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1.
Anticancer Res ; 39(10): 5695-5701, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570469

RESUMO

Large tumor size and arterioportal shunt are poor prognostic factors for hepatocellular carcinoma. Lenvatinib is a novel and potent multi-tyrosine kinase inhibitor developed in Japan. A 66-year-old woman with hepatocellular carcinoma and untreated hepatitis C was referred to our hospital. She was judged as unresectable and was treated with four sessions of transarterial chemoembolization; however, the therapeutic effect was unsatisfactory because of major arterioportal shunt. Lenvatinib was sequentially administered for 4 months. Thereafter, we observed tumor shrinkage, complete disappearance of arterioportal shunt, and obvious improvement in liver function. A curative conversion hepatectomy was successfully accomplished. The extremely high levels of tumor markers almost normalized; the pretreatment levels were 1,008,021 ng/ml for alpha-fetoprotein. At 1 year after the primary treatment, the patient has not experienced recurrence. To our knowledge, this is the first case of a patient with initially unresectable hepatocellular carcinoma with arterioportal shunt who underwent conversion hepatectomy after multidisciplinary treatment, including lenvatinib.


Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/cirurgia , Hepatectomia/métodos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/cirurgia , Compostos de Fenilureia/uso terapêutico , Quinolinas/uso terapêutico , Idoso , Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/metabolismo , Quimioembolização Terapêutica/métodos , Feminino , Humanos , Neoplasias Hepáticas/metabolismo , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/cirurgia , alfa-Fetoproteínas/metabolismo
2.
Anticancer Res ; 39(9): 4787-4794, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31519580

RESUMO

BACKGROUND/AIM: The aim of this study was to investigate the effects of the macrophage colony-stimulating factor (M-CSF) receptor antagonist on hepatic carcinogenesis in mice. MATERIALS AND METHODS: Mice were injected with diethylnitrosamine (DEN) and treated with M-CSF receptor antagonist GW2580 (GW) or a saline vehicle just after (early treated group) or 2 weeks after (late treated group) DEN injection. Animals were sacrificed after 28 weeks and incidence of tumor was assessed. Isolated Kupffer cells were co-cultured with M-CSF in the presence or absence of GW, and the concentration of VEGF was measured. RESULTS: The incidence of tumors was significantly blunted both in the early- and the late-treated groups. In addition, angiogenesis within the tumor was also suppressed in both groups. The concentration of VEGF increased in Kupffer cells treated with M-CSF compared to those cultured without M-CSF. This increase was blunted by GW. CONCLUSION: M-CSF and its receptor could be novel molecular targets for hepatocellular carcinoma.


Assuntos
Anisóis/farmacologia , Transformação Celular Neoplásica/efeitos dos fármacos , Pirimidinas/farmacologia , Receptor de Fator Estimulador de Colônias de Macrófagos/antagonistas & inibidores , Animais , Biomarcadores , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Proliferação de Células/efeitos dos fármacos , Imuno-Histoquímica , Macrófagos do Fígado/efeitos dos fármacos , Macrófagos do Fígado/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Masculino , Camundongos , Carga Tumoral/efeitos dos fármacos
3.
Anticancer Res ; 39(9): 5039-5045, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31519612

RESUMO

BACKGROUND/AIM: Although complete resection of liver metastases colorectal cancer (CLM) is the only potentially curative treatment, surgery alone is not enough, as the recurrence rate after resection is high. Therefore, in clinical practice, adjuvant chemotherapy is performed after resection of CLM. However, the evidence supporting the efficacy of such adjuvant chemotherapy is not sufficient. Previous reports have noted that adjuvant chemotherapy after resection of CLM is effective only in patients with a high risk of recurrence. The purpose of this study was to classify the risk of recurrence using systemic inflammatory markers reportedly associated with clinical outcomes in patients with various types of malignancies, and evaluate the efficacy of adjuvant chemotherapy according to the risk of recurrence. PATIENTS AND METHODS: The medical records of 119 patients with CLM who underwent potentially curative surgery between 1996 and 2017 were retrospectively reviewed. Preoperative blood samples were obtained within 2 weeks before resection of CLM. was calculated from the blood samples Dividing the serum C-reactive protein level by the serum albumin level derived the C-reactive protein-to-albumin ratio (CAR), reflecting the risk of recurrence. The optimal cut-off value of the CAR was determined according to receiver operating characteristic curve analysis, and then the patients were classified into the high-CAR (high recurrence risk) or low-CAR (low recurrence risk) group. The relationship between the CAR and relapse-free survival after resection of CLM was examined and the efficacy of adjuvant chemotherapy according to the risk of recurrence was evaluated. RESULTS: The cut-off value of the CAR was set at 0.0471. The relapse-free survival rate was significantly better in the low-CAR group than in the high-CAR group. Efficacy of adjuvant chemotherapy after resection of CLM was not recognized in the low-CAR group, whereas the relapse-free survival rates were significantly better for patients who were treated with adjuvant chemotherapy after resection of CLM in the high-CAR group. CONCLUSION: The preoperative CAR, as a systemic inflammatory marker, was found to be useful as a prognostic marker in patients with CLM who were treated with potentially curative resection. Furthermore, it was suggested that adjuvant chemotherapy after resection of CLM may be effective for preventing recurrence in patients with high levels of inflammatory markers who have a high risk of recurrence.


