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1.
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
2.
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
3.
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
4.
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
5.
Anticancer Res ; 41(4): 2171-2175, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33813429

RESUMEN

BACKGROUND: Although indications of laparoscopic hepatectomy have been expanded, the laparoscopic approach after right hepatic lobectomy has a very high burden. The purpose of this study was to evaluate patients undergoing laparoscopic repeat hepatectomy for recurrent hepatic tumors after open right lobectomy. PATIENTS AND METHODS: Five cases of laparoscopic repeat hepatectomy for recurrent hepatic tumors after open right lobectomy were included in the study. RESULTS: All the tumors in segment 3 were intraoperatively detected and curatively resected by partial hepatectomy. The tumors in segment 2 could not be detected intraoperatively due to hypertrophic liver deformity and adhesion. They were curatively resected by anatomical subsegmental approach. CONCLUSION: For recurrent tumors located in segment 2 after right lobectomy, anatomical subsegmental approach should be preferred, not only from an oncological standpoint, but also for securing curative laparoscopic resection and overcoming anatomical difficulties.


Asunto(s)
Carcinoma Hepatocelular/cirugía , Hepatectomía/métodos , Laparoscopía/métodos , Neoplasias Hepáticas/cirugía , Recurrencia Local de Neoplasia/cirugía , Reoperación/métodos , Anciano , Carcinoma Hepatocelular/patología , Humanos , Neoplasias Hepáticas/patología , Masculino , Persona de Mediana Edad , Tratamientos Conservadores del Órgano/métodos , Inducción de Remisión/métodos , Resultado del Tratamiento
6.
Anticancer Res ; 41(4): 2187-2192, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33813432

RESUMEN

BACKGROUND/AIM: The present study aimed to examine the therapeutic efficacy of ramucirumab compared with that of sorafenib as subsequent systemic therapy for patients with hepatocellular carcinoma (HCC) and serum α-fetoprotein (AFP) levels ≥400 ng/ml. PATIENTS AND METHODS: In our prospectively registered, real-world cohort, 13 and 11 patients treated with ramucirumab or sorafenib, respectively, were analyzed. Progression-free survival (PFS) was primarily compared between the ramucirumab and sorafenib groups. RESULTS: The PFS was significantly longer in the ramucirumab group than in the sorafenib group (median, 2.7 vs. 0.9 months, respectively; p=0.005). There were no significant differences in the objective response rates or the disease control rates between the ramucirumab and sorafenib groups (9.1% and 54.5% vs. 0.0% and 22.2%, respectively). CONCLUSION: Subsequent systemic therapy with ramucirumab showed a better ability to control tumor progression than sorafenib in HCC patients with serum AFP levels ≥400 ng/ml.


Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Sorafenib/uso terapéutico , Anciano , Anciano de 80 o más Años , Carcinoma Hepatocelular/sangre , Carcinoma Hepatocelular/mortalidad , Carcinoma Hepatocelular/patología , Quimioterapia Adyuvante/métodos , Estudios de Cohortes , Progresión de la Enfermedad , Femenino , Humanos , Japón/epidemiología , Neoplasias Hepáticas/sangre , Neoplasias Hepáticas/patología , Masculino , Persona de Mediana Edad , Supervivencia sin Progresión , Tasa de Supervivencia , Resultado del Tratamiento , alfa-Fetoproteínas/metabolismo
7.
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
8.
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
9.
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
10.
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
11.
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
12.
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
13.
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
14.
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
15.
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
16.
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
17.
Int J Mol Sci ; 22(6)2021 Mar 11.
Artículo en Inglés | MEDLINE | ID: mdl-33799789

