RESUMO
BACKGROUND: Studies have suggested that vessels encapsulating tumor clusters (VETC) is a strong predictor of prognosis in patients with hepatocellular carcinoma (HCC). METHODS: A systematic search was conducted in PubMed, Embase, Web of Science, and Scopus databases. Overall survival (OS) and tumor efficacy (TE) were two outcome measures used to evaluate the relationship between VETC and HCC prognosis. Hazard ratios (HR) and their 95% confidence intervals (CI) were used. RESULTS: Thirteen studies with 4429 patients were included in the meta-analysis. The results showed that VETC was significantly associated with both OS (HR 2.00; 95% CI 1.64-2.45) and TE (HR 1.70; 95% CI 1.44-1.99) in HCC patients. Furthermore, recurrence-free survival (RFS) was a stronger indicator of tumor efficacy (HR 1.73; 95% CI 1.44-2.07) than disease-free survival (DFS) (HR 1.69; 95% CI 1.22-2.35). This suggests that VETC-positive HCC has a higher risk of recurrence and a lower survival rate. CONCLUSION: In conclusion, the meta-analysis suggests that VETC is a significant predictor of overall survival and tumor efficacy in HCC patients and may be a valid prognostic indicator.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Humanos , Prognóstico , Recidiva Local de Neoplasia/patologia , Intervalo Livre de Doença , Taxa de Sobrevida , Neovascularização Patológica/patologiaAssuntos
Anilidas , Carcinoma Hepatocelular , Ipilimumab , Neoplasias Hepáticas , Nivolumabe , Piridinas , Humanos , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Nivolumabe/farmacologia , Nivolumabe/uso terapêutico , Piridinas/farmacologia , Piridinas/uso terapêutico , Anilidas/farmacologia , Anilidas/uso terapêutico , Ipilimumab/uso terapêutico , Ipilimumab/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologiaRESUMO
BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common types of malignant tumors, with a slow onset, rapid progression, and frequent recurrence. Previous research has implicated mitochondrial ribosomal genes in the development, metastasis, and prognosis of various cancers. However, further research is necessary to establish a link between mitochondrial ribosomal protein (MRP) family expression and HCC diagnosis, prognosis, ferroptosis-related gene (FRG) expression, m6A modification-related gene expression, tumor immunity, and drug sensitivity. METHODS: Bioinformatics resources were used to analyze data from patients with HCC retrieved from the TCGA, ICGC, and GTEx databases (GEPIA, UALCAN, Xiantao tool, cBioPortal, STRING, Cytoscape, TISIDB, and GSCALite). RESULTS: Among the 82 MRP family members, 14 MRP genes (MRPS21, MRPS23, MRPL9, DAP3, MRPL13, MRPL17, MRPL24, MRPL55, MRPL16, MRPL14, MRPS17, MRPL47, MRPL21, and MRPL15) were significantly upregulated differentially expressed genes (DEGs) in HCC tumor samples in comparison to normal samples. Receiver-operating characteristic curve analysis indicated that all 14 DEGs show good diagnostic performance. Furthermore, TCGA analysis revealed that the mRNA expression of 39 MRPs was associated with overall survival (OS) in HCC. HCC was divided into two molecular subtypes (C1 and C2) with distinct prognoses using clustering analysis. The clusters showed different FRG expression and m6A methylation profiles and immune features, and prognostic models showed that the model integrating 5 MRP genes (MRPS15, MRPL3, MRPL9, MRPL36, and MRPL37) and 2 FRGs (SLC1A5 and SLC5A11) attained a greater clinical net benefit than three other prognostic models. Finally, analysis of the CTRP and GDSC databases revealed several potential drugs that could target prognostic MRP genes. CONCLUSION: We identified 14 MRP genes as HCC diagnostic markers. We investigated FRG and m6A modification-related gene expression profiles and immune features in patients with HCC, and developed and validated a model incorporating MRP and FRG expression that accurately and reliably predicts HCC prognosis and may predict disease progression and treatment response.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , Prognóstico , Ribossomos , Proteínas Ribossômicas/genética , Biomarcadores Tumorais/genética , Antígenos de Histocompatibilidade Menor , Sistema ASC de Transporte de Aminoácidos , Proteínas de Transporte de Sódio-GlucoseRESUMO