Assuntos
Biomarcadores , Neoplasias Colorretais/patologia , Mediadores da Inflamação/metabolismo , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/secundário , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimioterapia Adjuvante , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Prognóstico , Curva ROC , Recidiva , Estudos Retrospectivos , Adulto Jovem
4.
Braz J Med Biol Res ; 52(10): e8631, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31531526

RESUMO

The long non-coding RNA (lncRNA) maternally expressed gene 3 (MEG3), a tumor suppressor, is critical for the carcinogenesis and progression of different cancers, including hepatocellular carcinoma (HCC). To date, the roles of lncRNA MEG3 in HCC are not well illustrated. Therefore, this study used western blot and qRT-PCR to evaluate the expression of MEG3, miR-9-5p, and Sex determining Region Y-related HMG-box 11 (SOX11) in HCC tissues and cell lines. RNA pull-down and luciferase reporter assay were used to evaluate these molecular interactions. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and flow cytometry detected the viability and apoptosis of HCC cells, respectively. The results showed that MEG3 and SOX11 were poorly expressed but miR-9-5p was highly expressed in HCC. The expression levels of these molecules suggested a negative correlation between MEG3 and miR-9-5p and a positive correlation with SOX11, confirmed by Pearson's correlation analysis and biology experiments. Furthermore, MEG3 could combine with miR-9-5p, and SOX11 was a direct target of miR-9-5p. Moreover, MEG3 over-expression promoted cell apoptosis and growth inhibition in HCC cells through sponging miR-9-5p to up-regulate SOX11. Therefore, the interactions among MEG3, miR-9-5p, and SOX11 might offer a novel insight for understanding HCC pathogeny and provide potential diagnostic markers and therapeutic targets for HCC.


Assuntos
Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , MicroRNAs/genética , RNA Longo não Codificante/genética , Fatores de Transcrição SOXC/genética , Apoptose/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Proliferação de Células/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Masculino , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Estadiamento de Neoplasias , RNA Longo não Codificante/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Fatores de Transcrição SOXC/metabolismo , Ativação Transcricional , Transfecção , Regulação para Cima
5.
Medicine (Baltimore) ; 98(32): e16748, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31393389

RESUMO

Several studies have investigated the relationship between Manganese (Mn) levels and hepatocellular carcinoma (HCC), but the results were inconsistent. Thus, we conducted a systematic review and meta-analysis to evaluate the association between Mn levels and HCC. Nine studies focusing on hair Mn levels, 6 studies on serum Mn levels and 6 studies on tissue Mn levels were identified in a systematic search of PubMed, CNKI, Wanfang and SinoMed databases. Standard mean differences (SMD) with the corresponding 95% confidence intervals (CI) were pooled to compare the Mn levels between HCC and controls. In serum, the Mn levels in HCC were significantly lower than in healthy controls (SMD (95% CI): -0.941 (-1.559, -0.323)). In hair, the Mn levels in HCC were slightly lower than in healthy controls, but not significant (SMD (95% CI): -0.168 (-0.766, 0.430)). In tissue, the Mn levels in tumors were significantly lower than in adjacent normal tissues (SMD (95% CI): -4.867 (-7.143, -2.592)). Subgroup analysis showed consistent results. In conclusion, this meta-analysis suggested an inverse association between Mn levels and HCC.


Assuntos
Carcinoma Hepatocelular/sangue , Neoplasias Hepáticas/sangue , Manganês/sangue , Grupo com Ancestrais do Continente Asiático , Carcinoma Hepatocelular/metabolismo , Cabelo/química , Humanos , Neoplasias Hepáticas/metabolismo , Manganês/análise , Estudos Observacionais como Assunto , Fatores de Risco
6.
Gene ; 716: 144031, 2019 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-31377314

RESUMO

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


Assuntos
Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , RNA/metabolismo , Apoptose , Carcinoma Hepatocelular/enzimologia , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Ciclo Celular , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Humanos , Neoplasias Hepáticas/enzimologia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Fosfatidilinositol 3-Quinase/antagonistas & inibidores , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Regulação para Cima
7.
Oncol Rep ; 42(4): 1380-1390, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31364737

