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1.
Yonsei Med J ; 62(5): 409-416, 2021 May.
Artículo en Inglés | MEDLINE | ID: mdl-33908211

RESUMEN

PURPOSE: The optimal timing for radiotherapy (RT) after incomplete transarterial chemoembolization (TACE) remains unclear. This study investigated the optimal timing to initiate RT after incomplete TACE in patients with Barcelona Clinic Liver Cancer stage B hepatocellular carcinoma. MATERIALS AND METHODS: This study included 116 lesions in 104 patients who were treated with RT after TACE between 2001 and 2016. The time interval between the last TACE session and RT initiation was retrospectively analyzed. The optimal cut-off time interval that maximized the difference in local failure-free rates (LFFRs) was determined using maximally selected rank statistics. RESULTS: The median time interval was 26 days (range: 2-165 days). At a median follow-up of 18 months (range: 3-160 months), the median overall survival was 18 months. The optimal cut-off time interval appeared to be 5 weeks; using this cut-off, 65 and 39 patients were classified into early and late RT groups, respectively. Early RT group had a significantly poorer Child-Pugh class and higher alpha-fetoprotein levels compared to late RT group. Other characteristics, including tumor size (7 cm vs. 6 cm; p=0.144), were not significantly different between the groups. The 1-year LFFR was significantly higher in the early RT group than in the late RT group (94.6% vs. 70.8%; p=0.005). On multivariate analysis, early RT was identified as an independent predictor of favorable local failure-free survival (hazard ratio: 3.30, 95% confidence interval: 1.50-7.29; p=0.003). CONCLUSION: The optimal timing for administering RT after incomplete TACE is within 5 weeks. Early administration of RT is associated with better local control.


Asunto(s)
Carcinoma Hepatocelular , Quimioembolización Terapéutica , Neoplasias Hepáticas , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/terapia , Humanos , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/terapia , Estadificación de Neoplasias , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Resultado del Tratamiento
2.
World J Surg Oncol ; 19(1): 121, 2021 Apr 17.
Artículo en Inglés | MEDLINE | ID: mdl-33865414

RESUMEN

BACKGROUND: It has been reported that long-chain non-coding RNA (lncRNA) zinc finger E-box binding homeobox 1 antisense 1 (ZEB1-AS1) is an oncogene in various cancers, including hepatocellular carcinoma (HCC). We investigated the role and mechanism of ZEB1-AS1 as a competitive endogenous RNA (ceRNA) combined with miR-23c in HCC cell proliferation and invasion. METHODS: QRT-PCR was used to detect ZEB1-AS1 and miR-23c expressions in HCC tissues and cells. The dual luciferase reporter assay detected the targeted regulation of miR-23c and ZEB1-AS1. We also performed the correlation analysis of their expression in HCC tissues by the Spearman's correlation analysis. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used to detect the proliferation of hepatoma cells. Cell invasion was assessed by the Transwell assay. RESULTS: QRT-PCR results indicated ZEB1-AS1 was upregulated and miR-23c was downregulated in HCC tissues and cell lines. ZEB1-AS1 knockdown hampered the proliferation and invasion of HCC cells. Dual luciferase reporter assay showed that miR-23c is a target of ZEB1-AS1, and ZEB1-AS1 was significantly negatively correlated with the miR-23c expression in HCC tissues. The results of MTT and Transwell assay showed that miR-23c inhibition restored the inhibitory effect of ZEB1-AS1 knockdown on HCC cells proliferation and invasion. CONCLUSIONS: As a ceRNA, lncRNA ZEB1-AS1 may play a vital role in inhibiting HCC progression through miR-23c, which will provide new clues and theoretical basis for the HCC diagnosis and treatment.


Asunto(s)
Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , ARN Largo no Codificante/genética , Homeobox 1 de Unión a la E-Box con Dedos de Zinc/genética , Apoptosis/genética , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Proliferación Celular/genética , Progresión de la Enfermedad , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Hepáticas/patología , MicroARNs/genética , Pronóstico
3.
Int J Mol Sci ; 22(6)2021 Mar 19.
Artículo en Inglés | MEDLINE | ID: mdl-33808647

RESUMEN

Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies worldwide. HCC is associated with several etiological factors, including HBV/HCV infections, cirrhosis, and fatty liver diseases. However, the molecular mechanism underlying HCC development remains largely elusive. The advent of high-throughput sequencing has unveiled an unprecedented discovery of a plethora of long noncoding RNAs (lncRNAs). Despite the lack of coding capacity, lncRNAs have key roles in gene regulation through interacting with various biomolecules. It is increasingly evident that the dysregulation of lncRNAs is inextricably linked to HCC cancer phenotypes, suggesting that lncRNAs are potential prognostic markers and therapeutic targets. In light of the emerging research in the study of the regulatory roles of lncRNAs in HCC, we discuss the association of lncRNAs with HCC. We link the biological processes influenced by lncRNAs to cancer hallmarks in HCC and describe the associated functional mechanisms. This review sheds light on future research directions, including the potential therapeutic applications of lncRNAs.


