RESUMO
UNLABELLED: Hepatocyte nuclear factor 4α (HNF4α) is a liver enriched transcription factor and is indispensable for liver development. However, the role of HNF4α in hepatocellular carcinoma (HCC) progression remains to be elucidated. We report that reduced HNF4α expression correlated well with the aggressive clinicopathological characteristics of HCC and predicted poor prognosis of patients. HNF4α levels were even lower in metastatic HCCs, and ectopic HNF4α expression suppressed the metastasis of hepatoma cells both in vitro and in vivo. Forced HNF4α expression attenuated the expression and nuclear translocation of RelA (p65) and impaired NF-κB activation through an IKK-independent mechanism. Blockage of RelA robustly attenuated the suppressive effect of HNF4α on hepatoma cell metastasis. MicroRNA (miR)-7 and miR-124 were transcriptionally up-regulated by HNF4α, which repressed RelA expression by way of interaction with RelA-3' untranslated region (UTR). In addition, nuclear factor kappa B (NF-κB) up-regulated the expression of miR-21 in hepatoma cells, resulting in decreased HNF4α levels through down-regulating HNF4α-3'UTR activity. CONCLUSIONS: Collectively, an HNF4α-NF-κB feedback circuit including miR-124, miR-7, and miR-21 was identified in HCC, and the combination of HNF4α and NF-κB exhibited more powerful predictive efficiency of patient prognosis. These findings broaden the knowledge of hepatic inflammation and cancer initiation/progression, and also provide novel prognostic biomarkers and therapeutic targets for HCC.
Assuntos
Carcinoma Hepatocelular/metabolismo , Fator 4 Nuclear de Hepatócito/metabolismo , Neoplasias Hepáticas/metabolismo , MicroRNAs/metabolismo , NF-kappa B/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Carcinoma Hepatocelular/mortalidade , Células Cultivadas , China/epidemiologia , Progressão da Doença , Transição Epitelial-Mesenquimal , Retroalimentação Fisiológica , Feminino , Humanos , Neoplasias Hepáticas/mortalidade , Masculino , Pessoa de Meia-Idade , Ratos Wistar , Fator de Transcrição RelA/metabolismo , Adulto JovemRESUMO
UNLABELLED: MicroRNA 370 (miR-370) is located within the DLK1/DIO3 imprinting region on human chromosome 14, which has been identified as a cancer-associated genomic region. However, the role of miR-370 in malignances remains controversial. Here, we report that miR-370 was repressed in human hepatocellular carcinoma (HCC) tissues and hepatoma cell lines. Using gain-of-function and loss-of-function experiments, we demonstrated that miR-370 inhibited the malignant phenotype of HCC cells in vitro. Overexpression of miR-370 inhibited growth and metastasis of HCC cells in vivo. Moreover, the RNA-binding protein, LIN28A, was identified as a direct functional target of miR-370, which, in turn, blocked the biogenesis of miR-370 by binding to its precursor. LIN28A also mediated the suppressive effects of miR-370 on migration and invasion of HCC cells by post-transcriptionally regulating RelA/p65, which is an important effector of the canonical nuclear factor kappa B (NF-κB) pathway. Interleukin-6 (IL-6), a well-known NF-κB downstream inflammatory molecule, reduced miR-370 but increased LIN28A levels in HCC. Furthermore, miR-370 levels were inversely correlated with LIN28A and IL-6 messenger RNA (mRNA) levels, whereas LIN28A mRNA expression was positively correlated with IL-6 expression in human HCC samples. Interestingly, reduction of miR-370 expression was associated with the development of HCC in rats, as well as with aggressive tumor behavior and short survival in HCC patients. CONCLUSIONS: These data demonstrate the involvement of a novel regulatory circuit consisting of miR-370, LIN28A, RelA/p65 and IL-6 in HCC progression. Manipulating this feedback loop may have beneficial effect in HCC treatment.