RESUMO

The dysregulation of microRNAs (miRNAs) is associated with the development and progression of a variety of cancers, including liver cancer. Aberrant expression of miRNA (miR)­124 has been demonstrated in liver cancer, but its functional mechanism in liver cancer is still largely unknown. Metastasis of liver cancer is one of the most common causes of mortality. The present study showed that miR­124 inhibited the proliferation, migration and invasion of liver cancer cells. Furthermore, chloride intracellular channel 1 (CLIC1) was identified as a novel target of miR­124 in liver cancer cells. Overexpression of miR­124 reduced CLIC1 expression at both the protein and mRNA levels in liver cancer cells. Downregulation of CLIC1 decreased the migration and invasion of liver cancer cells without affecting cell proliferation. Taken together, these results showed that CLIC1 is a critical target for miR­124­mediated inhibitory effects on cell migration and invasion. Thus, miR­124 or suppression of CLIC1 may have diagnostic value and therapeutic potential for the treatment of human liver cancer.


Assuntos
Canais de Cloreto/metabolismo , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , MicroRNAs/metabolismo , Regiões 3' não Traduzidas , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Movimento Celular/fisiologia , Canais de Cloreto/genética , Progressão da Doença , Regulação para Baixo , Técnicas de Silenciamento de Genes , Genes Supressores de Tumor , Células Hep G2 , Humanos , Neoplasias Hepáticas/genética , MicroRNAs/biossíntese , MicroRNAs/genética , Invasividade Neoplásica , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
8.
Cancer Sci ; 110(10): 3110-3121, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31385398

RESUMO

Hepatocellular carcinoma (HCC) is one of the most common malignancies and the fourth leading cause of cancer-related death worldwide. Our previous study showed that EYA4 functioned by suppressing growth of HCC tumor cells, but its molecular mechanism is still not elucidated. Based on the results of gene microassay, EYA4 was inversely correlated with MYCBP and was verified in human HCC tissues by immunohistochemistry and western blot. Overexpressed and KO EYA4 in human HCC cell lines confirmed the negative correlation between EYA4 and MYCBP by qRT-PCR and western blot. Transfected siRNA of MYCBP in EYA4 overexpressed cells and overexpressed MYCBP in EYA4 KO cells could efficiently rescue the proliferation and G2/M arrest effects of EYA4 on HCC cells. Mechanistically, armed with serine/threonine-specific protein phosphatase activity, EYA4 reduced nuclear translocation of ß-catenin by dephosphorylating ß-catenin at Ser552, thereby suppressing the transcription of MYCBP which was induced by ß-catenin/LEF1 binding to the promoter of MYCBP. Clinically, HCC patients with highly expressed EYA4 and poorly expressed MYCBP had significantly longer disease-free survival and overall survival than HCC patients with poorly expressed EYA4 and highly expressed MYCBP. In conclusion, EYA4 suppressed HCC tumor cell growth by repressing MYCBP by dephosphorylating ß-catenin S552. EYA4 combined with MYCBP could be potential prognostic biomarkers in HCC.


Assuntos
Carcinoma Hepatocelular/metabolismo , Proteínas de Ligação a DNA/genética , Neoplasias Hepáticas/metabolismo , Transativadores/genética , Transativadores/metabolismo , Fatores de Transcrição/genética , beta Catenina/metabolismo , Adulto , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/genética , Linhagem Celular Tumoral , Núcleo Celular/metabolismo , Proliferação de Células , Proteínas de Ligação a DNA/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hepáticas/genética , Masculino , Pessoa de Meia-Idade , Fosforilação , Prognóstico , Serina/metabolismo , Análise de Sobrevida , Fatores de Transcrição/metabolismo , Transcrição Genética , beta Catenina/química
9.
DNA Cell Biol ; 38(10): 1112-1124, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31464520

RESUMO

In this study, we mined out hepatocellular carcinoma (HCC) driver genes from MEDLINE literatures by bioinformatics methods of pathway crosstalk and protein interaction network. Furthermore, the relationship between driver genes and their clinicopathological characteristics, as well as classification effectiveness was verified in the public databases. We identified 560 human genes reported to be associated with HCC in 1074 published articles. Functional analysis revealed that biological processes and biochemical pathways relating to tumor pathogenesis, cancer disease, tumor cell molecule, and hepatic disease were enriched in these genes. Pathway crosstalk analysis indicated that significant pathways could be divided into three modules: cancer disease, virus infection, and tumor signaling pathway. The HCC-related protein-protein interaction network comprised 10,212 nodes, and 56,400 edges were mined out to identify 18 modules corresponding to 14 driver genes. We verified that these 14 driver genes have high classification effectiveness to distinguish cancer samples from normal samples and the classification effectiveness was better than that of randomly selected genes. Present study provided pathway crosstalk and protein interaction network for understanding potential tumorigenesis genes underlying HCC. The 14 driver genes identified from this study are of great translational value in HCC diagnosis and treatment, as well as in clinical study on the pathogenesis of HCC.