Asunto(s)
Biomarcadores de Tumor , Carcinoma Hepatocelular/genética , Susceptibilidad a Enfermedades , Regulación Neoplásica de la Expresión Génica , Neoplasias Hepáticas/genética , ARN Largo no Codificante , Animales , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/terapia , Transformación Celular Neoplásica/genética , Manejo de la Enfermedad , Genes Supresores de Tumor , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Técnicas de Diagnóstico Molecular , Terapia Molecular Dirigida , Oncogenes , Transducción de Señal/efectos de los fármacos
4.
Medicine (Baltimore) ; 100(15): e25374, 2021 Apr 16.
Artículo en Inglés | MEDLINE | ID: mdl-33847635

RESUMEN

ABSTRACT: The pathogenesis of hepatocellular carcinoma (HCC) can be divided into viral infection (VIR) and nonviral (NVIR) infection. Two types of HCC performed different tumor immune microenvironment (TIME) which directly affected prognosis of HCC. This study aimed to identify an effective 2 types of HCC prognostic gene signature that related to immune TIME.The differential expression genes (DEGs) were analyzed by Limma R package from the Cancer Genome Atlas. Immune related genes getting from IMMport database were matched to DEGs for testing prognosis. Prognostic index (PI) consisted of prognostic immune related genes was calculated in different types of HCC by COX regression and the correlation with the abundance of immune infiltrates, including 6 type cells, via gene modules. Tumor immune estimation resource database was applied to analyze TIME. Finally, the correlations between PI of DEGs and TIICs were analyzed by the Spearman method.Results showed that PI consisted of 11 messenger RNAs in VIR and 12 messenger RNAs in NVIR groups. The PI related to HCC prognosis has different correlations with immune infiltrating cells in VIR and NVIR groups. The PI value of DEGs has significant correlations with neutrophils (R = 0.22, P-value = .029) and dendritic (R = 0.21, P-value = .036) infiltration levels in VIR group. However, in NVIR group, the result showed there were no significant correlations between PI and other 5 type cell infiltration levels (P-value > .05).The 11-gene signature in VIR and 12-gene signature in NVIR group selected based on data from the Cancer Genome Atlas database had a different correlation with immune infiltrating cells of HCC patients.


Asunto(s)
Carcinoma Hepatocelular/etiología , Carcinoma Hepatocelular/genética , Hepatitis/complicaciones , Neoplasias Hepáticas/etiología , Neoplasias Hepáticas/genética , Microambiente Tumoral/genética , Biomarcadores de Tumor , Carcinoma Hepatocelular/inmunología , Carcinoma Hepatocelular/patología , Femenino , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Hepatitis/epidemiología , Humanos , Estimación de Kaplan-Meier , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas/patología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , ARN Mensajero/biosíntesis , Microambiente Tumoral/inmunología
5.
Anticancer Res ; 41(4): 1975-1983, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33813404

RESUMEN

BACKGROUND/AIM: Few studies have established a definite conclusion regarding the limitation of surgical treatment for patients with Barcelona Clinic Liver Cancer (BCLC) stage B and C hepatocellular carcinoma (HCC). PATIENTS AND METHODS: A retrospective analysis was performed on 717 consecutive patients who underwent initial hepatectomy for HCC. RESULTS: Reductive hepatectomy was performed in 103 patients, with a median survival time (MST) of 18.0 months. Total bilirubin and albumin levels were identified as independent prognostic factors. The predictive score of these factors ranged from 0 to 2. Subsequent local treatment was performed in 91.0, 75.0, and 25.0% of patients who scored 0, 1, and 2, respectively. The MST for patients with a score of 0, 1, and 2 was 20.1, 14.8, and 2.7 months, respectively, with a significant difference. CONCLUSION: Patients with BCLC stage B and C could be properly treated with reductive hepatectomy and subsequent local treatments.


Asunto(s)
Carcinoma Hepatocelular/cirugía , Procedimientos Quirúrgicos de Citorreducción , Hepatectomía/métodos , Neoplasias Hepáticas/cirugía , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/mortalidad , Carcinoma Hepatocelular/patología , Procedimientos Quirúrgicos de Citorreducción/efectos adversos , Procedimientos Quirúrgicos de Citorreducción/métodos , Estudios de Factibilidad , Femenino , Estudios de Seguimiento , Hepatectomía/efectos adversos , Humanos , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/patología , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/diagnóstico , Recurrencia Local de Neoplasia/etiología , Recurrencia Local de Neoplasia/mortalidad , Estadificación de Neoplasias , Neoplasia Residual/diagnóstico , Neoplasia Residual/etiología , Neoplasia Residual/mortalidad , Pronóstico , Estudios Retrospectivos , Resultado del Tratamiento
6.
Anticancer Res ; 41(4): 2007-2016, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33813407

