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1.
Life Sci ; 268: 119007, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33428878

RESUMO

The γ-secretase complex is a key hydrolase for many type 1 transmembrane proteins. It is very important for activation of the Notch receptor and regulation of target-gene transcription. Abnormal activation and expression of the Notch pathway are closely related to the occurrence and development of many tumor types, including breast cancer and liver cancer. In this review, we elaborated on the basic situation of γ-secretase complex and the biological function and role of γ-secretase in APP and Notch signal pathway are described in detail. Subsequently, all currently known γ-secretase inhibitors and γ-secretase modulators are listed and their mechanism of action, value of IC50, chemical structure and current research stage are summarized. Next, the selection presented the treatment progress of γ-secretase inhibitors in breast cancer and hepatocellular carcinoma in the past five years. Finally, the mechanism of action of γ-secretase-mediated breast cancer and hepatocellular carcinoma and the advantages and disadvantages of γ-secretase inhibitors are discussed, and the concept of further research is proposed.


Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Neoplasias da Mama/tratamento farmacológico , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Inibidores de Proteases/farmacologia , Secretases da Proteína Precursora do Amiloide/metabolismo , Antineoplásicos/química , Antineoplásicos/farmacologia , Neoplasias da Mama/enzimologia , Carcinoma Hepatocelular/enzimologia , Feminino , Humanos , Neoplasias Hepáticas/enzimologia , Oligopeptídeos/farmacologia , Inibidores de Proteases/química , Receptores Notch/metabolismo , Tetra-Hidronaftalenos/farmacologia , Valina/análogos & derivados , Valina/farmacologia
2.
Anticancer Res ; 41(2): 645-660, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33517269

RESUMO

BACKGROUND/AIM: Sorafenib is a multikinase inhibitor approved as a first-line therapy for hepatocellular carcinoma. This study examined the sorafenib resistance mechanism. MATERIALS AND METHODS: Hepatoma HepG2 cells were exposed to sorafenib, and the biological activity of the conditioned media was analyzed using cell proliferation/apoptosis assays, multiplex immunoassays, ELISA, and western blot analyses. The effect of urokinase-type plasminogen activator (uPA) inhibitors or siRNA-mediated gene silencing was examined in culture experiments and a mouse xenograft tumor model. RESULTS: Sorafenib increased uPA secretion, which was abrogated by an Akt inhibitor. The growth-inhibitory effect of sorafenib was significantly enhanced by the uPA inhibitors UK122 and amiloride. Sorafenib-induced apoptosis was increased 2.4-fold in uPA siRNA-transduced cells (p<0.05). Combined therapy with sorafenib and amiloride significantly decreased tumor volumes [mean volume: 759 mm3 (sorafenib) vs. 283 mm3 (sorafenib plus amiloride), p<0.05]. CONCLUSION: uPA may play a critical role in sorafenib resistance.


Assuntos
Antineoplásicos/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos , Neoplasias Hepáticas/tratamento farmacológico , Proteínas de Membrana/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Sorafenibe/farmacologia , Amilorida/farmacologia , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/enzimologia , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Células Hep G2 , Humanos , Neoplasias Hepáticas/enzimologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Masculino , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/genética , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteínas Proto-Oncogênicas c-akt/metabolismo , Interferência de RNA , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Biomed Pharmacother ; 134: 111154, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33360931