Intrauterine growth restriction (IUGR) due to fetal exposure to glucocorticoid excess results in metabolic inflexibility and hepatic steatosis upon nutritional stress during adulthood. We previously demonstrated that rats born to dexamethasone (DEX)-treated mothers developed hepatic steatosis when exposed to 10% fructose solution during adult life. Persistent triacylglyceride (TAG) accumulation in the liver, in turn, is a feature of non-alcoholic fatty liver disease (NAFLD), which serves as a risk factor for non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC). In the present study, we demonstrate that the combination of IUGR and fructose treatment during adulthood also results in increased hepatic myeloperoxidase (MPO) activity, AKT phosphorylation and serum aspartate transaminase. Growth-restricted rats also presented reduced hepatic TRIB3 and GADD45a after fructose treatment. Other markers of cell proliferation, such as Cyclin D, PCNA, Hgf and Hspa4/Hsp70 expression and the number of Ki-67 positive cells, were all increased in the liver of growth- restricted rats treated with fructose. On the other hand, the combination of IUGR and fructose treatment during adult life reduced the levels of IGF-1. In conclusion, our data indicate that after exposure to fructose, adult rats subjected to dexamethasone-induced IUGR display exacerbated molecular changes in markers of NASH and HCC.
RESUMO
Background: Barcelona Clinic Liver Cancer (BCLC) is a recognized guideline to standardize treatment allocation for hepatocellular carcinoma (HCC); however, many centers criticize its restrictive liver resection recommendations and have published good results after more liberal hepatectomy indications. The objective is to evaluate the results of HCC resection in a single center, with a more liberal indication for resection than proposed by the BCLC guideline. It was performed a retrospective cohort study including all patients who underwent liver resection for HCC in a single center between April 2008 and November 2018. Methods: The results of 150 patients who underwent hepatectomy were evaluated and compared facing both 2010 and 2018 BCLC guidelines. Overall and disease-free survival after resection in patients with none, one, two, or three of the risk factors, as proposed by the BCLC, as contraindications to resection (portal hypertension, portal invasion, and more than one nodule) were analyzed. Results: Nodule size and presence of portal invasion alone did not affect prognosis. If the BCLC 2010 and 2018 guidelines were followed, 46.7% and 26.7% of the patients, respectively, would not have received potentially curative treatment. The median overall and disease-free survival for patients with one BCLC contraindication factor were 43.3 and 15.1 months, respectively. The presence of two risk factors had a negative impact on overall survival (OS) and disease-free survival (DFS), although some patients had long-term survival. The only patient with the three risk factors had a poor outcome. Conclusions: Selected patients with one BCLC contraindication factor may undergo resection with good results, whereas those with two factors should be allocated for hepatectomy only in favorable scenarios. Patients with the three risk factors do not appear to benefit from resection.
