fígado/metabolismo , RNA Mensageiro/metabolismo , Toxicogenética , Transcriptoma
13.
J Tradit Chin Med ; 41(1): 157-166, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33522209

RESUMO

OBJECTIVE: To investigate the therapeutic effect of the Jianpi Liqi Fang ( ,JPLQF) combined with transcatheter arterial chemoembolization (TACE) in patients with hepatocellular carcinoma (HCC) and spleen deficiency syndrome (SDS) and identify a potential indicator of efficacy. METHODS: Ninety-nine patients with HCC who were diagnosed with SDS, non-spleen deficiency syndrome (NSDS), or no syndrome (NS) were treated with JPLQF combined with TACE for three periods. Therapeutic efficacy was compared among the groups. Plasma proteins were screened using label-free discovery analysis and verified via enzyme-linked immunosorbent assay (ELISA). Furthermore, receiver operating characteristic (ROC) curves were analyzed to evaluate therapeutic indicators. RESULTS: After treatment, the Karnofsky Performance Status was significantly improved in the SDS group and significantly better than that in the NS group. The Traditional Chinese Medicine (TCM) syndrome scores were lower in the SDS group after treatment and lower than those in the NSDS group. However, alanine aminotransferase, carbohydrate antigen 19-9, alpha-fetoprotein, and carcinoembryonic antigen levels and white blood cell and platelet counts did not differ among the groups. Serum aspartate aminotransferase levels in the SDS group were significantly lower after treatment than before treatment, and total bilirubin levels were significantly lower in the SDS group than in the NSDS group. Label-free analysis identified 24 differentially expressed proteins (DEPs) between the SDS and NS groups, including 17 and 7 upregulated and downregulated proteins, respectively. Fibulin-5 (FBLN5) displayed the largest difference in expression between the groups. ELISA confirmed that FBLN5 levels were significantly lower in the NSDS and NS groups than in the SDS group. Following treatment with JPLQF and TACE, FBLN5 expression was upregulated only in the SDS group. Furthermore, ROC curve analysis indicated that FBLN5 may serve as a potential indicator of the efficacy of JPLQF combined with TACE in patients with HCC and SDS. CONCLUSION: JPLQF combined with TACE improved quality of life, clinical TCM symptoms, and liver function in patients with HCC and SDS. FBLN5 expression was significantly altered by treatment with JPLQF and TACE in patients with HCC and SDS.


Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Quimioembolização Terapêutica , Medicamentos de Ervas Chinesas/administração & dosagem , Neoplasias Hepáticas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Artérias/efeitos dos fármacos , Carcinoma Hepatocelular/fisiopatologia , Carcinoma Hepatocelular/terapia , Terapia Combinada , Feminino , Humanos , Neoplasias Hepáticas/fisiopatologia , Neoplasias Hepáticas/terapia , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Baço/efeitos dos fármacos , Baço/fisiopatologia , Adulto Jovem
14.
J Pineal Res ; 70(3): e12724, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33615553

RESUMO

Cancer-related fatigue (CRF) and stress are common symptoms in cancer patients and represent early side effects of cancer treatment which affect the life quality of the patients. CRF may partly depend on disruption of the circadian rhythm. Locomotor activity and corticosterone rhythms are two important circadian outputs which can be used to analyze possible effects on the circadian function during cancer development and treatment. The present study analyzes the relationship between locomotor activity rhythm, corticosterone levels, hepatocellular carcinoma (HCC) development, and radiotherapy treatment in a mouse model. HCC was induced in mice by single injection of diethylnitrosamine (DEN) and chronic treatment of phenobarbital in drinking water. Another group received chronic phenobarbital treatment only. Tumor bearing animals were divided randomly into four groups irradiated at four different Zeitgeber time points. Spontaneous locomotor activity was recorded continuously; serum corticosterone levels and p-ERK immunoreaction in the suprachiasmatic nucleus (SCN) were investigated. Phenobarbital treated mice showed damped corticosterone levels and a less stable 24 hours activity rhythm as well as an increase in activity during the light phase, reminiscent of sleep disruption. The tumor mice showed an increase in corticosterone level during the inactive phase and decreased activity during the dark phase, reminiscent of CRF. After irradiation, corticosterone levels were further increased and locomotor activity rhythms were disrupted. Lowest corticosterone levels were observed after irradiation during the early light phase; thus, this time might be the best to apply radiotherapy in order to minimize side effects.