RESUMEN

BACKGROUND/AIM: The benefit of direct-acting antiviral therapy (DAA) in chronic hepatitis C (CHC) infected patients who received curative treatment for early-stage hepatocellular carcinoma (HCC) is well known, but is unclear for intermediate stage HCC. PATIENTS AND METHODS: CHC patients with Barcelona Clinic Liver Cancer (BCLC) stage B HCC receiving chemoembolization were identified. Univariate, multivariate analyses, and Kaplan-Meier curve were used to identify factors associated with survival outcomes. RESULTS: Among 113 included patients, the median survival of DAA treated group (n=14) and non-treated group (n=99) were 40.1 months and 22.9 months, respectively. Multivariate analysis showed that Eastern Cooperative Oncology Group (ECOG) score, DAA, and serum albumin were key independent factors associated with overall survival. Moreover, the time-to-complete remission (TTCR) was improved in the DAA treated group. CONCLUSION: ECOG, DAA, and serum albumin were prognostic factors for CHC/intermediate-stage HCC patients. DAA was also a beneficial factor for TTCR.


Asunto(s)
Antivirales/uso terapéutico , Carcinoma Hepatocelular/tratamiento farmacológico , Hepatitis C Crónica/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Anciano , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/virología , Estudios de Cohortes , Femenino , Hepatitis C Crónica/complicaciones , Hepatitis C Crónica/patología , Humanos , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/virología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Estudios Retrospectivos , Resultado del Tratamiento
7.
Anticancer Res ; 41(4): 2025-2032, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33813409

RESUMEN

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


Asunto(s)
Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Hígado/efectos de los fármacos , Hígado/fisiopatología , Compuestos de Fenilurea/uso terapéutico , Quinolinas/uso terapéutico , Factores de Edad , Edad de Inicio , Anciano , Anciano de 80 o más Años , Carcinoma Hepatocelular/epidemiología , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/fisiopatología , Femenino , Humanos , Hígado/patología , Pruebas de Función Hepática , Neoplasias Hepáticas/epidemiología , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/fisiopatología , Masculino , Compuestos de Fenilurea/farmacología , Quinolinas/farmacología , Estudios Retrospectivos
8.
Int J Mol Sci ; 22(5)2021 Mar 06.
Artículo en Inglés | MEDLINE | ID: mdl-33800884

RESUMEN

The nucleotide analog sofosbuvir, licensed for the treatment of hepatitis C, recently revealed activity against the Zika virus (ZIKV) in vitro and in animal models. However, the ZIKV genetic barrier to sofosbuvir has not yet been characterized. In this study, in vitro selection experiments were performed in infected human hepatoma cell lines. Increasing drug pressure significantly delayed viral breakthrough (p = 0.029). A double mutant in the NS5 gene (V360L/V607I) emerged in 3 independent experiments at 40-80 µM sofosbuvir resulting in a 3.9 ± 0.9-fold half- maximal inhibitory concentration (IC50) shift with respect to the wild type (WT) virus. A triple mutant (C269Y/V360L/V607I), detected in one experiment at 80 µM, conferred a 6.8-fold IC50 shift with respect to the WT. Molecular dynamics simulations confirmed that the double mutant V360L/V607I impacts the binding mode of sofosbuvir, supporting its role in sofosbuvir resistance. Due to the distance from the catalytic site and to the lack of reliable structural data, the contribution of C269Y was not investigated in silico. By a combination of sequence analysis, phenotypic susceptibility testing, and molecular modeling, we characterized a double ZIKV NS5 mutant with decreased sofosbuvir susceptibility. These data add important information to the profile of sofosbuvir as a possible lead for anti-ZIKV drug development.


Asunto(s)
Sustitución de Aminoácidos , Antivirales/farmacología , Mutación Puntual , Sofosbuvir/farmacología , Proteínas no Estructurales Virales/antagonistas & inhibidores , Virus Zika/efectos de los fármacos , Animales , Antivirales/uso terapéutico , Sitios de Unión , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Chlorocebus aethiops , Humanos , Concentración 50 Inhibidora , Neoplasias Hepáticas/patología , Modelos Moleculares , Simulación de Dinámica Molecular , Unión Proteica , Conformación Proteica , ARN Viral/biosíntesis , ARN Viral/genética , /metabolismo , Selección Genética , Sofosbuvir/uso terapéutico , Células Vero , Proteínas no Estructurales Virales/genética , Proteínas no Estructurales Virales/metabolismo , Replicación Viral/efectos de los fármacos , Virus Zika/enzimología , Virus Zika/genética
9.
Int J Mol Sci ; 22(6)2021 Mar 23.
Artículo en Inglés | MEDLINE | ID: mdl-33807071