RESUMEN

It is challenging to overcome the low response rate of everolimus in the treatment of patients with hepatocellular carcinoma (HCC). To overcome this challenge, we combined everolimus with Ku0063794, the inhibitor of mTORC1 and mTORC2, to achieve higher anticancer effects. However, the precise mechanism for the synergistic effects is not clearly understood yet. To achieve this aim, the miRNAs were selected that showed the most significant variation in expression according to the mono- and combination therapy of everolimus and Ku0063794. Subsequently, the roles of specific miRNAs were determined in the processes of the treatment modalities. Compared to individual monotherapies, the combination therapy significantly reduced viability, increased apoptosis, and reduced autophagy in HepG2 cells. The combination therapy led to significantly lower expression of miR-4790-3p and higher expression of zinc finger protein225 (ZNF225)-the predicted target of miR-4790-3p. The functional study of miR-4790-3p and ZNF225 revealed that regarding autophagy, miR-4790-3p promoted it, while ZNF225 inhibited it. In addition, regarding apoptosis, miR-4790-3p inhibited it, while ZNF225 promoted it. It was also found that HCC tissues were characterized by higher expression of miR-4790-3p and lower expression of ZNF225; HCC tissues were also characterized by higher autophagic flux. We, thus, conclude that the potentiated anticancer effect of the everolimus and Ku0063794 combination therapy is strongly associated with reduced autophagy resulting from diminished expression of miR-4790-3p, as well as higher expression of ZNF225.


Asunto(s)
Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Everolimus/farmacología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , MicroARNs/genética , Morfolinas/farmacología , Pirimidinas/farmacología , Antineoplásicos/farmacología , Apoptosis/genética , Autofagia/genética , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/genética , Sinergismo Farmacológico , Proteína 1 de la Respuesta de Crecimiento Precoz/genética , Proteína 1 de la Respuesta de Crecimiento Precoz/metabolismo , Inhibidores Enzimáticos/farmacología , Células Hep G2 , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Diana Mecanicista del Complejo 1 de la Rapamicina/antagonistas & inhibidores , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Diana Mecanicista del Complejo 2 de la Rapamicina/antagonistas & inhibidores , Diana Mecanicista del Complejo 2 de la Rapamicina/metabolismo
18.
Int J Mol Sci ; 22(6)2021 Mar 11.
Artículo en Inglés | MEDLINE | ID: mdl-33799862

RESUMEN

Excess calorie intake and a sedentary lifestyle have made non-alcoholic fatty liver disease (NAFLD) one of the fastest growing forms of liver disease of the modern world. It is characterized by abnormal accumulation of fat in the liver and can range from simple steatosis and non-alcoholic steatohepatitis (NASH) to cirrhosis as well as development of hepatocellular carcinoma (HCC). Biopsy is the golden standard for the diagnosis and differentiation of all NAFLD stages, but its invasiveness poses a risk for patients, which is why new, non-invasive ways of diagnostics ought to be discovered. Lipocalin-2 (LCN2), which is a part of the lipocalin transport protein family, is a protein formally known for its role in iron transport and in inflammatory response. However, in recent years, its implication in the pathogenesis of NAFLD has become apparent. LCN2 shows significant upregulation in several benign and malignant liver diseases, making it a good candidate for the NAFLD biomarker or even a therapeutic target. What makes LCN2 more interesting to study is the fact that it is overexpressed in HCC development induced by chronic NASH, which is one of the primary causes of cancer-related deaths. However, to this day, neither its role as a biomarker for NAFLD nor the molecular mechanisms of its implication in NAFLD pathogenesis have been completely elucidated. This review aims to gather and closely dissect the current knowledge about, sometimes conflicting, evidence on LCN2 as a biomarker for NAFLD, its involvement in NAFLD, and NAFLD-HCC related pathogenesis, while comparing it to the findings in similar pathologies.


Asunto(s)
Biomarcadores/metabolismo , Carcinoma Hepatocelular/metabolismo , Lipocalina 2/metabolismo , Neoplasias Hepáticas/metabolismo , Hígado/metabolismo , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Biopsia , Carcinoma Hepatocelular/patología , Humanos , Hígado/patología , Cirrosis Hepática/metabolismo , Cirrosis Hepática/patología , Neoplasias Hepáticas/patología , Enfermedad del Hígado Graso no Alcohólico/patología
19.
Int J Nanomedicine ; 16: 1553-1564, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33658783