Assuntos
Ciclos de Atividade , Comportamento Animal , Carcinoma Hepatocelular/radioterapia , Ritmo Circadiano , Corticosterona/sangue , Neoplasias Hepáticas Experimentais/radioterapia , Locomoção , Núcleo Supraquiasmático/fisiopatologia , Animais , Biomarcadores/sangue , Carcinoma Hepatocelular/sangue , Carcinoma Hepatocelular/induzido quimicamente , Carcinoma Hepatocelular/fisiopatologia , Cronoterapia , Dietilnitrosamina , Progressão da Doença , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Neoplasias Hepáticas Experimentais/sangue , Neoplasias Hepáticas Experimentais/induzido quimicamente , Neoplasias Hepáticas Experimentais/fisiopatologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas Circadianas Period/genética , Fenobarbital , Fosforilação , Núcleo Supraquiasmático/metabolismo , Fatores de Tempo
15.
Medicine (Baltimore) ; 100(1): e24060, 2021 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-33429769

RESUMO

ABSTRACT: Explore the predictive power of Circulating Tumor Cells (CTCs) for evaluating the prognosis of transarterial chemoembolization (TACE) treatment on advanced hepatocellular carcinoma (HCC) patients, and use it to construct a prediction model.We retrospectively analyzed 43 patients with Barcelona Clinic Liver Cancer stage C HCC who underwent TACE treatment.The survival time of 43 advanced HCC patients were 2 to 60 months, with the median survival time of 12 months, 1-, 3-, and 5-year survival rates were 42.9%, 9.0%, and 3.6%, respectively. The OS of patients with high level of CTCs before TACE (CTC1 > 2) was significantly lower than that of patients with low level of CTCs (8 vs 12 months, P = .040), but there was no significant difference in PFS between the 2 groups (P = .926). Meanwhile, there was no significant difference in OS and PFS between patients with high level CTCs and those with low level CTCs at 1 week and 4 weeks after TACE (P all > .05). In univariate and multivariate Cox regression analysis, the number of lesions and CTC before TACE were the independent influencing factors for prognosis in these patients, and the HR was 3.01 and 1.20, respectively (all P < .05). The area under curve of COX regression model to predict OS increased with the increase of follow-up time, ranging from 0.56 to 0.85.The CTCs number before TACE is an effective biomarker for predicting the OS of advanced HCC patients. The joint prediction model based on CTCs and tumor number can effectively predict the prognosis of patients with advanced HCC.


Assuntos
Carcinoma Hepatocelular/terapia , Quimioembolização Terapêutica/normas , Prognóstico , Adulto , Idoso , Carcinoma Hepatocelular/fisiopatologia , Quimioembolização Terapêutica/métodos , Quimioembolização Terapêutica/estatística & dados numéricos , Intervalo Livre de Doença , Feminino , Humanos , Neoplasias Hepáticas/fisiopatologia , Neoplasias Hepáticas/terapia , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Análise de Sobrevida
16.
Arch Biochem Biophys ; 699: 108754, 2021 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-33450239

RESUMO

Drug resistance is one of the major challenges for treatment of hepatocellular carcinoma (HCC) with sorafenib. Our present study found that sorafenib resistant (SR) HCC cells showed epithelial-mesenchymal transition (EMT) characteristics with the downregulation of epithelial marker and upregulation of mesenchymal makers. The expression of Snail, a core factor of EMT, was increased in HCC/SR cells, while knockdown of Snail can restore sorafenib sensitivity and EMT potential of HCC/SR cells. Further, the upregulation of protein stability was responsible for the upregulation of Snail in HCC/SR cells. ATM and CSN2, which can stabilize Snail protein, were increased in HCC/SR cells. Knockdown of ATM and CSN2 can suppress the expression of Snail and increase sorafenib sensitivity of HCC/SR cells. It indicated that targeted inhibition of Snail might be helpful to overcome sorafenib resistance of HCC patients.