RESUMO

A promising direction in Biopharmaceuticals is the development of specific peptide-based systems to improve drug delivery. This approach may increase tumor specificity and drug penetration into the target cell. Similar systems have been designed for several antitumor drugs. However, for photodynamic therapy drugs, such studies are not yet enough. Previously, we have developed a method of inclusion of chlorin e6 (Ce6), a photosensitizer used in photodynamic therapy, in phospholipid nanoparticles with a diameter of up to 30 nm, and reported an increase in its effectiveness in the experiments in vivo. In this work, we propose to modify a previously developed delivery system for Ce6 by the addition of cell-penetrating (R7) and/or targeting NGR peptides. The interaction of the compositions developed with HepG2 and MCF-7 tumor cells is shown. The expression of CD13 protein with affinity to NGR on the surface of these cells has been studied using flow cytometry. The expression of this protein on the HepG2 cells and its absence on MCF-7 was demonstrated. After incubation of tumor cells with the resulting Ce6 compositions, we evaluated the cellular accumulation, photoinduced, and dark cytotoxicity of the drugs. After irradiation, the highest level of cytotoxicity was observed when R7 peptide was added to the system, either alone or in combination with NGR. In addition to R7, the NGR-motif peptide increased the internalization of Ce6 in HepG2 cells without affecting its photodynamic activity. In this work we also discuss possible mechanisms of action of the cell-penetrating peptide when attached to phospholipid nanoparticles.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Antígenos CD13/metabolismo , Carcinoma Hepatocelular/tratamento farmacológico , Peptídeos Penetradores de Células/metabolismo , Portadores de Fármacos , Neoplasias Hepáticas/tratamento farmacológico , Nanopartículas , Fosfolipídeos/química , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacologia , Porfirinas/farmacologia , Neoplasias da Mama/enzimologia , Neoplasias da Mama/patologia , Carcinoma Hepatocelular/enzimologia , Carcinoma Hepatocelular/patologia , Sobrevivência Celular/efeitos dos fármacos , Peptídeos Penetradores de Células/química , Composição de Medicamentos , Células Hep G2 , Humanos , Neoplasias Hepáticas/enzimologia , Neoplasias Hepáticas/fisiopatologia , Células MCF-7 , Oligopeptídeos/química , Oligopeptídeos/metabolismo , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/metabolismo , Porfirinas/química , Porfirinas/metabolismo
4.
Int J Mol Sci ; 21(24)2020 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-33371259

RESUMO

The lysyl oxidase (LOX) family members are secreted copper-dependent amine oxidases, comprised of five paralogues: LOX and LOX-like l-4 (LOXL1-4), which are characterized by catalytic activity contributing to the remodeling of the cross-linking of the structural extracellular matrix (ECM). ECM remodeling plays a key role in the angiogenesis surrounding tumors, whereby a corrupt tumor microenvironment (TME) takes shape. Primary liver cancer includes hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), ranked as the seventh most common cancer globally, with limited therapeutic options for advanced stages. In recent years, a growing body of evidence has revealed the key roles of LOX family members in the pathogenesis of liver cancer and the shaping of TME, indicating their notable potential as therapeutic targets. We herein review the clinical value and novel biological roles of LOX family members in tumor progression and the TME of liver cancers. In addition, we highlight recent insights into their mechanisms and their potential involvement in the development of target therapy for liver cancer.


Assuntos
Neoplasias Hepáticas/patologia , Proteína-Lisina 6-Oxidase/metabolismo , Microambiente Tumoral/imunologia , Animais , Progressão da Doença , Humanos , Neoplasias Hepáticas/enzimologia , Neoplasias Hepáticas/imunologia , Proteína-Lisina 6-Oxidase/classificação
5.
J Pathol ; 251(2): 213-223, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32297656

RESUMO

Colorectal cancer liver metastases (CRCLM) that present with a replacement histopathological growth pattern (HGP) are resistant to neoadjuvant anti-angiogenic therapy. Surrogate biomarkers are not available to preoperatively identify patients with these tumors. Here we identify differentially expressed genes between CRCLM with a replacement HGP and those with a desmoplastic HGP using RNA sequencing. We demonstrate that LOXL4 is transcriptionally upregulated in replacement HGP CRCLM compared with desmoplastic HGP CRCLM and the adjacent normal liver. Interestingly, lysyl oxidase-like 4 (LOXL4) protein was expressed by neutrophils present in the tumor microenvironment in replacement HGP CRCLM. We further demonstrate that LOXL4 expression is higher in circulating neutrophils of cancer patients compared with healthy control patients and its expression can be induced by stimulation with lipopolysaccharide and TNF-α. Our study is the first to show the expression of LOXL4 in neutrophils and reveals the potential for LOXL4-expressing neutrophils to support the replacement HGP phenotype and to serve as a surrogate biomarker for this subtype of CRCLM. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Biomarcadores Tumorais/metabolismo , Neoplasias Colorretais/patologia , Resistencia a Medicamentos Antineoplásicos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/enzimologia , Neutrófilos/efeitos dos fármacos , Proteína-Lisina 6-Oxidase/metabolismo , Biomarcadores Tumorais/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/secundário , Neutrófilos/enzimologia , Fenótipo , Proteína-Lisina 6-Oxidase/genética , Transdução de Sinais , Transcrição Genética , Microambiente Tumoral , Regulação para Cima
7.
Medicine (Baltimore) ; 99(11): e19438, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32176073