RESUMEN

Purpose: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. Most current therapeutic strategies primarily include localized treatment, lacking effective systemic strategies. Meanwhile, recent studies have suggested that RNA vaccines can effectively activate antigen-presenting cells (APCs) and lymphocytes to produce a strong systemic immune response and inhibit tumor growth. However, tumor vaccines loaded with a single tumor antigen may induce immunosuppression and immune evasion, while identifying tumor-specific antigens can require expensive and laborious procedures. Therefore, the use of whole tumor cell antigens are currently considered to be promising, potentially effective, methods. Previously, we developed a targeted liposome-polycation-DNA (LPD) complex nanoparticle that possess a small size, high RNA encapsulation efficiency, and superior serum stability. These particles were found to successfully deliver RNA to tumor sites. In the current study, we encapsulated total tumor-derived RNA in lipid nanoparticles (LNPs) to target dendritic cells (DCs) to incite expeditious and robust anti-tumor immunity. Methods: Total tumor-derived RNA was extracted from liver cancer cells (Hepa1-6 cells). LNPs loaded with tumor RNA were then prepared thin-film hydration method. The ability of RNA LNPs to induce DC maturation, cytotoxicity, and anti-tumor activity, was investigated in vitro and in vivo. Results: The average particle size of LNPs and RNA LNPs was 102.22 ± 4.05 nm and 209.68 ± 6.14 nm, respectively, while the zeta potential was 29.97 ± 0.61 mV and 42.03 ± 0.42 mV, respectively. Both LNPs and RNA LNP vaccines exhibited good distribution and stability. In vitro, RNA LNP vaccines were capable of promoting DC maturation and inducing T lymphocytes to kill Hepa1-6 cells. In vivo, RNA LNP vaccines effectively prevent and inhibit HCC growth. Conclusion: RNA LNPs may serve as an effective antigen specific vaccine to induce anti-tumor immunity for HCC.


Asunto(s)
Carcinoma Hepatocelular/inmunología , Carcinoma Hepatocelular/terapia , Inmunoterapia , Lípidos/química , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas/terapia , Nanopartículas/química , ARN Neoplásico/metabolismo , Animales , Vacunas contra el Cáncer/inmunología , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Humanos , Activación de Linfocitos/inmunología , Masculino , Ratones Endogámicos C57BL , Nanopartículas/administración & dosificación , Tamaño de la Partícula , Linfocitos T/inmunología
20.
Int J Nanomedicine ; 16: 1575-1586, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33664572

RESUMEN

Background: Exosomes are a type of membrane vesicles secreted by living cells. Recent studies suggest exosome-like nanovesicles (ELNVs) from fruits and vegetables are involved in tissue renewal process and functional regulation against inflammatory diseases or cancers. However, there are few reports on ELNVs derived from medicinal plants. Methods: ELNVs derived from Asparagus cochinchinensis (Lour.) Merr. (ACNVs) were isolated and characterized. Cytotoxicity, antiproliferative and apoptosis-inducing capacity of ACNVs against hepatoma carcinoma cell were assessed. The endocytosis mechanism of ACNVs was evaluated on Hep G2 cells in the presence of different endocytosis inhibitors. In vivo distribution of ACNVs was detected in healthy and tumor-bearing mice after scavenger receptors (SRs) blockade. PEG engineering of ACNVs was achieved through optimizing the pharmacokinetic profiles. In vivo antitumor activity and toxicity were evaluated in Hep G2 cell xenograft model. Results: ACNVs were isolated and purified using a differential centrifugation method accompanied by sucrose gradient ultracentrifugation. The optimized ACNVs had an average size of about 119 nm and showed a typical cup-shaped nanostructure containing lipids, proteins, and RNAs. ACNVs were found to possess specific antitumor cell proliferation activity associated with an apoptosis-inducing pathway. ACNVs could be internalized into tumor cells mainly via phagocytosis, but they were quickly cleared once entering the blood. Blocking the SRs or PEGylation decoration prolonged the blood circulation time and increased the accumulation of ACNVs in tumor sites. In vivo antitumor results showed that PEGylated ACNVs could significantly inhibit tumor growth without side effects. Conclusion: This study provides a promising functional nano platform derived from edible Asparagus cochinchinensis that can be used in antitumor therapy with negligible side effects.


Asunto(s)
Asparagaceae/química , Carcinoma Hepatocelular/patología , Exosomas/metabolismo , Neoplasias Hepáticas/patología , Nanopartículas/química , Nanotecnología , Animales , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Carcinoma Hepatocelular/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Endocitosis/efectos de los fármacos , Humanos , Neoplasias Hepáticas/metabolismo , Masculino , Ratones Endogámicos BALB C , Ratones Desnudos , Nanopartículas/efectos adversos , Nanopartículas/ultraestructura , Polietilenglicoles/química , Distribución Tisular/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto
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