Assuntos
Carcinoma Hepatocelular/genética , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Neoplasias Hepáticas/genética , MicroRNAs/genética , Proteínas de Neoplasias/genética , Idoso , Carcinogênese/genética , Carcinogênese/metabolismo , Carcinogênese/patologia , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Biologia Computacional/métodos , Progressão da Doença , Feminino , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Masculino , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Proteínas de Neoplasias/metabolismo , Mapeamento de Interação de Proteínas , Curva ROC , Transdução de Sinais
10.
J Surg Oncol ; 120(6): 966-975, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31401809

RESUMO

BACKGROUND AND OBJECTIVES: Gastrinomas are the most prevalent functioning neuroendocrine tumors (NET) in multiple endocrine neoplasia type 1 (MEN1). Guidelines suggest medical therapy in most patients, but surgery may be considered in a subgroup. Currently, factors to guide management are necessary. This population-based cohort study assessed prognostic factors of survival in patients with MEN1-related gastrinomas. METHODS: Patients with MEN1 having gastrinomas were identified in the Dutch MEN1 database from 1990 to 2014 based on fasting serum gastrin (FSG) levels and/or pathology. Predictors of overall survival were assessed using Cox regression. RESULTS: Sixty-three patients with gastrinoma (16% of the MEN1 population) were identified. Five- and 10-year overall survival rates were 83% and 65%, respectively. Prognostic factors associated with overall survival were initial FSG levels ≥20x upper limit of normal (ULN) (hazard ratio [HR], 6.2 [95% confidence interval, 1.7-23.0]), pancreatic NET ≥2 cm (HR 4.5; [1.5-13.1]), synchronous liver metastases (HR 8.9; [2.1-36.7]), gastroduodenoscopy suspicious for gastric NETs (HR 12.7; [1.4-115.6]), and multiple concurrent NETs (HR 5.9; [1.2-27.7]). CONCLUSION: Life expectancy of patients with MEN1 gastrinoma is reduced. FSG levels and pancreatic NETs ≥2 cm are prognostic factors. FSG levels might guide surveillance intensity, step-up to additional diagnostics, or provide arguments in selecting patients who might benefit from surgery.


Assuntos
Gastrinoma/mortalidade , Neoplasias Intestinais/mortalidade , Neoplasias Hepáticas/mortalidade , Tumores Neuroendócrinos/mortalidade , Neoplasias Pancreáticas/mortalidade , Proteínas Proto-Oncogênicas/metabolismo , Neoplasias Gástricas/mortalidade , Estudos de Coortes , Feminino , Seguimentos , Gastrinoma/metabolismo , Gastrinoma/patologia , Gastrinoma/cirurgia , Humanos , Neoplasias Intestinais/metabolismo , Neoplasias Intestinais/patologia , Neoplasias Intestinais/cirurgia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/cirurgia , Masculino , Pessoa de Meia-Idade , Países Baixos , Tumores Neuroendócrinos/metabolismo , Tumores Neuroendócrinos/patologia , Tumores Neuroendócrinos/cirurgia , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/cirurgia , Prognóstico , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Neoplasias Gástricas/cirurgia , Taxa de Sobrevida
11.
Cancer Imaging ; 19(1): 49, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31307551

RESUMO

BACKGROUND: Partial hepatectomy is the first option for intrahepatic mass-forming cholangiocarcinoma (IMCC) treatment, which would prolong survival. The main reason for the poor outcome after curative resection is the high incidence of early recurrence (ER). The aim of this study was to investigate the combined predictive performance of qualitative and quantitative magnetic resonance imaging (MRI) features and prognostic immunohistochemical markers for the ER of IMCC. METHODS: Forty-seven patients with pathologically proven IMCC were enrolled in this retrospective study. Preoperative contrast-enhanced MRI and post-operative immunohistochemical staining of epidermal growth factor receptors (EGFR), vascular endothelial growth factor receptor (VEGFR), P53 and Ki67 were performed. Univariate analysis identified clinic-radiologic and pathological risk factors of ER. Radiomics analysis was performed based on four MRI sequences including fat suppression T2-weighted imaging (T2WI/FS), arterial phase (AP), portal venous phase (PVP), and delayed phase (DP) contrast enhanced imaging. A clinicoradiologic-pathological (CRP) model, radiomics model, and combined model were developed. And ROC curves were used to explore their predictive performance for ER stratification. RESULTS: Enhancement patterns and VEGFR showed significant differences between the ER group and non-ER group (P = 0.001 and 0.034, respectively). The radiomics model based on AP, PVP and DP images presented superior AUC (0.889, 95% confidence interval (CI): 0.783-0.996) among seven radiomics models with a sensitivity of 0.938 and specificity of 0.839. The combined model, containing enhancement patterns, VEGFR and radiomics features, showed a preferable ER predictive performance compared to the radiomics model or CRP model alone, with AUC, sensitivity and specificity of 0.949, 0.875 and 0.774, respectively. CONCLUSIONS: The combined model was the superior predictive model of ER. Combining qualitative and quantitative MRI features and VEGFR enables ER prediction, thus facilitating personalized treatment for patients with IMCC.