RESUMO

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


Assuntos
Fosfatase Alcalina/sangue , Biomarcadores Tumorais/sangue , Carcinoma Hepatocelular/enzimologia , Neoplasias Hepáticas/enzimologia , Carcinoma Hepatocelular/mortalidade , Humanos , Neoplasias Hepáticas/mortalidade , Prognóstico , Análise de Sobrevida
8.
Toxicology ; 437: 152438, 2020 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-32199159

RESUMO

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


Assuntos
Citocromo P-450 CYP2E1/metabolismo , Proteínas de Membrana/genética , Micronúcleos com Defeito Cromossômico/induzido quimicamente , Simulação de Acoplamento Molecular , Mutação , Bifenilos Policlorados/toxicidade , Ativação Metabólica , Animais , Carcinoma Hepatocelular/enzimologia , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Domínio Catalítico , Cricetulus , Citocromo P-450 CYP2E1/química , Citocromo P-450 CYP2E1/genética , Fibroblastos/efeitos dos fármacos , Fibroblastos/enzimologia , Fibroblastos/patologia , Células Hep G2 , Humanos , Neoplasias Hepáticas/enzimologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Pulmão/efeitos dos fármacos , Pulmão/enzimologia , Pulmão/patologia , Bifenilos Policlorados/química , Bifenilos Policlorados/metabolismo , Ligação Proteica , Conformação Proteica
9.
BMC Cancer ; 20(1): 132, 2020 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-32070301

RESUMO

BACKGROUND: Microvascular invasion (MVI) is an independent risk factor for poor prognosis in hepatocellular carcinoma (HCC). However, there is still a lack of preoperative markers to predict MVI in HCC. This study intends to explore the potential application value of the gamma-glutamyl transpeptidase (GGT) to lymphocyte count ratio (GLR) in predicting MVI in HCC and provide guidance for clinical diagnosis and treatment. METHODS: From March 2010 to December 2015, 230 HCC patients who underwent surgical treatment in the Affiliated Hospital of Guilin Medical University were selected. Clinicopathological parameters between the MVI group (n = 115) and the non-MVI group (n = 115) were comparatively analyzed. The GLR was used as the potential risk factor for HCC with MVI, and its optimal cut-off value was estimated by using the receiver operating characteristic (ROC) curve. The Kaplan-Meier method was used to analyze the survival of HCC patients, and univariate and multivariate Cox regression analyses were used to establish independent predictors affecting postoperative HCC patients. RESULTS: The GLR levels in the MVI group and non-MVI group were 84.83 ± 61.84 and 38.42 ± 33.52 (p <  0.001), respectively. According to ROC curve analysis, the optimal cut-off value of GLR was 56.0, and the area under the ROC curve (AUC) was 0.781 (95% CI, 0.719-0.833) for the risk prediction of MVI in HCC patients. Multivariate analysis showed that tumor size > 5 cm, HCC combined with MVI and GLR >  56.0 were independent risk factors for poor prognosis in HCC patients. In addition, compared with the non-MVI group, patients in the MVI group had shorter progression-free survival (PFS) and overall survival (OS). CONCLUSION: GLR could be a predictive biomarker of HCC after operation and a potential predictor of HCC combined with MVI.