RESUMO
INTRODUCTION AND OBJECTIVES: This study aimed to investigate miR-3682 as a biomarker in hepatocellular carcinoma (HCC). MATERIALS AND METHODS: MiRNA and RNA profiles of 375 HCC tissues and 50 normal liver samples were downloaded from The Cancer Genome Atlas (TCGA) database. Multivariate Cox regression and Kaplan-Meier analyses were applied to examine the prognostic value of factors. Target genes of miR-3682 were analyzed by TargetScan and dual-luciferase reporter assay. Online Database for Annotation, Visualization, and Integrated Discovery (DAVID) to perform KEGG pathway enrichment. Cell counting kit-8, colony formation and migration and invasion assays were performed to analyze biological behaviors of HCC cells. RESULTS: MiR-3682 was identified to be highly expressed in HCC tissues and cell lines. And miR-3682 was negatively and independently associated with the outcome of HCC patients. Inhibition of miR-3682 suppressed HCC cell viability and mobility. ADRA1A, predicted and confirmed as the novel target of miR-3682, was an independent and positive prognostic predictor for HCC. In addition, the knockdown of ADRA1A partially offset the inhibitory effect of miR-3682 inhibitor on the growth and mobility of HCC cells. DAVID enrichment and western blot of key signaling-related proteins analyses revealed that miR-3682 inactivated 5'-AMP-activated protein kinase (AMPK) signaling by negatively regulating ADRA1A. Mechanically, it was partially through suppressing AMPK signaling via targeting ADRA1A that miR-3682 supported the HCC cell malignant phenotype. CONCLUSIONS: This study implicates that miR-3682 plays an oncogenetic role in HCC and can be considered a novel therapeutic target and prognostic indicator of HCC.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , MicroRNAs , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hepáticas/patologia , MicroRNAs/genética , MicroRNAs/metabolismo , Receptores Adrenérgicos alfa 1/genética , Receptores Adrenérgicos alfa 1/metabolismoRESUMO
PURPOSE: Elongation factor Tu GTP-binding domain containing 2 (EFTUD2) is an essential constituent of U5 small nuclear ribonucleoproteins (snRNPs) and plays a crucial role in spliceosome activation and cancer. The mechanism of EFTUD2 on carcinogenesis and development of liver cancer still need further study. METHODS: Bioinformatic analysis was performed to find differential expressed genes and related pathways. Western blotting and quantitative PCR assays were used to verify the EFTUD2 expression in HCC cell lines and tumor tissues of liver cancer patients. Transfection of shRNAs in SKHEP1 and Huh7 cell lines was conducted to explore the mechanisms of EFTUD2 in HCC. CCK-8 method, colony formation, and cell cycle detection kit were used to detect the proliferation. A tumor model in nude mice was used to explore the role of EFTUD2 in liver cancer in vivo. RESULTS: Based on the tumor tissues and para-tumor tissues in our HCC patients, we identified EFTUD2 as highly expressed in HCC tissues (P < 0.001). Bioinformatic analysis from the TCGA database also supported this biological phenomenon (P = 1.911e-17). Furtherly, the results of clinical specimens and TCGA data suggested that higher EFTUD2 expression levels correlated with high histologic grades, high pathological grades, and poor survival prognoses in HCC patients. And knockdown of EFTUD2 suppressed cell proliferation and colony formation in vitro. In vivo, knockdown of EFTUD2 constrained the tumor growing and expansion derived from SKHEP1 cells and induced a decrease in the tumor volume and tumor weight resected from nude mice. Furthermore, RNA sequencing based on EFTUD2 knockdown revealed that EFTUD2 affected target genes concerned with the cell cycle. Flow cytometric analyses in the SKHEP1 cell model revealed that knockdown significantly suppressed cell cycle course and caused cell cycle arrest in the G1 phase. CyclinD1 proteins were also inhibited by knocking down of EFTUD2. CONCLUSION: EFTUD2 is markedly overexpressed in HCC tumor tissues. High EFTUD2 expression in HCC patients is associated with clinical features. Moreover, we confirmed that EFTUD2 shows a pivotal role in HCC cell proliferation and cell cycle course and could be a possible therapeutic avenue in HCC through disturbing EFTUD2.