RESUMEN

Hepatocellular carcinoma (HCC), the most common malignant tumor in the liver, grows and metastasizes rapidly. Despite advances in treatment modalities, the five-year survival rate of HCC remains less than 30%. We sought genetic mutations that may affect the oncogenic properties of HCC, using The Cancer Genome Atlas (TCGA) data analysis. We found that the GNAQ T96S mutation (threonine 96 to serine alteration of the Gαq protein) was present in 12 out of 373 HCC patients (3.2%). To examine the effect of the GNAQ T96S mutation on HCC, we transfected the SK-Hep-1 cell line with the wild-type or the mutant GNAQ T96S expression vector. Transfection with the wild-type GNAQ expression vector enhanced anchorage-independent growth, migration, and the MAPK pathways in the SK-Hep-1 cells compared to control vector transfection. Moreover, cell proliferation, anchorage-independent growth, migration, and the MAPK pathways were further enhanced in the SK-Hep-1 cells transfected with the GNAQ T96S expression vector compared to the wild-type GNAQ-transfected cells. In silico structural analysis shows that the substitution of the GNAQ amino acid threonine 96 with a serine may destabilize the interaction between the regulator of G protein signaling (RGS) protein and GNAQ. This may reduce the inhibitory effect of RGS on GNAQ signaling, enhancing the GNAQ signaling pathway. Single nucleotide polymorphism (SNP) genotyping analysis for Korean HCC patients shows that the GNAQ T96S mutation was found in only one of the 456 patients (0.22%). Our data suggest that the GNAQ T96S hotspot mutation may play an oncogenic role in HCC by potentiating the GNAQ signal transduction pathway.


Asunto(s)
Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Subunidades alfa de la Proteína de Unión al GTP Gq-G11/genética , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Mutación , Transducción de Señal , Alelos , Sustitución de Aminoácidos , Carcinoma Hepatocelular/patología , Movimiento Celular/genética , Proliferación Celular , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , Susceptibilidad a Enfermedades , Subunidades alfa de la Proteína de Unión al GTP Gq-G11/química , Subunidades alfa de la Proteína de Unión al GTP Gq-G11/metabolismo , Expresión Génica , Genotipo , Humanos , Neoplasias Hepáticas/patología , Sistema de Señalización de MAP Quinasas , Modelos Moleculares , Oncogenes , Conformación Proteica , Relación Estructura-Actividad
10.
Int J Mol Sci ; 22(6)2021 Mar 22.
Artículo en Inglés | MEDLINE | ID: mdl-33809908

RESUMEN

Endoglin (CD105) is a type-1 integral transmembrane glycoprotein and coreceptor for transforming growth factor-ß (TGF-ß) ligands. The endoglin/TGF-ß signaling pathway regulates hemostasis, cell proliferation/migration, extracellular matrix (ECM) synthesis and angiogenesis. Angiogenesis contributes to early progression, invasion, postoperative recurrence, and metastasis in hepatocellular carcinoma (HCC), one of the most widespread malignancies globally. Endoglin is overexpressed in newly formed HCC microvessels. It increases microvessel density in cirrhotic and regenerative HCC nodules. In addition, circulating endoglin is present in HCC patients, suggesting potential for use as a diagnostic or prognostic factor. HCC angiogenesis is dynamic and endoglin expression varies by stage. TRC105 (carotuximab) is an antibody against endoglin, and three of its clinical trials were related to liver diseases. A partial response was achieved when combining TRC105 with sorafenib. Although antiangiogenic therapy still carries some risks, combination therapy with endoglin inhibitors or other targeted therapies holds promise.


Asunto(s)
Carcinoma Hepatocelular/etiología , Carcinoma Hepatocelular/metabolismo , Susceptibilidad a Enfermedades , Endoglina/genética , Endoglina/metabolismo , Neoplasias Hepáticas/etiología , Neoplasias Hepáticas/metabolismo , Animales , Biomarcadores de Tumor , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/terapia , Endoglina/sangre , Endoglina/química , Células Endoteliales/metabolismo , Regulación Neoplásica de la Expresión Génica , Hepacivirus/fisiología , Hepatitis C/metabolismo , Hepatitis C/virología , Humanos , Neoplasias Hepáticas/patología , Técnicas de Diagnóstico Molecular , Terapia Molecular Dirigida , Neovascularización Patológica/genética , Neovascularización Patológica/metabolismo , Transducción de Señal , Relación Estructura-Actividad , Proteínas del Núcleo Viral/metabolismo
11.
Int J Mol Sci ; 22(6)2021 Mar 18.
Artículo en Inglés | MEDLINE | ID: mdl-33803555