Assuntos
Neoplasias dos Ductos Biliares/diagnóstico por imagem , Biomarcadores Tumorais/metabolismo , Colangiocarcinoma/diagnóstico por imagem , Neoplasias Hepáticas/diagnóstico por imagem , Imagem por Ressonância Magnética/métodos , Recidiva Local de Neoplasia/diagnóstico por imagem , Neoplasias dos Ductos Biliares/metabolismo , Neoplasias dos Ductos Biliares/patologia , Colangiocarcinoma/metabolismo , Colangiocarcinoma/patologia , Feminino , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Masculino , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia
12.
Gut ; 68(9): 1676-1687, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31315892

RESUMO

BACKGROUND & OBJECTIVES: Hepatocellular carcinoma (HCC) is the second leading cause of cancer death worldwide. Several types of chronic liver disease predispose to HCC, and several different signalling pathways have been implicated in its pathogenesis, but no common molecular event has been identified. Ca2+ signalling regulates the proliferation of both normal hepatocytes and liver cancer cells, so we investigated the role of intracellular Ca2+ release channels in HCC. DESIGN: Expression analyses of the type 3 isoform of the inositol 1, 4, 5-trisphosphate receptor (ITPR3) in human liver samples, liver cancer cells and mouse liver were combined with an evaluation of DNA methylation profiles of ITPR3 promoter in HCC and characterisation of the effects of ITPR3 expression on cellular proliferation and apoptosis. The effects of de novo ITPR3 expression on hepatocyte calcium signalling and liver growth were evaluated in mice. RESULTS: ITPR3 was absent or expressed in low amounts in hepatocytes from normal liver, but was expressed in HCC specimens from three independent patient cohorts, regardless of the underlying cause of chronic liver disease, and its increased expression level was associated with poorer survival. The ITPR3 gene was heavily methylated in control liver specimens but was demethylated at multiple sites in specimens of patient with HCC. Administration of a demethylating agent in a mouse model resulted in ITPR3 expression in discrete areas of the liver, and Ca2+ signalling was enhanced in these regions. In addition, cell proliferation and liver regeneration were enhanced in the mouse model, and deletion of ITPR3 from human HCC cells enhanced apoptosis. CONCLUSIONS: These results provide evidence that de novo expression of ITPR3 typically occurs in HCC and may play a role in its pathogenesis.


Assuntos
Carcinoma Hepatocelular/metabolismo , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Neoplasias Hepáticas/metabolismo , Adulto , Animais , Apoptose/fisiologia , Sinalização do Cálcio/fisiologia , Carcinogênese/genética , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Proliferação de Células/fisiologia , Células Cultivadas , Metilação de DNA , Feminino , Regulação Neoplásica da Expressão Gênica/fisiologia , Hepatócitos/metabolismo , Humanos , Receptores de Inositol 1,4,5-Trifosfato/deficiência , Receptores de Inositol 1,4,5-Trifosfato/genética , Fígado/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Regeneração Hepática/fisiologia , Masculino , Camundongos Knockout , Pessoa de Meia-Idade , Análise de Sobrevida
13.
Biol Res ; 52(1): 36, 2019 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-31300048

RESUMO

BACKGROUND: Recent evidences indicated that some local anaesthetic agents played a role in inhibiting the proliferation of cancer cells; Whether ropivacaine is able to promote apoptosis of hepatocellular carcinoma (HCC) cells is still unclear. The aim of this study was to investigate the effect of ropivacaine on the apoptosis of HCC cells. METHODS: In the present study, we treated the HCC cell lines, Bel7402 and HLE with ropivacaine. MTT, DAPI stain, trypan blue exclusion dye assay, flow cytometry, electron microscopy, computational simulation, laser confocal microscope, Western blotting, and enzyme activity analysis of caspase-3 were applied to detect the growth and apoptosis of HCC cells and to explore the role mechanism of ropivacaine. RESULTS: Ropivacaine was able to inhibit proliferation and promote apoptosis of HCC cells in a dose- and time-dependent manner. Ropivacaine also has a trait to inhibit the migration of HCC cells; ropivacaine damaged the mitochondria of HCC cells. The results also indicated that ropivacaine was able to interact with caspase-3, promote cytoplasmic caspase-3 migration into the nucleus, stimulate cleavage of caspase-3 and PARP-1, caspase-9 proteins, inhibit the expression of Bcl-2, promote expression of Apaf-1 and mitochondria release cytochrome C, and activate the activity of caspase-3. CONCLUSIONS: Ropivacaine has a novel role in promoting apoptosis of HCC cells; The role mechanism of ropivacaine maybe involve in damaging the function of mitochondria and activating the caspase-3 signalling pathway in HCC cells. Our findings provide novel insights into the local anaesthetic agents in the therapy of HCC patients.