Assuntos
Carcinoma Hepatocelular/fisiopatologia , Resistencia a Medicamentos Antineoplásicos/fisiologia , Neoplasias Hepáticas/fisiopatologia , Fatores de Transcrição da Família Snail/metabolismo , Sorafenibe/farmacologia , Proteínas Mutadas de Ataxia Telangiectasia/genética , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Complexo do Signalossomo COP9/genética , Complexo do Signalossomo COP9/metabolismo , Linhagem Celular Tumoral , Transição Epitelial-Mesenquimal/fisiologia , Inativação Gênica , Humanos , Estabilidade Proteica , RNA Interferente Pequeno/farmacologia , Fatores de Transcrição da Família Snail/química , Fatores de Transcrição da Família Snail/genética , Regulação para Cima/efeitos dos fármacos
17.
Metabolism ; 117: 154708, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33444607

RESUMO

Nonalcoholic fatty liver disease (NAFLD) includes a broad spectrum of liver dysfunctions and it is predicted to become the primary cause of liver failure and hepatocellular carcinoma. Mitochondria are highly dynamic organelles involved in multiple metabolic/bioenergetic pathways in the liver. Emerging evidence outlined that hepatic mitochondria adapt in number and functionality in response to external cues, as high caloric intake and obesity, by modulating mitochondrial biogenesis, and maladaptive mitochondrial response has been described from the early stages of NAFLD. Indeed, mitochondrial plasticity is lost in progressive NAFLD and these organelles may assume an aberrant phenotype to drive or contribute to hepatocarcinogenesis. Severe alimentary regimen and physical exercise represent the cornerstone for NAFLD care, although the low patients' compliance is urging towards the discovery of novel pharmacological treatments. Mitochondrial-targeted drugs aimed to recover mitochondrial lifecycle and to modulate oxidative stress are becoming attractive molecules to be potentially introduced for NAFLD management. Although the path guiding the switch from bench to bedside remains tortuous, the study of mitochondrial dynamics is providing intriguing perspectives for future NAFLD healthcare.


Assuntos
Mitocôndrias/fisiologia , Dinâmica Mitocondrial/fisiologia , Hepatopatia Gordurosa não Alcoólica/fisiopatologia , Animais , Carcinoma Hepatocelular/fisiopatologia , Humanos , Fígado/fisiopatologia , Neoplasias Hepáticas/fisiopatologia , Estresse Oxidativo/fisiologia
18.
Hepatology ; 73(4): 1365-1380, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-32594528

RESUMO

BACKGROUND AND AIMS: The development and progression of hepatocellular carcinoma (HCC) is dependent on its local microenvironment. Tumor-associated macrophages (TAMs) are deemed a key factor for the tumor microenvironment and attribute to contribute to tumor aggressiveness. However, the detailed mechanism underlying the pro-metastatic effect of TAMs on HCC remains undefined. APPROACH AND RESULTS: The present study proved that TAMs were enriched in HCC. TAMs were characterized by an M2-polarized phenotype and accelerated the migratory potential of HCC cells in vitro and in vivo. Furthermore, we found that M2-derived exosomes induced TAM-mediated pro-migratory activity. With the use of mass spectrometry, we identified that integrin, αM ß2 (CD11b/CD18), was notably specific and efficient in M2 macrophage-derived exosomes (M2 exos). Blocking either CD11b and/or CD18 elicited a significant decrease in M2 exos-mediated HCC cell metastasis. Mechanistically, M2 exos mediated an intercellular transfer of the CD11b/CD18, activating the matrix metalloproteinase-9 signaling pathway in recipient HCC cells to support tumor migration. CONCLUSIONS: Collectively, the exosome-mediated transfer of functional CD11b/CD18 protein from TAMs to tumor cells may have the potency to boost the migratory potential of HCC cells, thus providing insights into the mechanism of tumor metastasis.