RESUMEN

In this study, detailed information on hepatocellular carcinoma (HCC) cells (HepG-2, SMMC-7721, and HuH-7) and normal human liver cell L02 treated by ferrocene derivatives (compounds 1, 2 and 3) is provided. The cell viability assay showed that compound 1 presented the most potent and selective anti-HCC activity. Further mechanism study indicated that the proliferation inhibition effect of compound 1 was associated with the cycle arrest at the G0/G1 phase and downregulation of cyclin D1/CDK4. Moreover, compound 1 could induce apoptosis in HCC cells by loss of mitochondrial membrane potential (ΔΨm), accumulation of reactive oxygen species (ROS), decrease in Bcl-2, increase in BAX and Bad, translocation of Cytochrome c, activation of Caspase-9, -3, and cleavage of PARP. These results indicated that compound 1 would be a promising candidate against HCC through G0/G1 cell cycle arrest-related proliferation inhibition and mitochondrial pathway-dependent apoptosis.


Asunto(s)
Apoptosis/efectos de los fármacos , Carcinoma Hepatocelular/patología , Compuestos Ferrosos/farmacología , Puntos de Control de la Fase G1 del Ciclo Celular/efectos de los fármacos , Neoplasias Hepáticas/patología , Metalocenos/farmacología , Mitocondrias/metabolismo , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Citocromos c/metabolismo , Humanos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Modelos Biológicos , Especies Reactivas de Oxígeno/metabolismo , Fase de Descanso del Ciclo Celular/efectos de los fármacos
12.
Int J Nanomedicine ; 16: 2569-2584, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33833512

RESUMEN

Background: Multidrug resistance (MDR) has emerged to be a major hindrance in cancer therapy, which contributes to the reduced sensitivity of cancer cells toward chemotherapeutic drugs mainly owing to the over-expression of drug efflux transporters. The combination of gene therapy and chemotherapy has been considered as a potential approach to improve the anti-cancer efficacy by reversing the MDR effect. Materials and Methods: The AS1411 aptamer-functionalized micelles were constructed through an emulsion/solvent evaporation strategy for the simultaneous co-delivery of doxorubicin and miR-519c. The therapeutic efficacy and related mechanism of micelles were explored based on the in vitro and in vivo active targeting ability and the suppression of MDR, using hepatocellular carcinoma cell line HepG2 as a model. Results: The micelle was demonstrated to possess favorable cellular uptake and tumor penetration ability by specifically recognizing the nucleolin in an AS1411 aptamer-dependent manner. Further, the intracellular accumulation of doxorubicin was significantly improved due to the suppression of ABCG2-mediated drug efflux by miR-519c, resulting in the efficient inhibition of tumor growth. Conclusion: The micelle-mediated co-delivery of doxorubicin and miR-519c provided a promising strategy to obtain ideal anti-cancer efficacy through the active targeting function and the reversion of MDR.


Asunto(s)
Aptámeros de Nucleótidos/administración & dosificación , Carcinoma Hepatocelular/terapia , Doxorrubicina/farmacología , Sistemas de Liberación de Medicamentos/métodos , Micelas , MicroARNs/administración & dosificación , Oligodesoxirribonucleótidos/administración & dosificación , Fosfoproteínas/antagonistas & inhibidores , Proteínas de Unión al ARN/antagonistas & inhibidores , Animales , Antibióticos Antineoplásicos/administración & dosificación , Antibióticos Antineoplásicos/farmacología , Apoptosis , Aptámeros de Nucleótidos/química , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patología , Ciclo Celular , Movimiento Celular , Proliferación Celular , Doxorrubicina/administración & dosificación , Resistencia a Múltiples Medicamentos , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/terapia , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Oligodesoxirribonucleótidos/química , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto
13.
Pan Afr Med J ; 38: 99, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33889265

RESUMEN

Hepatocellular carcinoma (HCC) is a major public health problem in Senegal, and the third most common cancer in terms of incidence. However, there are no recent data on the characteristics of this pathology in our country. The aim was to describe the epidemiological, clinical, aetiological and therapeutic aspects of HCC at Hôpital Principal de Dakar, Senegal. We did a descriptive retrospective study, including patients hospitalized from January 2012 to December 2017. We included 229 patients. The mean age was 47.4 years (21 - 88 years), and 77 patients (33.6%) were under 40 years of age. The sex ratio was 6.6. Twelve patients (5.2%) had a family history of 1st degree cirrhosis or HCC. Ten patients (4.4%) were previously treated with nucleotide analogues. The most common clinical sign at diagnosis was abdominal pain (91.7%). Alpha-fetoprotein level was normal in 12.2% of patients, and greater than 400 ng/ml in 68.1% of cases. Abdominal ultrasound found nodular HCC in 122 patients (68.2%), infiltrative HCC in 19 patients (10.6%), and was normal in 38 cases (21.2%). Subjacent cirrhosis was detected in 71.3% of cases. Abdominal computed tomography (CT) scan showed compatible HCC lesions in 88.8% of cases. A histological diagnosis was obtained in 2 patients (0.9%). The most common etiological factor was hepatitis B virus (69.4%), characterized mostly by a younger age (p = 0.001). In 20.9% of cases, no aetiology was found. An advanced or terminal stage (BCLC C/D) was found in 217 cases (94.8%). The treatment was curative in 12 patients (5.2%), and palliative in 7 cases (3.1%). The evolution at one year was favourable in 6 patients (2.6%). Hepatocellular carcinoma (HCC) is a disease that mainly affects young male adults in Senegal. The main aetiological factor remains HBV infection. The diagnosis is made at an advanced stage and the prognosis very bad.