Assuntos
Anestésicos Locais/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/patologia , Caspase 3/metabolismo , Neoplasias Hepáticas/patologia , Ropivacaina/farmacologia , Apoptose/fisiologia , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Citometria de Fluxo , Humanos , Neoplasias Hepáticas/metabolismo , Microscopia Confocal , Microscopia de Fluorescência , Mitocôndrias/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
14.
Oncol Rep ; 42(4): 1487-1496, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31322272

RESUMO

Fibrolamellar hepatocellular carcinoma (FL­HCC) is a variant of hepatocellular carcinoma (HCC) that most commonly affects adolescents and young adults and is associated with an extremely poor prognosis due to the lack of effective chemotherapeutic agents. Mutations in p53 are a common oncogenic driver in HCC but not in FL­HCC. However, in tumors lacking a p53 mutation, the tumor suppressor activity of p53 has been revealed to be dysregulated in several different cancer types. One mechanism has been attributed to the overexpression of mouse double minute 4 protein (MDM4), a negative regulator of p53, which inhibits the normal functions of p53 including induction of apoptosis and DNA repair. Therefore, restoring the normal function of p53 in cancer cells by targeting MDM4 has become a potential therapeutic strategy. Hence, in the present study the components of the DNA damage response (DDR) pathway were examined; ATM, p53, and MDM4 in FL­HCC. Seven FL­HCC tumors along with their adjacent non­neoplastic hepatic tissues were examined. Ataxia­telangiectasia mutated (ATM), p53, and MDM4 protein expression was assessed using western blot analysis and cellular localization was determined using immunohistochemistry (IHC). MDM4 mRNA transcript levels were assessed using RT­qPCR. The present results demonstrated that the DNA damage sensor, ATM, is phosphorylated and localized to the nuclei of tumor cells. While there was a significant increase in total p53 protein in tumor cells, phosphorylated p53 was revealed to preferably localize to the cytoplasmic compartment of tumor cells. Notably, the present results revealed that MDM4 transcript levels were increased in the majority of tumor samples and the nuclear MDM4 levels were significantly increased in tumor tissue compared to their adjacent non­neoplastic liver tissue. The present results indicated that increased MDM4 expression and nuclear localization may be a potential mechanism for p53 dysregulation in FL­HCC.


Assuntos
Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , Proteínas Nucleares/biossíntese , Proteínas Proto-Oncogênicas/biossíntese , Adolescente , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Criança , Feminino , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Masculino , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Proteína Supressora de Tumor p53/metabolismo
15.
Cancer Sci ; 110(10): 3197-3203, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31361379

RESUMO

Intrahepatic cholangiocarcinoma is a rare malignant biliary neoplasm that causes a poor prognosis even after curative hepatectomy. Liver metastasis is the major recurrence pattern of intrahepatic cholangiocarcinoma; therefore, the prevention of liver metastasis is a desirable objective. The aim of this study is to identify gene(s) related to liver metastasis of intrahepatic cholangiocarcinoma and to examine the inhibitory effects on metastasis of intrahepatic cholangiocarcinoma by controlling such gene(s). We collected 3 pairs of intrahepatic cholangiocarcinoma frozen samples, and 36 pairs (primary and metastatic lesions) of intrahepatic cholangiocarcinoma formalin-fixed paraffin-embedded samples, from patients who underwent surgical resection at hospitals related to the Kyushu Study Group of Liver Surgery between 2002 and 2016. We carried out cDNA microarray analyses and immunohistochemistry to identify candidate genes, and evaluated one of them as a therapeutic target using human cholangiocarcinoma cell lines. We identified 4 genes related to liver metastasis using cDNA microarray, and found that CXCL12 was the only gene whose expression was significantly higher in liver metastasis than in primary intrahepatic cholangiocarcinoma by immunohistochemistry (P = .003). In prognosis, patients in the high CXCL12 group showed a significantly poor prognosis in disease-free (P < .0001) and overall survival (P = .0004). By knockdown of CXCL12, we could significantly suppress the invasive and migratory capabilities of 2 human cholangiocarcinoma cell lines. Therefore, CXCL12 might be associated with metastasis and poor prognosis in intrahepatic cholangiocarcinoma.


