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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.
Life Sci ; 236: 116933, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31614146

RESUMO

AIMS: Hepatocellular carcinoma (HCC) pathogenesis involves the interplay of multiple signalling pathways. Notch and Hedgehog (Hh) are two major developmental pathways that act in concert to regulate adult cell repair. CK2α -serine-threonine kinase-down-regulation enhanced apoptotic activity and was proven beneficial for HCC patients. Quercetin is a bioactive flavonoid and has been shown to protect against HCC through its antioxidant activity. This study was carried out to elucidate the antineoplastic effect of quercetin through regulating both Notch and Hh pathways, apoptosis, cell proliferation and CK2α activity. MAIN METHODS: Hepatocellular carcinoma was induced in male Sprague Dawley rats by thioacetamide. Quercetin was administered in both protective and curative doses. Parameters of liver function and oxidative stress were assessed. CK2α, Notch and Hh pathways were evaluated using RT-PCR and ELISA. Apoptosis was investigated by detecting caspase-3, caspase-8 and p53. Proliferative and cell cycle markers as cyclin D1 and Ki-67 were detected immunohistochemically. KEY FINDINGS: Quercetin inhibited CK2α and downregulated mRNA and protein expression of Notch1 and Gli2. Quercetin also suppressed caspase-3 expression but not caspase-8. Quercetin elevated p53 expression whereas proliferative and cell cycle markers cyclin D1 and Ki-67 were downregulated. Markers of hepatic cellular integrity such as AST, ALT, ALP, GGT, albumin and bilirubin were significantly ameliorated. This was confirmed by histological examination. Quercetin also alleviated oxidative stress as shown by SOD, GSH, MDA and NO levels. SIGNIFICANCE: We can conclude that in addition to its antioxidant power, quercetin blocked Notch, Hedgehog, regulated the apoptotic and proliferative pathways and inhibited CK2α in HCC.


Assuntos
Antioxidantes/farmacologia , Carcinoma Hepatocelular/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias Hepáticas/metabolismo , Quercetina/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Caseína Quinase II/antagonistas & inibidores , Caseína Quinase II/metabolismo , Proliferação de Células/efeitos dos fármacos , Proteínas Hedgehog/antagonistas & inibidores , Proteínas Hedgehog/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Masculino , Estresse Oxidativo , Ratos , Ratos Sprague-Dawley , Receptores Notch/antagonistas & inibidores , Receptores Notch/metabolismo
3.
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
4.
Life Sci ; 235: 116817, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31476309

RESUMO

AIMS: In the tumor microenvironment, dysregulated immune cells could promote tumor progression, invasion and metastasis, by establishing a symbiotic relationship with cancer cells. A pivotal role is played by monocyte recruitment and induction of tumor-associated macrophages (TAMs), which provide immunosuppression and tumorigenesis. The effect of nemorosone, an antiproliferative phytocomponent present in Cuban Propolis, on TAM-induced tumor progression remains to be elucidated. Here we investigated the symbiotic relationship between monocytic leukemia THP-1 and hepatocellular carcinoma HepG2 cells, and the role of nemorosone in preventing TAM-induced tumor growth. MAIN METHODS: Macrophage differentiation induced by HepG2-conditioned medium was assessed by flow cytometry, analysis of secreted molecules and cytokine expression. The effect of nemorosone and/or conditioned THP-1-medium on HepG2 proliferation was evaluated by MTT assay, colony formation, cells cycle and migration assays. KEY FINDINGS: HepG2 cells induced THP-1 recruitment and differentiation to macrophages. When compared with control THP-1 cells, differentiated THP-1 showed a significant increase of the matrix metalloproteinases MMP-2 and MMP-9 expression (P < 0.01), and slightly induced HepG2 cells growth. This effect was counteracted by nemorosone, which also significantly inhibited colony formation (P < 0.01) and migratory capacity of HepG2 cells, driving a high percentage of cells (80%) to the G0/G1 phase. SIGNIFICANCE: HepG2-conditioned medium is a suitable model for THP-1 modulation and differentiation. Moreover, nemorosone significantly inhibits the proliferation of HepG2 cells, both in presence and absence of the soluble factors secreted by TAMs. Further studies are needed to elucidate the role of this natural compound in the HCC-TAM relationship.