Asunto(s)
Carcinoma Hepatocelular/epidemiología , Cirrosis Hepática/epidemiología , Neoplasias Hepáticas/epidemiología , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/patología , Femenino , Hepatitis B/complicaciones , Hepatitis B/epidemiología , Humanos , Incidencia , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/patología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Estudios Retrospectivos , Senegal/epidemiología , Factores Sexuales , Tomografía Computarizada por Rayos X , Ultrasonografía , Adulto Joven
14.
Medicine (Baltimore) ; 100(14): e25335, 2021 Apr 09.
Artículo en Inglés | MEDLINE | ID: mdl-33832108

RESUMEN

ABSTRACT: The systemic immune-inflammation index (SII) is an independent prognostic predictor of hepatocellular carcinoma (HCC). The present investigation examined whether an association exists between preoperative SII value and postoperative acute kidney injury (pAKI) in HCC patients.The study included 479 hepatitis B virus (HBV)-associated HCC patients undergoing hepatectomy. The SII was calculated as P × N/L, where P, N, and L represent the counts of platelets, neutrophils, and lymphocytes in routine blood test, respectively. After propensity score matching, logistic regression analysis was used to explore independent predictors of pAKI in HCC patients.pAKI was confirmed in 51 patients (10.8%). The average SII value was higher in patients with pAKI than patients without pAKI. After multivariate logistic regression analysis, SII, history of hypertension, and tumor size, among others, were found to be predictors of pAKI. The optimal threshold value of SII for predicting pAKI was found to be 547.84 × 109/L. Multivariate analysis performed after propensity score matching confirmed that SII ≥ 547.84 × 109/L was an independent predictor of pAKI.The preoperative SII qualifies as a novel, independent predictor of pAKI in HCC patients with HBV infection who underwent hepatectomy.


Asunto(s)
Lesión Renal Aguda/etiología , Lesión Renal Aguda/inmunología , Carcinoma Hepatocelular/cirugía , Indicadores de Salud , Hepatectomía/efectos adversos , Neoplasias Hepáticas/cirugía , Lesión Renal Aguda/patología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma Hepatocelular/etiología , Carcinoma Hepatocelular/patología , Comorbilidad , Hepatitis B/complicaciones , Humanos , Recuento de Leucocitos , Pruebas de Función Hepática , Neoplasias Hepáticas/etiología , Neoplasias Hepáticas/patología , Modelos Logísticos , Persona de Mediana Edad , Periodo Posoperatorio , Pronóstico , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Carga Tumoral , Adulto Joven
15.
Int J Nanomedicine ; 16: 2803-2818, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33880025

RESUMEN

Background: Circular RNAs (circRNAs) have been identified as key factors in the development of hepatocellular carcinoma (HCC). However, the role and potential molecular mechanism of circRNAs in HCC remain largely unclear. In addition, exosomes are known as important messengers of the cross-talk between tumor cells and immune cells, while the role of extracellular circRNAs in the cell-to-cell communication of tumor cells and immune cells remains not unclear. Methods: The level of hsa_circ_0074854 in HCC cell lines and HCC cell-derived exosomes was assessed using RT-qPCR assay. In addition, CCK-8 and transwell assays were used to determine the viability, migration and invasion of HCC cells. Results: Hsa_circ_0074854 expression was upregulated in HCC tissues and HCC cell lines. Additionally, hsa_circ_0074854 knockdown was found to inhibit HCC growth in vitro and in vivo. Mechanistically, hsa_circ_0074854 knockdown inhibited the migration and invasion of HCC cells via interacting with human antigen R (HuR) to reduce its stability. Furthermore, hsa_circ_0074854 can be transferred from HCC cells to macrophages via exosomes. Exosomes with downregulated hsa_circ_0074854 suppressed macrophage M2 polarization, which in turn suppressing migration and invasion of HCC cells both in vitro and in vivo. Conclusion: Downregulation of hsa_circ_0074854 suppresses the migration and invasion in hepatocellular carcinoma via interacting with HuR and via suppressing exosomes-mediated macrophage M2 polarization. Collectively, these findings may help to understand the diagnosis and treatment of HCC.