Assuntos
Neoplasias dos Ductos Biliares/patologia , Quimiocina CXCL12/genética , Quimiocina CXCL12/metabolismo , Colangiocarcinoma/patologia , Neoplasias Hepáticas/secundário , Idoso , Neoplasias dos Ductos Biliares/genética , Neoplasias dos Ductos Biliares/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Colangiocarcinoma/genética , Colangiocarcinoma/metabolismo , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Prognóstico , Regulação para Cima
16.
Clin Nucl Med ; 44(9): 702-706, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31348076

RESUMO

Prostate specific membrane antigen (PSMA) expression has been demonstrated in tumor neovasculature of many solid tumors, including hepatocellular carcinoma (HCC). The purpose of this study is to evaluate PSMA expression in patients with HCC. MATERIALS AND METHODS: Nineteen HCC patients who underwent F-fluorodeoxyglucose (F-FDG) positron emission tomography (PET) as part of restaging procedure also underwent Ga-PSMA PET. F-FDG PET and Ga-PSMA findings were compared visually as well as quantitatively using maximized standardized uptake values (SUVmax). RESULTS: FDG was positive in 15 patients while 16 patients demonstrated PSMA expression. The only extrahepatic finding was one metastatic lymph node detected by both tracers. Mean SUVmax of liver lesions on FDG PET/CT was 8.3 ± 2.3 and mean tumor to background ratio was 2.3 ± 1.5. Respective values for Ga-PSMA PET/CT were 17.4 ± 9 and 3.3 ± 2.2. On visual and quantitative evaluation uptake was higher with PSMA in nine patients and higher with FDG in four patients. PSMA and FDG activity were similar in three patients. One of the FDG positive patients was PSMA negative whereas two patients were PSMA positive but FDG negative. Heterogeneous uptake pattern was observed in three patients. Comparison of mean SUVmax and T/B values between PET studies revealed no statistically significant difference (P > 0.1). The mean survival was 25 months (range: 18-32 months) and SUVmax of PSMA (P = 0.05) and FDG (P = 0.012) showed medium strength of correlation with overall survival. CONCLUSION: PSMA expression in advanced HCC can be demonstrated by Ga-PSMA PET but is not superior to FDG PET however it could be useful for identifying patients with limited therapeutic options.


Assuntos
Carcinoma Hepatocelular/diagnóstico por imagem , Carcinoma Hepatocelular/metabolismo , Regulação Neoplásica da Expressão Gênica , Glutamato Carboxipeptidase II/metabolismo , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/metabolismo , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Idoso , Ácido Edético/análogos & derivados , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Oligopeptídeos
17.
Eur J Med Chem ; 179: 515-526, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31276896

RESUMO

Nineteen organoselenides were synthesized and tested for their intrinsic cytotoxicity in hepatocellular carcinoma (HepG2) and breast adenocarcinoma (MCF-7) cell lines and their corresponding selective cytotoxicity (SI) was estimated using normal lung fibroblast (WI-38) cells. Most of the organic selenides exhibited good anticancer activity, and this was more pronounced in HepG2 cells. Interestingly, the naphthoquinone- (5), thiazol- (12), and the azo-based (13) organic selenides demonstrated promising SI (up to 76). Furthermore, the amine 4c, naphthoquinone 5, and azo-based 13 and 15 organic selenides were able to down-regulate the expression of Bcl-2 and up-regulate the expression levels of IL-2, IL-6 and CD40 in HepG2 cells compared to untreated cells. Moreover, most of the synthesized candidates manifested good free radical-scavenging and GPx-like activities comparable to vitamin C and ebselen. The obtained results suggested that some of the presented organoselenium candidates have promising anti-HepG2 and antioxidant activities.


Assuntos
Antineoplásicos/farmacologia , Antioxidantes/farmacologia , Neoplasias da Mama/tratamento farmacológico , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Compostos Organosselênicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Antioxidantes/síntese química , Antioxidantes/química , Compostos de Bifenilo/antagonistas & inibidores , Compostos de Bifenilo/metabolismo , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Células Hep G2 , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Células MCF-7 , Estrutura Molecular , Compostos Organosselênicos/síntese química , Compostos Organosselênicos/química , Picratos/antagonistas & inibidores , Picratos/metabolismo , Relação Estrutura-Atividade
18.
Anticancer Res ; 39(7): 3469-3485, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31262871

RESUMO

BACKGROUND/AIM: Isothiocyanates (ITCs) are phytochemicals with potential cancer-preventative properties derived from the breakdown of glucosinolates that exist in cruciferous vegetables. Studies, to date, have demonstrated that various ITCs possess the ability to act as anticancer agents in different cancer types. This study investigated the anticancer properties of dietary ITCs (allyl-ITC, benzyl-ITC, phenylethyl-ITC) and synthetic (phenylbutyl-ITC and phenylhexyl-ITC) on liver and prostate carcinoma cells in vitro. MATERIALS AND METHODS: The effects of ITCs on cellular viability, migration, invasion, clonogenicity, apoptosis induction and reactive oxygen species generation were assessed in HepG2, DU145 and 22Rv1 cells. RESULTS: All ITCs reduced metabolic activity in each cell line with the most significant being phenylethyl-ITC. Both dietary and synthetic ITCs suppressed the migratory and invasive potential of all cell lines, inhibited colony-forming capability and induced apoptosis. Phenylethyl-ITC exposure resulted in the significant generation of reactive oxygen species. CONCLUSION: These data highlight the potential advantages of utilizing ITCs to delay the carcinogenic process and the potential for dietary and synthetic ITCs to act as anticancer agents.