Assuntos
Carcinoma Hepatocelular/patologia , Proteínas de Ligação a DNA/metabolismo , Neoplasias Hepáticas/patologia , MicroRNAs/fisiologia , NF-kappa B/metabolismo , Animais , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Linhagem Celular Tumoral , Regulação para Baixo , Humanos , Interleucina-6/farmacologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Camundongos , Proteínas de Ligação a RNA , Fator de Transcrição RelA/fisiologiaRESUMO
BACKGROUND: Critically ill patients can benefit from enteral nutrition with postpyloric feeding tubes, but the low success rate limits its wide use. Erythromycin could elevate the success rate of tube insertion, but its clinical efficiency still remains controversial. METHODS: Included studies must be RCTs which assessed the success rate of postpyloric feeding tube insertion using erythromycin. RESULTS: 284 patients were enrolled in six studies. Meta-analysis showed that erythromycin significantly increases the rate of successful postpyloric feeding tube placement (RR 1.45, 95% CI (1.12, 1.86)) and did not increase the risk of adverse effects (RR 2.15, 95% CI (0.20, 22.82)). Subgroup analysis showed that unweighted feeding tubes (RR 1.47, 95% CI (1.03, 2.11)) could significantly increase the success rate. Country of study, intravenous route of erythromycin, and year of participant enrollment did not influence these results. CONCLUSIONS: Erythromycin significantly increases the success rate of postpyloric feeding tube placement. This suggests that erythromycin can be used as an auxiliary method to improve the success rate of bedside insertion.
RESUMO
Previous studies provided substantial evidence of a striking suppressive effect of hepatocyte nuclear factor 4α (HNF4α) on hepatocellular carcinoma (HCC). Apoptosis signal-regulating kinase 1 (ASK1) is involved in death receptor-mediated apoptosis and may acts as a tumor suppressor in hepatocarcinogenesis. However, the status and function of ASK1 during HCC progression are unclear. In this study, we found that HNF4α increased ASK1 expression by directly binding to its promoter. ASK1 expression was dramatically suppressed and correlated with HNF4α levels in HCC tissues. Reduced ASK1 expression was associated with aggressive tumors and poor prognosis for human HCC. Moreover, ASK1 inhibited the malignant phenotype of HCC cells in vitro. Intratumoral ASK1 injection significantly suppressed the growth of subcutaneous HCC xenografts in nude mice. More interestingly, systemic ASK1 delivery strikingly inhibited the growth of orthotopic HCC nodules in NOD/SCID mice. In addition, inhibition of endogenous ASK1 partially reversed the suppressive effects of HNF4α on HCC. Collectively, this study highlights the suppressive effect of ASK1 on HCC and its biological significance in HCC development. These outcomes broaden the knowledge of ASK1 function in HCC progression, and provide a novel potential prognostic biomarker and therapeutic target for advanced HCC.
Assuntos
Carcinoma Hepatocelular/genética , Fator 4 Nuclear de Hepatócito/genética , Neoplasias Hepáticas/genética , MAP Quinase Quinase Quinase 5/genética , Animais , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica , Fator 4 Nuclear de Hepatócito/metabolismo , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , MAP Quinase Quinase Quinase 5/metabolismo , Sistema de Sinalização das MAP Quinases/genética , Masculino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos NOD , Camundongos Nus , Camundongos SCID , Regiões Promotoras Genéticas/genética , Ligação Proteica , Transplante HeterólogoRESUMO
OBJECTIVE: To evaluate the efficacy, safety and tolerability of different doses of rifaximin in Chinese patients with liver cirrhosis. METHODS: This random prospective study included a screening visit, a 2-week treatment period and a subsequent 4-week observation phase. Patients with liver cirrhosis were randomly assigned to a low-dose rifaximin group, a high-dose rifaximin group and the control group in a ratio of 1:1:1. The low-dose and high-dose groups received 400 mg or 600 mg rifaximin per 12 h for 2 weeks, respectively. All other therapeutic strategies remained unchanged in the three groups as long as possible. RESULTS: In total, 60 patients with liver cirrhosis were screened and 43 of them met the eligibility criteria. After 2-week treatment serum endotoxin levels in the low-dose (1.1 ± 0.8 EU/mL) and high-dose rifaximin groups (1.0 ± 0.8 EU/mL) were significantly lower than that in the control group (2.5 ± 1.8 EU/mL), while no significant difference was found between the two rifaximin-treated groups. The effect of high-dose rifaximin on endotoxemia lasted for at least 4 weeks after drug withdrawal. A significant reduction in the abundance of the Veillonellaceae taxa and an increase in the abundance of Bacteroidaceae were shown after 2 weeks of rifaximin therapy. The incidence of adverse events and severe adverse events was similar among the three groups. CONCLUSION: Low-dose (800 mg/day) rifaximin could be analogous to high-dose (1200 mg/day) rifaximin to reduce the serum endotoxin level after 2 weeks of treatment.