Assuntos
Benzofenonas/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Neoplasias Hepáticas/tratamento farmacológico , Monócitos/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Diferenciação Celular/efeitos dos fármacos , Meios de Cultivo Condicionados/farmacologia , Células Hep G2 , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Monócitos/citologia , Monócitos/metabolismo , Células THP-1
5.
Cell Biochem Funct ; 37(7): 525-533, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31478234

RESUMO

Increasing evidence has indicated the important roles of long noncoding RNA small nucleolar RNA host gene 7 (SNHG7) in tumourigenesis as a potential oncogene. However, the function of SNHG7 in hepatic carcinoma remains unclear. In the present study, we found that SNHG7 expression was significantly upregulated in hepatic carcinoma tissues, especially in aggressive cases, and it was closely correlated with the poor prognosis. Furthermore, knockdown of SNHG7 inhibited the proliferation, migration, and invasion of hepatic carcinoma cell lines in vitro. Mechanistically, SNHG7 directly interacted with miR-425 as a ceRNA. Moreover, knockdown of SNHG7 significantly inhibited the tumorigenic Wnt/ß-catenin/EMT pathway. SNHG7 regulated Wnt/ß-catenin/EMT pathway through sponging miR-425 and played an oncogenic role in hepatic carcinoma progression. Together, our study elucidated the role of SNHG7 as a ceRNA in hepatic carcinoma, provided new potential diagnosis and therapeutic application in hepatic carcinoma progression. SIGNIFICANCE OF THE STUDY: SNHG7 could promote proliferation and metastasis of hepatic carcinoma cell in vitro and in vivo, suggesting that SNHG7 exerts tumorigenic role in hepatic carcinoma progression. Further mechanism research revealed that SNHG7 exhibited the tumorigenic role through Wnt/ß-catenin/EMT pathway as a miR-425 sponge. These findings provided new cues to understand the molecular signalling network in carcinogenesis of hepatic carcinoma, and it may provide new evidence for therapeutic application in hepatic carcinoma.


Assuntos
Carcinoma Hepatocelular/metabolismo , Movimento Celular , Proliferação de Células , Transição Epitelial-Mesenquimal , Neoplasias Hepáticas/metabolismo , MicroRNAs/metabolismo , RNA Longo não Codificante/metabolismo , Via de Sinalização Wnt , Animais , Carcinoma Hepatocelular/diagnóstico , Células Hep G2 , Humanos , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas Experimentais/diagnóstico , Neoplasias Hepáticas Experimentais/metabolismo , Camundongos , Camundongos Nus , RNA Longo não Codificante/genética
6.
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
7.
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
8.
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
9.
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
10.
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
11.
Life Sci ; 233: 116673, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31336121

RESUMO

AIMS: Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related mortality worldwide. Indeed, chemotherapeutic drugs-induced systemic toxicity results in suboptimal cancer treatment. Consequently, there is a need for exploring of a safe and effective therapy for cancer patients. This study aimed to evaluate the hepatoprotective effect of thymoquinone (TQ) against thioacetamide (TAA)-induced HCC. Also, we investigated TQ's ability to sensitize cancer cells toward TRAIL/TRAILR2 apoptotic pathway. MAIN METHODS: Forty male Sprague Dawley rats were divided into 4 groups (n = 10) as follows: control group, CMC group, HCC group and HCC + TQ group. Serum levels of liver function biomarkers and Alpha-Fetoprotein (AFP), as well as hepatic levels of glutathione (GSH) and Alpha-Fetoprotein (MDA) were measured. Transforming growth factor-beta 1 (TGF-ß1), TRAILR2, TRAIL, caspase-3, caspase-9, caspase-8 and B cell lymphoma-2 (Bcl-2) mRNA levels were assessed by Quantitative, Real-Time PCR. Fibrosis percentage and necroinflammation were quantified by histopathological examination. KEY FINDINGS: Our results indicated improvement in liver functions, decrease in AFP level and attenuation of HCC progression in TQ treated rats. TQ upregulated TRAIL/TRAILR2 and subsequently enhanced apoptosis as hinted by caspase-3 upregulation and Bcl-2 downregulation. Also, TQ decreased TGF-ß1 gene expression level. Moreover, HCC + TQ group showed significant increase in hepatic GSH level and marked decrease in hepatic MDA level. SIGNIFICANCE: This study proved that TQ is able to suppress HCC development via decreasing oxidative stress, suppression of TGF-ß1 and induction of TRAIL-mediated apoptosis.


Assuntos
Benzoquinonas/farmacologia , Carcinoma Hepatocelular/prevenção & controle , Modelos Animais de Doenças , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias Hepáticas Experimentais/prevenção & controle , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Animais , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Proliferação de Células/efeitos dos fármacos , Neoplasias Hepáticas Experimentais/metabolismo , Neoplasias Hepáticas Experimentais/patologia , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/genética , Ligante Indutor de Apoptose Relacionado a TNF/genética
12.
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
13.
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
14.
Eur J Med Chem ; 179: 916-935, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31306818

RESUMO

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors. Traditional chemotherapy drugs are hard to reach a satisfactory therapeutic effect since advanced HCC is highly chemo-resistant. Sorafenib is an oral multikinase inhibitor that can suppress tumor cell proliferation, angiogenesis and induce cancer cell apoptosis. However, the poor solubility, rapid metabolism and low bioavailability of sorafenib greatly restricted its further clinical application. During the past decade, numerous sorafenib derivatives have been designed and synthesized to overcome its disadvantages and improve its clinical performance. This article focuses on the therapeutic effects and mechanisms of various sorafenib derivatives with modifications on the N-methylpicolinamide group, urea group, central aromatic ring or others. More importantly, this review summarizes the current status of the structure-activity relationship (SAR) of reported sorafenib derivatives, which can provide some detailed information of future directions for further structural modifications of sorafenib to discovery new anti-tumor drugs with improved clinical performance.