Asunto(s)
Carcinoma Hepatocelular/genética , Movimiento Celular/genética , Polaridad Celular , Regulación hacia Abajo , Proteína 1 Similar a ELAV/metabolismo , Exosomas/metabolismo , Macrófagos/patología , ARN Circular/metabolismo , Animales , Apoptosis/genética , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Proliferación Celular/genética , Regulación hacia Abajo/genética , Transición Epitelial-Mesenquimal/genética , Regulación Neoplásica de la Expresión Génica , Técnicas de Silenciamiento del Gen , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Macrófagos/metabolismo , Ratones Endogámicos BALB C , Ratones Desnudos , Invasividad Neoplásica , Unión Proteica , ARN Circular/genética
16.
BMC Cancer ; 21(1): 443, 2021 Apr 21.
Artículo en Inglés | MEDLINE | ID: mdl-33882892

RESUMEN

BACKGROUND: This study intends to investigate the immunological effects of tumor ablation with irreversible electroporation (IRE). METHODS: We evaluated the systemic immune response in patients with hepatocellular carcinoma (HCC) after IRE treatment. Furthermore, we analyzed the tumor infiltrating T lymphocytes and the level of serum cytokines in IRE and control groups of tumor-bearing mice. RESULTS: We observed that IRE induced an increase in WBC, neutrophil and monocyte counts and a decrease in lymphocyte count 1 day post-IRE and returned to baseline values within 7 days in the patients. Meanwhile, circulating CD4+ T cell subsets, but not CD8+, decreased 1 day post-IRE. The activated T cells and natural killer (NK) cells increased, and regulatory T (Treg) cells decreased. Furthermore, a significant increase in cytotoxic CD8+ T cells infiltration was observed on ablative tumors in mice. The level of serum IFN-γ also significantly increased in the IRE group. CONCLUSIONS: Our study demonstrated that IRE upregulated activated T cells and downregulated Tregs in the peripheral blood of patients. Meanwhile, the results from the animal model indicated that IRE could induce antitumor adaptive immunity dominated by the infiltration of cytotoxic CD8+ T cells into the tumors, accompanied by reduced Tregs.


Asunto(s)
Carcinoma Hepatocelular/inmunología , Inmunomodulación , Neoplasias Hepáticas/inmunología , Anciano , Animales , Biomarcadores , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Citocinas/metabolismo , Electroporación , Femenino , Citometría de Flujo , Humanos , Inmunidad Innata , Inmunohistoquímica , L-Lactato Deshidrogenasa/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Masculino , Ratones , Persona de Mediana Edad , Escape del Tumor
17.
Medicine (Baltimore) ; 100(16): e25627, 2021 Apr 23.
Artículo en Inglés | MEDLINE | ID: mdl-33879737

RESUMEN

ABSTRACT: The aim of the current study was to explore the value of tumor attenuation and quantitative analysis of perfusion parameters obtained from traditional tri-phasic CT scans in grading hepatocellular carcinoma (HCC).Totally 39 patients (42 lesion samples) with pathologically confirmed HCC who underwent tri-phasic CT scans were enrolled. HCC lesions were divided into non-poorly differentiated HCC (NP-HCC; n = 31) and poorly differentiated HCC (pHCC; n = 11). All lesions were divided into 5 groups according to the attenuation on different CT enhancement phase. The values of tumor attenuation on different scanning phases were measured. The following parameters were calculated: arterial enhancement fraction (AEF), portal venous supply coefficient (PVC), and hepatic arterial supply coefficient (HAC). The relationship of perfusion parameters with the histological grade of HCC was analyzed. Receiver operating characteristic curves were generated.No significant correlation was observed between the perfusion parameters and tumor grading. Only HAC showed a non-significant trend in different grades of HCC (pHCC < NP-HCC; P = .07). The pHCC cases had significantly decreased values of tumor attenuation on the unenhanced phase (TAu), tumor attenuation on the portal phase portal phase (TAp), and equilibrium phase (TAe) (P < .01). The difference of tumor attenuation between the portal phase and the unenhanced phase (TAp-TAu) of the pHCC cases was decreased than that of the NP-HCC cases (P < .01), whereas the difference of attenuation between the equilibrium phase and portal phase (TAe-TAp) was significantly higher in the pHCC cases than that in the NP-HCC cases (P < .01). TAe-TAp had the highest area under the curve. The number of tumor enhancement pattern in Group 5 of HCCs with a diameter of 3 cm or more was significantly more than that of HCCs with a diameter of less than 3 cm or with other different enhancement patterns (P < .01).Histological HCC grading cannot be predicted by the perfusion parameters derived from traditional tri-phasic CT scans, whereas the tumor attenuation on different phases and the tumor attenuation differences among different phases, especially the mean value of TAe-TAp, might be useful for non-invasive prediction on the degree of HCC differentiation.