Assuntos
Carcinoma Hepatocelular/etiologia , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Fatores de Alongamento de Peptídeos/fisiologia , Ribonucleoproteína Nuclear Pequena U5/fisiologia , Animais , Células Cultivadas , Correlação de Dados , Feminino , Humanos , Masculino , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Invasividade Neoplásica , Taxa de SobrevidaRESUMO
BACKGROUND: Hepatocellular carcinoma (HCC) is the most common primary liver cancer in the world. Clinical and laboratory evaluation of a cirrhotic patient with a liver nodule may show alterations suggesting malignancy. There is a lack of questions related to diagnosis of HCC and evaluation of liver imaging reporting and data system (LI-RADS) could be a tool for early diagnosis of HCC. This aims to confirm an association between clinical and laboratory characteristics in cirrhotic patients with hepatic nodule after LI-RADS categorization. METHODS: A cross-sectional retrospective study was performed with 62 patients grouped according to LI-RADS algorithm. Differences between groups were confirmed using association tests and the Kappa test was employed to provide further confirmation. RESULTS: Associations were observed after univariate analysis with higher values of aspartate aminotransferase (AST) (P=0.008), alanine aminotransferase (ALT) (P=0.019), alkaline phosphatase (ALP) (P=0.0052), gamma glutamyl transferase (GGT) (P=0.0023), alpha-fetoprotein (AFP) (P=0.0001), nodule size (P=0.0001) and age (P=0.007) in LR 5 group compared to LR 3. Univariate analysis also revealed higher levels for the LR5 group of ALP (P=0.0228), AFP (P=0.022) and age (P=0.046) in relation to LR 1+2 group. AFP also had higher serum levels in the LR 4 group compared to LR 1+2 (P=0.004). After multivariate analysis, higher levels in LR5 group of nodule size (P=0.047) and ALP (P=0.027) were observed in relation to LR3, and were therefore considered predictors of HCC diagnosis. CONCLUSIONS: The study suggests that the combination of clinical-laboratory and radiological factors, such as heightened serum levels of ALP and hepatic nodule size, may support the screening of HCC in cirrhotic patients with hepatic nodules using the LI-RADS algorithm.
RESUMO
BACKGROUND: Liver transplantation is the main treatment for hepatocellular carcinoma (HCC). However, because of the limited supply of transplant organs, it is necessary to adopt a criterion that selects patients who will achieve adequate survival after transplantation. The aim of this review is to compare the two main staging criteria of HCC for the indication of liver transplantation (Milan and UCSF) and to analyze the post-transplantation survival rate at 1, 3 and 5 years. METHODS: This is a systematic review and meta-analysis in which scientific articles from 5 databases (PubMed, Lilacs, Embase, Central, and Cinahl) were analyzed. The studies included in the review consisted of liver transplantation in patients with HCC in different subgroups according to donor type (deceased × living), population (eastern × western) and tumor evaluation (radiological × pathological) and adopted the Milan or UCSF criteria for the indication of the procedure. RESULTS: There was no significant difference between the Milan and UCSF criteria in the overall survival rate at 1, 3 or 5 years, and the overall estimated value found was 1.03 [0.90, 1.17] at 1 year, 1.06 [0.96, 1.16] at 3 years and 1.04 [0.96, 1.12] at 5 years. Regarding the analysis of the subgroups, no significant difference was observed in any of the subgroups with a follow-up of 1, 3 or 5 years. CONCLUSIONS: Both the Milan and UCSF criteria have equivalent survival rate. Thus, less restrictive method would not result in a great loss in the final overall survival rate and would benefit a greater number of patients.
RESUMO
BACKGROUND: The prognostic role of intratumoral programmed cell death ligand 1 (PD-L1) expression in hepatocellular carcinoma (HCC) has been investigated by several meta-analyses. However, the prognostic value of pretreatment peripheral PD-L1 (PPPD-L1) level in HCC remains undetermined. Thus, this systemic review aimed to establish PPPD-L1 as a new prognostic marker in HCC according to available evidence. METHODS: Case-control studies investigating the prognostic role of PPPD-L1 in HCC were systemically sought in the database of PubMed and Web of Science until March 25th, 2020. Our main concern is survival results, including overall survival (OS), disease-free survival (DFS), and progression-free survival (PFS). The combined results were summarized in narrative form according to data extracted from each included study. RESULTS: Finally, nine studies published from 2011 to 2019, were incorporated into this systemic review. Among these, six studies evaluated the PD-L1 expression by enzyme-linked immunosorbent assay (ELISA) from blood serum, and three studies evaluated the PD-L1 expression by flow cytometric analysis from peripheral blood mononuclear cells (PBMC). According to the extracted evidence, high PPPD-L1 expression, measured in either blood serum or PBMC, is associated with poor OS, poor DFS, and poor PFS. Meanwhile, PPPD-L1 was also correlated with enlarged tumor size and more likely with advanced tumor stage as well as vascular invasion. CONCLUSION: High PPPD-L1 level is associated with increased mortality rate and increased recurrence rate in HCC. As a convenient serum marker, PPPD-L1 could be a promising marker of prognosis in HCC patients.