Assuntos
Antibacterianos/administração & dosagem , Endotoxemia/tratamento farmacológico , Cirrose Hepática/complicações , Rifamicinas/administração & dosagem , Adolescente , Adulto , Idoso , Antibacterianos/efeitos adversos , Antibacterianos/uso terapêutico , Citocinas/sangue , Relação Dose-Resposta a Droga , Endotoxemia/sangue , Endotoxemia/etiologia , Feminino , Humanos , Masculino , Microbiota/efeitos dos fármacos , Pessoa de Meia-Idade , Estudos Prospectivos , Rifamicinas/efeitos adversos , Rifamicinas/uso terapêutico , Rifaximina , Receptores Toll-Like/sangue , Adulto JovemRESUMO
BACKGROUND: Serum ascites albumin gradient (SAAG) has been recognized as a reliable marker in the differential diagnosis of ascites. The etiological background of cirrhosis is rather different between western countries and eastern countries. The threshold of SAAG in Chinese ascitic patients has not been evaluated yet. The aim of this study was to define a new reasonable threshold of SAAG in Chinese ascitic patients. METHODS: Adult patients with ascites admitted to the Shanghai Changzheng Hospital from Jan 2004 to Jun 2010 were retrospectively analyzed. The diagnostic criteria for cirrhotic ascites are clinical manifestations, radiological features and esophageal-gastric varicosis, or histopathology. Serum was detected by chemical method using a commercial kit. We used receiver operating characteristic (ROC) analysis to achieve maximal sensitivity and specificity of SAAG. RESULTS: The mean value of SAAG in portal-hypertension-related ascites was significantly higher than that in the non-portal-hypertension-related ascites (21.15 ± 4.38 g/L vs 7.48 ± 3.64 g/L, P = 0.002). The SAAG cut-off value under 12.50 g/L predicted portal hypertension ascites with the sensitivity of 99.20%, specificity of 95.10% and accuracy of 97.65%. CONCLUSIONS: SAAG is useful to distinguish portal-hypertension-related ascites and non-portal-hypertension-related ascites, and 12.50 g/L might present as a more reasonable threshold in Chinese ascitic patients. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1602582638991860.
Assuntos
Ascite/diagnóstico , Hipertensão Portal/etiologia , Cirrose Hepática/complicações , Albumina Sérica/análise , Adulto , Idoso , Ascite/sangue , Ascite/etiologia , Biomarcadores/sangue , China , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Curva ROC , Estudos Retrospectivos , Fatores de Risco , Albumina Sérica HumanaRESUMO
OBJECTIVE: To analyze drug-induced liver disease over an 8-year period from January 2000 to December 2007 in one gastroenterological department. METHODS: International consensus of standard definitions and criteria for assessing causality of adverse drug reactions were applied to all patients with abnormal hepatic test results. RESULTS: Drugs were implicated in hepatic injury in 30 patients (15 men and 15 women) in whom there was a causal or highly probable relationship between drug use and liver disease. The drugs responsible for liver damage were Chinese medicinal herbs (n = 12), cyclosporin (n = 2), fosfomycin, gentamicin, flutamide, acipimox and nimesulide (n = 1 each). Of the 30 patients, 19 (63.3%) were classified as having hepatocellular or mixed hepatitis, eight (26.7%) as having cholestatic injury and the remaining three as having a severe hepatic drug reaction (prothrombin < 50%), including death. CONCLUSION: A thorough history of medication should be taken in all patients presenting with abnormal hepatic test results. Chinese medicinal herbs were the most frequent hepatotoxic factor in our patients, although the liver injury was not severe in most cases and was relieved after the prompt withdrawal of the suspected drug.