Assuntos
Antígeno CD11b/metabolismo , Antígenos CD18/metabolismo , Carcinoma Hepatocelular , Exossomos/metabolismo , Neoplasias Hepáticas , Macrófagos Associados a Tumor/metabolismo , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/fisiopatologia , Carcinoma Hepatocelular/secundário , Linhagem Celular Tumoral , Exossomos/fisiologia , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/fisiopatologia , Neoplasias Hepáticas/secundário , Metástase Neoplásica/fisiopatologia , Transdução de Sinais , Microambiente Tumoral/fisiologia , Macrófagos Associados a Tumor/fisiologia
19.
J Gastroenterol Hepatol ; 36(3): 618-628, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32627853

RESUMO

Hepatocellular carcinoma is a common cancer with a poor prognosis, associated with high economic costs and a significant burden of disease. While it is often asymptomatic in the early stages, patients may experience great discomfort from advanced disease, treatment adverse effects, or decompensation of underlying cirrhosis. Palliative care has the potential to markedly improve quality of life, physical, and psychological symptoms in patients with end-stage liver disease, and has been shown to prolong survival in some nonhepatocellular carcinoma malignancies. However, this service is underutilized in hepatocellular carcinoma, and referrals are frequently late due to factors such as stigmatization, inadequate resources, lack of education for nonpalliative care physicians and inadequate modeling for integration of palliative and supportive care within liver disease services. In the future, education workshops, population-based awareness campaigns, increased funding and improved models of care, may improve the uptake of palliative care and subsequently optimize patient care, particularly towards the end of life.


Assuntos
Carcinoma Hepatocelular/terapia , Neoplasias Hepáticas/terapia , Cuidados Paliativos , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/fisiopatologia , Feminino , Humanos , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/fisiopatologia , Masculino , Estadiamento de Neoplasias , Cuidados Paliativos/métodos , Cuidados Paliativos/tendências , Prognóstico , Qualidade de Vida
20.
PLoS Biol ; 18(12): e3000803, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33275593

RESUMO

Loss of hepatic fructose-1, 6-bisphosphate aldolase B (Aldob) leads to a paradoxical up-regulation of glucose metabolism to favor hepatocellular carcinogenesis (HCC), but the upstream signaling events remain poorly defined. Akt is highly activated in HCC, and targeting Akt is being explored as a potential therapy for HCC. Herein, we demonstrate that Aldob suppresses Akt activity and tumor growth through a protein complex containing Aldob, Akt, and protein phosphatase 2A (PP2A), leading to inhibition of cell viability, cell cycle progression, glucose uptake, and metabolism. Interestingly, Aldob directly interacts with phosphorylated Akt (p-Akt) and promotes the recruitment of PP2A to dephosphorylate p-Akt, and this scaffolding effect of Aldob is independent of its enzymatic activity. Loss of Aldob or disruption of Aldob/Akt interaction in Aldob R304A mutant restores Akt activity and tumor-promoting effects. Consistently, Aldob and p-Akt expression are inversely correlated in human HCC tissues, and Aldob down-regulation coupled with p-Akt up-regulation predicts a poor prognosis for HCC. We have further discovered that Akt inhibition or a specific small-molecule activator of PP2A (SMAP) efficiently attenuates HCC tumorigenesis in xenograft mouse models. Our work reveals a novel nonenzymatic role of Aldob in negative regulation of Akt activation, suggesting that directly inhibiting Akt activity or through reactivating PP2A may be a potential therapeutic approach for HCC treatment.


Assuntos
Carcinoma Hepatocelular/metabolismo , Frutose-Bifosfato Aldolase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/fisiopatologia , Linhagem Celular Tumoral , Sobrevivência Celular/genética , China , Frutose-Bifosfato Aldolase/biossíntese , Frutose-Bifosfato Aldolase/genética , Glucose/metabolismo , Humanos , Neoplasias Hepáticas/metabolismo , Masculino , Camundongos , Camundongos Nus , Fosforilação , Proteína Fosfatase 2/metabolismo , Proteína Fosfatase 2/fisiologia , Ensaios Antitumorais Modelo de Xenoenxerto
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