Assuntos
Antígeno B7-H1/sangue , Biomarcadores Tumorais/sangue , Carcinoma Hepatocelular/sangue , Neoplasias Hepáticas/sangue , Carcinoma Hepatocelular/mortalidade , Estudos de Casos e Controles , Intervalo Livre de Doença , Humanos , Leucócitos Mononucleares/metabolismo , Neoplasias Hepáticas/mortalidade , Prognóstico , Intervalo Livre de ProgressãoRESUMO
Liver cancer ranks fifth in incidence and fourth in overall cancer-related mortality, with approximately 854,000 new cases and 810,000 deaths per year worldwide. Hepatocellular carcinoma (HCC) accounts for 90% of these cases, and, over time, both the incidence and mortality of this cancer have been rising in many regions. Several staging systems are used to assess the extent of primary tumor, presence of metastasis, and underlying liver disease, and thereby aid in the definition of treatment strategies and prognosis for these patients. The consequence of this heterogeneity in HCC staging is that no consensual definition of advanced disease exists, and there is still ongoing debate on the optimal treatment for these patients. Patients with advanced tumors can be candidates for multiple therapies, ranging from potentially curative options such as transplantation and resection-to locoregional and systemic treatments; these should be evaluated on an individual basis by a multidisciplinary team. This paper provides an overview of treatment options for advanced stage HCC, based on a review of the latest relevant literature and the personal experience of the authors.
RESUMO
PURPOSE: Transcatheter arterial embolization (TAE) has been widely used in treating non-curative hepatocellular carcinoma (HCC). However, it is noticed that TAE may cause invasion of some cancer cells into circulation, resulting in distal metastasis and poor therapeutic outcome. Here, we aimed to reduce the side effects of TAE using the inhibitors for epidermal growth factor receptor (EGFR). METHODS: Transient hepatic artery ligation (HAL) was used as a mouse model for TAE. EGFR inhibitors were applied. Tumor size, presence of tumor cells in circulation, distal tumor formation, and activation of genes associated with tumor cell invasion and metastasis were analyzed. RESULTS: Inhibitors for EGFR significantly reduced the size of primary tumor, presence of tumor cells in circulation, and distal tumor formation after HAL. Further studies showed that EGFR inhibition suppressed several genes associated with tumor cell invasion and metastasis, such as vascular endothelial growth factor-A, stromal cell-derived factor 1, and Slug. CONCLUSION: EGFR inhibitor application may reduce circulating cancer cells during TAE and thus improve the therapy for advanced HCC.
Assuntos
Carcinoma Hepatocelular/patologia , Embolização Terapêutica/efeitos adversos , Receptores ErbB/antagonistas & inibidores , Neoplasias Hepáticas/patologia , Células Neoplásicas Circulantes/efeitos dos fármacos , Animais , Antineoplásicos Imunológicos/farmacologia , Cetuximab/farmacologia , Células Hep G2 , Humanos , Masculino , Camundongos , Camundongos Nus , Células Neoplásicas Circulantes/patologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Hepatocellular carcinoma (HCC) is the fifth most prevalent cancer and it is linked with chronic liver disease. Liver transplantation (LT) is the best curative treatment modality, since it can cure simultaneously the underlying liver disease and HCC. Milan criteria (MC) are the benchmark for selecting patients with HCC for LT, achieving up to 91% 1-year survival post transplantation. However, when considering intention-to-treat (ITT) rates are substantially lower, mainly due dropout. Additionally, Milan criteria (MC) are too restrictive and more inclusive criteria have been reported with good outcomes. Mainly, in Eastern countries, deceased donors are scarce, therefore Asian centers have developed living-donor liver transplantation (LDLT) to a state-of-art status. There are many eastern centers reporting huge numbers of LDLT with outstanding results. Regarding HCC patients, they have reported many criteria including more advanced tumors achieving reasonable outcomes. Western countries have well-established deceased-donor liver transplantation (DDLT) programs. However, organ shortage and restrictive criteria for listing patients with HCC endorses LDLT as a good option to offer curative treatment to more HCC patients. However, there are some controversial reports claiming higher rates of HCC recurrence after LDLT than DDLT. An extensive review included 30 studies with cohorts of HCC patients who underwent LDLT in both East and West countries. We reported also the results of our Institution, in Brazil, where it was performed the first LDLT. This review also addresses the eligibility criteria for transplanting patients with HCC developed in Western and Eastern countries.