Asunto(s)
Carcinoma Hepatocelular/irrigación sanguínea , Carcinoma Hepatocelular/diagnóstico por imagen , Neoplasias Hepáticas/irrigación sanguínea , Neoplasias Hepáticas/diagnóstico por imagen , Clasificación del Tumor/métodos , Imagen de Perfusión/métodos , Tomografía Computarizada por Rayos X/métodos , Anciano , Anciano de 80 o más Años , Carcinoma Hepatocelular/patología , Femenino , Arteria Hepática/patología , Humanos , Hígado/irrigación sanguínea , Hígado/patología , Neoplasias Hepáticas/patología , Masculino , Persona de Mediana Edad , Variaciones Dependientes del Observador , Perfusión , Vena Porta/patología , Valor Predictivo de las Pruebas , Curva ROC , Estadísticas no Paramétricas
18.
Anticancer Res ; 41(4): 1883-1893, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33813393

RESUMEN

BACKGROUND/AIM: Hepatocellular carcinoma (HCC) is a highly prevalent disease and treatment is limited. Therefore, development of new therapeutic agents is urgent. The aim of this study was to investigate the in vitro and in vivo anti-cancer effects of Nardostachys jatamansi root extract (NJRE) against HCC and underlying mechanisms involved in such effects. MATERIALS AND METHODS: Effects of NJRE on viability of HCC cell lines were determined by MTT analysis and annexin/PI apoptosis assays. Expression levels of proteins in MAPK and STAT3 pathways and caspase-3 and PARP after treatment with NJRE in HCC cell lines were determined by western blotting. In a syngeneic model using mouse HCC cells Hepa1-6, inhibition of tumor formation after oral administration of NJRE was determined and expression levels of phospho-ERK and phospho-STAT3 in liver tissues were analyzed by immunohistochemical staining. RESULTS: NJRE reduced the activation of STAT3 by inhibiting the expression of ERK and finally attenuated the proliferation of HCC. CONCLUSION: NJRE has anti-cancer effects against HCC. It has potential to be used in the treatment of human HCC.


Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Carcinoma Hepatocelular/tratamiento farmacológico , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Neoplasias Hepáticas/tratamiento farmacológico , Nardostachys , Raíces de Plantas , Factor de Transcripción STAT3/metabolismo , Animales , Antineoplásicos Fitogénicos/aislamiento & purificación , Apoptosis/efectos de los fármacos , Carcinoma Hepatocelular/enzimología , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Humanos , Neoplasias Hepáticas/enzimología , Neoplasias Hepáticas/patología , Masculino , Ratones Endogámicos C57BL , Nardostachys/química , Fosforilación , Raíces de Plantas/química , Transducción de Señal , Carga Tumoral/efectos de los fármacos
20.
Int J Mol Sci ; 22(5)2021 Mar 05.
Artículo en Inglés | MEDLINE | ID: mdl-33807943

RESUMEN

We evaluated the effect of manganese ferrite nanoparticles (MFN) on radiosensitization and immunologic responses using the murine hepatoma cell line Hepa1-6 and the syngeneic mouse model. The clonogenic survival of Hepa1-6 cells was increased by hypoxia, while being restricted by ionizing radiation (IR) and/or MFN. Although MFN suppressed HIF-1α under hypoxia, the combination of IR and MFN enhanced apoptosis and DNA damage in Hepa1-6 cells. In the Hepa1-6 syngeneic mouse model, the combination of IR and MFN notably limited the tumor growth compared to the single treatment with IR or MFN, and also triggered more frequent apoptosis in tumor tissues than that observed under other conditions. Increased expression of PD-L1 after IR was not observed with MFN alone or the combination of IR and MFN in vitro and in vivo, and the percentage of tumor-infiltrating T cells and cytotoxic T cells increased with MFN, regardless of IR, in the Hepa1-6 syngeneic mouse model, while IR alone led to T cell depletion. MFN might have the potential to overcome radioresistance by alleviating hypoxia and strengthening antitumor immunity in the tumor microenvironment.


Asunto(s)
Carcinoma Hepatocelular/radioterapia , Compuestos Férricos/farmacología , Neoplasias Hepáticas/radioterapia , Compuestos de Manganeso/farmacología , Nanopartículas/uso terapéutico , Radiación Ionizante , Fármacos Sensibilizantes a Radiaciones/farmacología , Microambiente Tumoral/efectos de la radiación , Animales , Carcinoma Hepatocelular/inmunología , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Compuestos Férricos/química , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas/patología , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/patología , Compuestos de Manganeso/química , Ratones , Nanopartículas/química , Fármacos Sensibilizantes a Radiaciones/química , Linfocitos T/inmunología , Linfocitos T/patología , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/inmunología
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