Assuntos
Antineoplásicos/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Sorafenibe/farmacologia , Animais , Antineoplásicos/química , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Proliferação de Células/efeitos dos fármacos , Química Farmacêutica , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Estrutura Molecular , Inibidores de Proteínas Quinases/química , Sorafenibe/química
15.
Eur J Med Chem ; 180: 224-237, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31306909

RESUMO

Cytotoxic effects of (R)-4'-methylklavuzon were investigated on hepatocellular carcinoma cells (HuH-7 and HepG2) and HuH-7 EpCAM+/CD133+ cancer stem cells. IC50 of (R)-4'-methylklavuzon was found as 1.25 µM for HuH-7 parental cells while it was found as 2.50 µM for HuH-7 EpCAM+/CD133+ cancer stem cells. (R)-4'-methylklavuzon tended to show more efficient in vitro cytotoxicity with its lower IC50 values on hepatocellular carcinoma cell lines compared to its lead molecule, goniothalamin and FDA-approved drugs, sorafenib and regorafenib. Cell-based Sirtuin/HDAC enzyme activity measurements revealed that endogenous Sirtuin/HDAC enzymes were reduced by 40% compared to control. SIRT1 protein levels were upregulated indicating triggered DNA repair mechanism. p53 was overexpressed in HepG2 cells. (R)-4'-methylklavuzon inhibited CRM1 protein providing increased retention of p53 and RIOK2 protein in the nucleus. HuH-7 parental and EpCAM+/CD133+ cancer stem cell spheroids lost intact morphology. 3D HepG2 spheroid viabilities were decreased in a correlation with upregulation in p53 protein levels.


Assuntos
Antígeno AC133/antagonistas & inibidores , Antineoplásicos/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Molécula de Adesão da Célula Epitelial/antagonistas & inibidores , Carioferinas/antagonistas & inibidores , Neoplasias Hepáticas/tratamento farmacológico , Naftalenos/farmacologia , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores , Sirtuína 1/antagonistas & inibidores , Antígeno AC133/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/química , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Molécula de Adesão da Célula Epitelial/metabolismo , Células Hep G2 , Humanos , Carioferinas/metabolismo , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Estrutura Molecular , Naftalenos/síntese química , Naftalenos/química , Receptores Citoplasmáticos e Nucleares/metabolismo , Sirtuína 1/metabolismo , Relação Estrutura-Atividade , Células Tumorais Cultivadas
16.
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
17.
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
18.
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
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.
Chem Biol Interact ; 309: 108713, 2019 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-31226288

RESUMO

Liver cancer is one of the most frequently occurring types of cancer with high mortality rate. Hepatocellular carcinoma (HCC) frequently metastasizes to lung, portal vein, and portal lymph nodes and most HCCs show strong resistance to conventional anticancer drugs. Cancer stem cells (CSCs) are considered to be responsible for resistance to therapies. Hence, recent advancements in the use of liver cancer stem cells (LCSCs) are rapidly gaining recognition as an efficient and organized means for developing antitumor agents. We aimed to use a non-target-based high-throughput screening (HTS) approach to specifically target α-fetoprotein (AFP)+/cluster of differentiation (CD)133+ HCC present in mixed populations of HCC cells and hepatocytes. Herein, we identified actinomycin D (ActD) as a potential antitumor agent that significantly inhibits activity of LCSCs without affecting the co-cultured hepatocytes. To determine the mechanism of ActD-induced tumor-specificity in LCSC, we applied various cell-based assay models in vitro. In fact, ActD significantly increased reactive oxygen species (ROS) accumulation and DNA damage in Huh7 HCC cells, but not in Fa2N-4 cells, immortalized hepatocytes. Treatment of spheroid-forming LCSCs with ActD effectively decreased spheroid formation and the CD133+ HCC cell population. Importantly, these ActD-mediated effects are a result of inhibition of cystine/glutamate transporter xCT expression, via attenuation of CD133 synthesis. These results indicate that ActD suppresses stemness and malignant properties in HCC cells through destabilization of xCT, by inhibition of CD133 expression in LCSCs. The effects of ActD on LCSCs provide novel therapeutic strategies for targeting cancer stem-like cells in liver cancer.


Assuntos
Antígeno AC133/metabolismo , Sistema y+ de Transporte de Aminoácidos/metabolismo , Dactinomicina/farmacologia , Expressão Gênica/efeitos dos fármacos , Antígeno AC133/antagonistas & inibidores , Antígeno AC133/genética , Sistema y+ de Transporte de Aminoácidos/antagonistas & inibidores , Sistema y+ de Transporte de Aminoácidos/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Esferoides Celulares/efeitos dos fármacos
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