RESUMO
PURPOSE: Long noncoding RNAs (lncRNAs) are outstanding as novel cancer biomarkers with great prospects. Herein, we focused on summarizing the overall diagnostic evaluation of lncRNAs for hepatocellular carcinoma (HCC). METHODS: Relevant literature was collected from the online databases. The Quality Assessment for Studies of Diagnostic Accuracy checklist was used to assess the quality of included studies. The pooled sensitivity, specificity, and diagnostic odds ratio (DOR) were plotted using random-effects models. Summary receiver operating characteristic curve and the area under the curve (AUC) were used to estimate the overall test performance. Statistical analysis was performed by STATA 14.0 and Meta-DiSc 1.4 software. RESULTS: Ten studies with a total of 820 HCC patients and 785 healthy controls were included. For overall lncRNAs, the pooled sensitivity, specificity, and DOR to predict HCC patients were 80% [95% confidence interval (CI) 77-82%], 79% (95% CI 76-81%), and 27.66 (95% CI 14.26-53.63), respectively, corresponding to an AUC of 0.91. CONCLUSIONS: LncRNAs were a high diagnostic value for HCC and its expression could potentially be used as auxiliary biomarker in confirming HCC.
Assuntos
Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/diagnóstico , Neoplasias Hepáticas/diagnóstico , RNA Longo não Codificante/genética , Carcinoma Hepatocelular/genética , Humanos , Neoplasias Hepáticas/genética , PrognósticoRESUMO
BACKGROUND: Identification of patients with advanced HCC-deriving preferential benefit from sorafenib is desirable, and treatment-related adverse events are potential clinical biomarkers. METHODS: Survival and toxicity data for patients with HCC treated with sorafenib at the Christie NHS Foundation Trust from 11/09 to 02/15 were collected retrospectively. RESULTS: Eighty-five eligible patients were identified. The most common grade 3 or 4 treatment-related toxicities were hypertension (HTN, 45 %), fatigue (8 %), and hand-foot syndrome (HFS, 8 %). Any-grade HFS and/or worsening HTN (HFS/HTN) were experienced by 58 % of patients. Estimated median progression-free and overall survival (OS) were 4.6 (95 % CI 2.8-5.2) and 6.5 (95 % CI 4.9-8.01) months, respectively. Child-Pugh score (p value <0.001) and the development of HFS/HTN were independent prognostic factors impacting on OS on multivariable analysis. Patients who developed HFS/HTN had median OS of 8.2 months (95 % CI 6.5-12.4) compared with 4.1 (95 % CI 2.7-5.4) for those without this toxicity (Hazard Ratio (HR) 0.4, 95 % CI 0.2-0.7, p value 0.003). The prognostic impact of HFS/HTN was confirmed by landmark analyses limited to patients who lived a minimum of 2 months (p value 0.019) or who developed HFS/HTN in the first 3 months of treatment (p value 0.006). CONCLUSION(S): The development of toxicities specific to sorafenib is associated with prolonged survival in a UK-based HCC patient series; prospective assessment of their significance is required.