Assuntos
Antineoplásicos/farmacologia , Isotiocianatos/farmacologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias da Próstata/tratamento farmacológico , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Humanos , Neoplasias Hepáticas/metabolismo , Masculino , Neoplasias da Próstata/metabolismo , Espécies Reativas de Oxigênio/metabolismo
19.
Anticancer Res ; 39(7): 3571-3578, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31262881

RESUMO

BACKGROUND/AIM: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a cancer-selective, cell-death-inducing agent with little toxicity to normal cells. However, various human cancers and cancer cell lines have been reported to be resistant to TRAIL. Molecular clarification of resistance mechanism is needed. MATERIALS AND METHODS: Compound screening, proliferation assays, western blotting, and flow cytometry were used to examine the sensitizer activity of methyl transferase inhibitor BIX-01294 in combination with TRAIL, in hepatocellular carcinoma (HCC) cells. RNA sequencing analysis and single guide (sg)RNA-mediated gene deletion were used to investigate the role of survivin in sensitization. RESULTS: In HCC cells, BIX-01294 enhanced TRAIL sensitivity by reducing survivin expression at the RNA level. Small interference RNA-mediated gene knockdown demonstrated the mechanism of sensitization to be via the reduction of survivin. CONCLUSION: Euchromatin histone methyltransferase 2 (EHMT2) inhibition by BIX-01294 may be a potent anti-tumor therapeutic strategy for human HCC.


Assuntos
Azepinas/farmacologia , Carcinoma Hepatocelular/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Hepáticas/metabolismo , Quinazolinas/farmacologia , Survivina/metabolismo , Ligante Indutor de Apoptose Relacionado a TNF/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Linhagem Celular Tumoral , Regulação para Baixo/efeitos dos fármacos , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Survivina/genética
20.
Anticancer Res ; 39(7): 3621-3631, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31262888

RESUMO

BACKGROUND/AIM: Cetrimonium bromide (CTAB), a quaternary ammonium surfactant, is an antiseptic agent against bacteria and fungi. However, the mechanisms by which its pharmacological actions affect epithelial-mesenchymal transition (EMT) in hepatocellular carcinoma (HCC) cells, such as adenocarcinoma in SK-HEP-1 cells, have not been investigated. We, thereby, investigated whether CTAB inhibits cellular mobility and invasiveness of human hepatic adenocarcinoma in SK-HEP-1 cells. MATERIALS AND METHODS: SK-HEP-1 cells were treated with CTAB, and subsequent migration and invasion were measured by wound healing and transwell assays. Protein expression was detected by immunoblotting analysis. RESULTS: Our data revealed that treatment of SK-HEP-1 cells with CTAB altered their mesenchymal spindle-like morphology. CTAB exerted inhibitory effects on the migration and invasion of SK-HEP-1 cells dose-dependently, and reduced protein levels of matrix metalloproteinase-2 (MMP-2), MMP-9, snail, slug, twist, vimentin, fibronectin, N-cadherin, Smad2, Smad3, Smad4, phosphoinositide-3-kinase (PI3K), p-PI3K, Akt, p-Akt, ß-catenin, mammalian target of rapamycin (mTOR), p-mTOR, p-p70S6K, p-extracellular signal-regulated kinases (ERK)1/2, p-p38 mitogen-activated protein kinase (MAPK) and p-c-Jun N-terminal kinase (JNK), but increased protein levels of tissue inhibitor matrix metalloproteinase-1 (TIMP-1), TIMP-2, claudin-1 and p-GSK3ß. Based on these observations, we suggest that CTAB not only inhibits the canonical transforming growth factor-ß (TGF-ß) signaling pathway though reducing SMADs (an acronym from the fusion of Caenorhabditis elegans Sma genes and the Drosophila Mad, Mothers against decapentaplegic proteins), but also restrains the non-canonical TGF-ß signaling including MAPK pathways like ERK1/2, p38 MAPK, JNK and PI3K. CONCLUSION: CTAB is involved in the suppression of TGF-ß-mediated mesenchymal phenotype and could be a potent medical agent for use in controlling the migration and invasion of hepatic adenocarcinoma.


Assuntos
Adenocarcinoma/metabolismo , Antineoplásicos/farmacologia , Cetrimônio/farmacologia , Neoplasias Hepáticas/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Adenocarcinoma/tratamento farmacológico , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Invasividade Neoplásica , Transdução de Sinais/efeitos dos fármacos
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