Assuntos
Biomarcadores/sangue , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Linfócitos/patologia , Microvasos/patologia , gama-Glutamiltransferase/sangue , Carcinoma Hepatocelular/sangue , Carcinoma Hepatocelular/enzimologia , Feminino , Humanos , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/enzimologia , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Valor Preditivo dos Testes , Curva ROC , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida
10.
Eur J Med Chem ; 189: 112076, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-32007668

RESUMO

In this study, a series of thieno [2,3-d]pyrimidine derivatives were designed, synthesized and evaluated as novel AKT1 inhibitors. In vitro antitumor assay results showed that compounds 9d-g and 9i potently suppressed the enzymatic activities of AKT1 and potently inhibited the proliferation of HepG2, Hep3B, Huh-7 and SMMC-7721 cancer cell lines. Among these derivatives, the compound 9f demonstrated the best inhibitory activities on AKT1 (IC50 = 0.034 µM) and Huh-7 cell (IC50 = 0.076 µM). A panel of biological assays showed that compound 9f suppressed the cellular proliferation of Huh-7 through Akt/mTOR signaling pathway mediated autophagy mechanism. Furthermore, the antitumor capacity of 9f was validated in the subcutaneous Huh-7 xenograft models. Together, our results demonstrate that a novel small-molecule Akt1 inhibitor induces autophagy associated death in hepatocellular carcinoma, which may afford a potential drug candidate for targeted cancer therapy.


Assuntos
Antineoplásicos/farmacologia , Morte Celular Autofágica , Carcinoma Hepatocelular/patologia , Descoberta de Drogas , Neoplasias Hepáticas/patologia , Piperazinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Animais , Antineoplásicos/química , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/enzimologia , Proliferação de Células , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/enzimologia , Camundongos , Camundongos Nus , Piperazinas/química , Inibidores de Proteínas Quinases/química , Transdução de Sinais , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
11.
J Cancer Res Clin Oncol ; 146(4): 875-882, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32107624

RESUMO

PURPOSE: Presently, liver cancer is still one of the malignant tumors with high mortality. As far as the treatment of liver cancer is concerned, the most effective method is still liver transplantation. But every year, many liver cancer patients die from the lack of a proper liver transplant, or from waiting for a liver transplant. Therefore, it is very important to find new and effective treatment for patients with liver cancer. METHODS: Herein, the cell model and the orthotropic liver tumor mice model have been performed to verify the results of our treatment. We found that the in situ synthesized gold nanocluster-PTEN (GNC-PTEN) complexes can effectively target and realize the fluorescence imaging of the liver tumor. RESULTS: GNC-PTEN complexes could inhibit the proliferation, invasion, and metastasis of liver cancer cells. And the results also showed that GNC-PTEN complexes could be well targeted liver tumor at 6 h and the liver tumor in mice group treated with GNC-PTEN complexes almost disappeared. CONCLUSION: This is a simply and effectively method to realize liver cancer imaging and inhibition. This may raise the possibility for the accurate image/diagnosis and simultaneously efficient treatment of liver cancer in the relevant clinic application.


Assuntos
Ouro/administração & dosagem , Neoplasias Hepáticas/tratamento farmacológico , Nanopartículas Metálicas/administração & dosagem , PTEN Fosfo-Hidrolase/administração & dosagem , Animais , Ouro/química , Células Hep G2 , Humanos , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/enzimologia , Neoplasias Hepáticas/genética , Nanopartículas Metálicas/química , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , PTEN Fosfo-Hidrolase/química , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , Distribuição Aleatória , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Life Sci ; 244: 117343, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31978449

RESUMO

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


Assuntos
Proteína ADAM17/antagonistas & inibidores , Carcinoma Hepatocelular/tratamento farmacológico , Inibidores Enzimáticos/farmacologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Animais , Apoptose , Carcinoma Hepatocelular/enzimologia , Carcinoma Hepatocelular/patologia , Proliferação de Células , Humanos , Técnicas In Vitro , Neoplasias Hepáticas/enzimologia , Neoplasias Hepáticas/patologia , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/secundário , Camundongos , Camundongos Nus , Transdução de Sinais , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Genes Dev ; 34(1-2): 53-71, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31857346