Assuntos
Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/análise , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Niacinamida/análogos & derivados , Compostos de Fenilureia/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Hepatocelular/tratamento farmacológico , Feminino , Seguimentos , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Niacinamida/uso terapêutico , Prognóstico , Estudos Retrospectivos , Sorafenibe , Taxa de SobrevidaRESUMO
PURPOSE: To investigate biological impact of the downregulation of yes-associated protein (YAP) through RNA interference in the process of epithelial-mesenchymal transition in MHCC97H and MHCC97L. METHODS: MHCC97H and MHCC97L cells were transiently transfected by YAP-siRNA. Furthermore, protein expressions and mRNA levels of characteristic markers of epithelial-mesenchymal transition (E-cadherin, N-cadherin) were examined by Western blotting and real-time polymerase chain reaction, and transwell invasion assay was used to detect changes of invasiveness of MHCC97H and MHCC97L cells. RESULTS: The transfected group with YAP-siRNA in MHCC97H after 72 h by Western blotting showed obviously higher expression of E-cadherin compared with the control group (P < 0.05), and lower expression of N-cadherin (P < 0.05). In MHCC97L cells, the expression of E-cadherin was also significantly increased (P < 0.05); however, N-cadherin expression did not significantly change (P > 0.05). Moreover, compared with the control group, Transwell invasion assay showed that the number of the transfected groups was significantly decreased in MHCC97H and MHCC97L cell lines (both P < 0.05). The result of real-time polymerase chain reaction indicated that mRNA levels of E-cadherin increased (P < 0.05), but the mRNA levels of N-cadherin did not significantly change (P > 0.05) in these two cell lines, indicating some effects of post-transcriptional regulation mechanism after silencing YAP. CONCLUSIONS: YAP expression in human hepatocellular carcinoma cell lines MHCC97H and MHCC97L is closely related with the characteristic markers of epithelial-mesenchymal transition, N-cadherin and E-cadherin expression.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Carcinoma Hepatocelular/patologia , Transição Epitelial-Mesenquimal/fisiologia , Neoplasias Hepáticas/patologia , Fosfoproteínas/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Western Blotting , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Regulação para Baixo , Técnicas de Silenciamento de Genes , Humanos , Neoplasias Hepáticas/metabolismo , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Fosfoproteínas/genética , RNA Interferente Pequeno , Reação em Cadeia da Polimerase em Tempo Real , Fatores de Transcrição , Transfecção , Proteínas de Sinalização YAPRESUMO
In liver cancer tumor-infiltrating regulatory T cells (Ti-Treg) are potent suppressors of tumor-specific T-cell responses and express high levels of the Treg-associated molecules cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and glucocorticoid-induced tumor necrosis factor receptor (GITR). In this study, we have evaluated the capacity of GITR-ligation, CTLA-4-blockade and a combination of both treatments to alleviate immunosuppression mediated by Ti-Treg. Using ex vivo isolated cells from individuals with hepatocellular carcinoma (HCC) or liver metastases from colorectal cancer (LM-CRC) we show that treatment with a soluble form of the natural ligand of GITR (GITRL), or with blocking antibodies to CTLA-4, reduces the suppression mediated by human liver tumor-infiltrating CD4+Foxp3+ Treg, thereby restoring proliferation and cytokine production by effector T cells. Importantly, combined treatment with low doses of both molecules exhibited stronger recovery of T cell function compared with either treatment alone. Our data suggest that in patients with primary and secondary liver cancer both GITR-ligation and anti-CTLA-4 mAb can improve the antitumor immunity by abrogating Ti-Treg mediated suppression.
RESUMO
No se puede hablar de una sola historia natural para el carcinoma hepatocelular (CHC), ya que se trata de una enfermedad multifactorial, con un comportamiento biológico además diferente, no solo por el comportamiento del crecimiento tumoral, sino por el tipo de expresión, dependiendo de las características del huésped. Por otro lado, los síntomas inespecíficos y la mayoría de veces ausentes no ayudan a determinar tampoco el curso de la enfermedad. Así, es necesario comentar su presentación dependiendo de los diferentes tópicos que pueden incluir en ella.
No one can speak of just one natural history for hepatocellular carcinoma (HCC). HCC is a multifactorial disease whose behavior differs from one case to the next. This is true not only for the behavior of tumor growth but also for the type of expression depending on the hosts characteristics. Furthermore, symptoms are not specific for HCC and most often are absent, so they cannot help to determine the course of the disease. Consequently, it is necessary to discuss HCCs presentation based on different topics which may be included in it.