RESUMO

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


Assuntos
Carcinogênese/genética , Quinases Ciclina-Dependentes/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/enzimologia , Drosophila melanogaster/metabolismo , Proteínas Nucleares/metabolismo , Transativadores/metabolismo , Animais , Antineoplásicos/farmacologia , Carcinogênese/efeitos dos fármacos , Linhagem Celular , Linhagem Celular Tumoral , Núcleo Celular/metabolismo , Quinases Ciclina-Dependentes/genética , Drosophila melanogaster/genética , Ativação Enzimática , Regulação Neoplásica da Expressão Gênica/genética , Técnicas de Silenciamento de Genes , Humanos , Neoplasias Hepáticas/enzimologia , Neoplasias Hepáticas/fisiopatologia , Camundongos , Tamanho do Órgão/genética , Fenilenodiaminas/farmacologia , Proteólise , Pirimidinas/farmacologia
14.
Oncology ; 98(3): 186-194, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31846974

RESUMO

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


Assuntos
Biomarcadores Tumorais/análise , Carcinoma Hepatocelular/enzimologia , Neoplasias Hepáticas/enzimologia , Recidiva Local de Neoplasia , Proteínas Proto-Oncogênicas c-met/análise , Idoso , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/terapia , Progressão da Doença , Feminino , Humanos , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/terapia , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Regulação para Cima
15.
Environ Int ; 134: 105313, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31731000

RESUMO

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


Assuntos
Carcinoma Hepatocelular/genética , Exposição Ambiental/efeitos adversos , Epigênese Genética , Interação Gene-Ambiente , Neoplasias Hepáticas/genética , Praguicidas/efeitos adversos , Grupo com Ancestrais do Continente Asiático , Carcinoma Hepatocelular/enzimologia , Estudos de Casos e Controles , China , Genótipo , Glutationa Transferase/genética , Humanos , Neoplasias Hepáticas/enzimologia
16.
Toxicol Lett ; 319: 155-159, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31706005

RESUMO

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


Assuntos
Citocromo P-450 CYP1A2/genética , Vetores Genéticos/genética , Hepatoblastoma/enzimologia , Hepatoblastoma/genética , Lentivirus/genética , Neoplasias Hepáticas/enzimologia , Neoplasias Hepáticas/genética , Aflatoxina B1/toxicidade , Linhagem Celular Tumoral , Citocromo P-450 CYP1A2/biossíntese , Impressões Digitais de DNA/métodos , Humanos , Fígado/metabolismo , Mycoplasma/química , Fenacetina/farmacocinética , Plasmídeos/genética
17.
Hepatology ; 71(2): 549-568, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31215069

RESUMO

Cancer cells undergo metabolic adaptation to sustain uncontrolled proliferation. Aerobic glycolysis and glutaminolysis are two of the most essential characteristics of cancer metabolic reprogramming. Hyperactivated phosphoinositide 3-kinase (PI3K)/Akt serine/threonine kinase (Akt) and mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) signaling pathways play central roles in cancer cell metabolic adaptation given that their downstream effectors, such as Akt and c-Myc, control most of the glycolytic and glutaminolysis genes. Here, we report that the cytosolic flavoprotein, NAD(P)H quinone dehydrogenase 1 (Nqo1), is strongly overexpressed in mouse and human hepatocellular carcinoma (HCC). Knockdown of Nqo1 enhanced activity of the serine/threonine phosphatase, protein phosphatase 2A, which operates at the intersection of the PI3K/Akt and MAPK/ERK pathways and dephosphorylates and inactivates pyruvate dehydrogenase kinase 1, Akt, Raf, mitogen-activated protein kinase kinase, and ERK1/2. Nqo1 ablation also induced the expression of phosphatase and tensin homolog, a dual protein/lipid phosphatase that blocks PI3K/Akt signaling, through the ERK/cAMP-responsive element-binding protein/c-Jun pathway. Together, Nqo1 ablation triggered simultaneous inhibition of the PI3K/Akt and MAPK/ERK pathways, suppressed the expression of glycolysis and glutaminolysis genes and blocked metabolic adaptation in liver cancer cells. Conversely, Nqo1 overexpression caused hyperactivation of the PI3K/Akt and MAPK/ERK pathways and promoted metabolic adaptation. Conclusion: In conclusion, Nqo1 functions as an upstream activator of both the PI3K/Akt and MAPK/ERK pathways in liver cancer cells, and Nqo1 ablation blocked metabolic adaptation and inhibited liver cancer cell proliferation and HCC growth in mice. Therefore, our results suggest that Nqo1 may function as a therapeutic target to inhibit liver cancer cell proliferation and inhibit HCC.


Assuntos
Carcinoma Hepatocelular/enzimologia , MAP Quinases Reguladas por Sinal Extracelular/fisiologia , Neoplasias Hepáticas/enzimologia , NAD(P)H Desidrogenase (Quinona)/fisiologia , Fosfatidilinositol 3-Quinases/fisiologia , Proteínas Proto-Oncogênicas c-akt/fisiologia , Animais , Carcinoma Hepatocelular/metabolismo , Humanos , Neoplasias Hepáticas/metabolismo , Masculino , Camundongos , Transdução de Sinais
18.
Handb Exp Pharmacol ; 259: 3-17, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31321542

RESUMO

Hepatocellular carcinoma (HCC) is primarily diagnosed in the latter stages of disease progression and is the third leading cause of cancer deaths worldwide. Thus, there is a need to find biomarkers of early HCC as well as the development of more effective treatments for the disease. Sphingosine-1-phosphate (S1P) is a pleiotropic lipid signaling molecule produced by two isoforms of sphingosine kinase (SphK1 and SphK2) that is involved in regulation of many aspects of mammalian physiology and pathophysiology, including inflammation, epithelial and endothelial barrier function, cancer, and metastasis, among many others. Abundant evidence indicates that SphK1 and S1P promote cancer progression and metastasis in multiple types of cancers. However, the role of SphK/S1P in HCC is less well studied. Here, we review the current state of knowledge of SphKs and S1P in HCC, including evidence for the correlation of SphK1 expression and S1P levels with progression of HCC and negative outcomes, and discuss how this information could lead to the design of more effective diagnostic and treatment modalities for HCC.


Assuntos
Carcinoma Hepatocelular/enzimologia , Neoplasias Hepáticas/enzimologia , Lisofosfolipídeos/análise , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Esfingosina/análogos & derivados , Animais , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Esfingosina/análise
19.
J Pharm Pharmacol ; 72(1): 29-43, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31617221

RESUMO

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


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/tratamento farmacológico , Furanos/farmacologia , Lignanas/farmacologia , Neoplasias Hepáticas/tratamento farmacológico , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Carcinoma Hepatocelular/enzimologia , Carcinoma Hepatocelular/patologia , Ativação Enzimática , Células Hep G2 , Humanos , Neoplasias Hepáticas/enzimologia , Neoplasias Hepáticas/patologia , Camundongos Endogâmicos BALB C , Camundongos Nus , Transdução de Sinais , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Dis Markers ; 2019: 2046825, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31814857

RESUMO

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


Assuntos
Aspartato Aminotransferases/metabolismo , Plaquetas/patologia , Carcinoma Hepatocelular/patologia , Hepatite B Crônica/complicações , Hepatite C Crônica/complicações , Neoplasias Hepáticas/patologia , Carcinoma Hepatocelular/enzimologia , Carcinoma Hepatocelular/etiologia , Estudos de Coortes , Hepacivirus/isolamento & purificação , Vírus da Hepatite B/isolamento & purificação , Hepatite B Crônica/virologia , Hepatite C Crônica/virologia , Humanos , Neoplasias Hepáticas/enzimologia , Neoplasias Hepáticas/etiologia , Prognóstico
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