RESUMO
BACKGROUND: Hepatic resection and radiofrequency ablation (RFA) are treatment options for early-stage hepatocellular carcinoma (HCC). Whether tumour recurrence and long-term survival favour either treatment has not been established. This randomized trial aimed to test the hypothesis that RFA is superior to hepatic resection in terms of lower tumour recurrence rate and better long-term survival. METHODS: Patients with early-stage HCC (solitary tumour no larger than 5 cm; or no more than 3 tumours, each 3 cm or smaller) were randomized into hepatic resection and RFA groups. Demographic and clinical characteristics, and short- and long-term outcome measures were compared between groups. Primary and secondary outcome measures were overall tumour recurrence and survival respectively. RESULTS: Clinicopathological data were similar in the two groups, which each contained 109 patients. The RFA group had a shorter treatment duration, less blood loss and shorter hospital stay than the resection group. Mortality and morbidity rates were similar in the two groups. The overall tumour recurrence rate was similar in the resection and RFA groups (71·3 versus 81·7 per cent respectively). The 1-, 3-, 5- and 10-year overall survival rates were 94·5, 80·6, 66·5 and 47·6 per cent respectively in the resection group, compared with 95·4, 82·3, 66·4 and 41·8 per cent in the RFA group (P = 0·531). Corresponding disease-free survival rates were 74·1, 50·9, 41·5 and 31·9 per cent in the resection group, and 70·6, 46·6, 33·6 and 18·6 per cent in the RFA group (P = 0·072). CONCLUSION: RFA for early-stage HCC is not superior to hepatic resection, in terms of tumour recurrence, overall survival and disease-free survival. Registration number: HKUCTR-10 (http://www.hkuctr.com).
Assuntos
Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/cirurgia , Ablação por Cateter , Hepatectomia , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/cirurgia , Recidiva Local de Neoplasia , Adulto , Idoso , Idoso de 80 Anos ou mais , Perda Sanguínea Cirúrgica , Carcinoma Hepatocelular/patologia , Corantes , Intervalo Livre de Doença , Feminino , Hepatite C/complicações , Hong Kong/epidemiologia , Humanos , Verde de Indocianina , Tempo de Internação , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Prognóstico , Adulto JovemAssuntos
Antagonistas de Aminoácidos Excitatórios/efeitos adversos , Ketamina/efeitos adversos , Disfunção do Esfíncter da Ampola Hepatopancreática/induzido quimicamente , Transtornos Relacionados ao Uso de Substâncias/complicações , Adulto , Colestase/etiologia , Colestase/cirurgia , Feminino , Humanos , Disfunção do Esfíncter da Ampola Hepatopancreática/diagnóstico , Disfunção do Esfíncter da Ampola Hepatopancreática/cirurgia , Adulto JovemAssuntos
Adenoma/complicações , Glândulas Duodenais/patologia , Neoplasias Duodenais/complicações , Adenoma/diagnóstico , Adenoma/patologia , Idoso , Neoplasias Duodenais/diagnóstico , Neoplasias Duodenais/patologia , Obstrução Duodenal/etiologia , Hemorragia Gastrointestinal/etiologia , Humanos , Masculino , Tomografia Computadorizada por Raios XRESUMO
Deregulation of Wnt/ß-catenin pathway is a hallmark of major gastrointestinal cancers including hepatocellular carcinoma (HCC). The oncogenic role of ß-catenin is well defined but reasons for its accumulation in HCC remain unclear. Dickkopf 4 (DKK4) acts as a negative regulator of Wnt/ß-catenin pathway but its functional role in liver carcinogenesis has not been studied. We investigated the role of DKK4 in ß-catenin regulation in HCC. Reduced expression of DKK4 was found in 47% (38/81) of HCC, as measured by quantitative real time PCR. Ectopic expression of DKK4 in two HCC cell lines, PLC/PRF/5 (PLC) and MHCC97L (97L), attenuated ß-catenin responsive luciferase activity, and decreased both ß-catenin and cyclin D1 protein levels. To study the effect of DKK4 on cell growth and tumourigenicity, two stable HCC cell lines were established from PLC and 97L cells. Functional assays demonstrated that overexpression of DKK4 hampered cell proliferation, reduced colony formation and retarded cell migration. When DKK4-expressing 97L stable cells were used to induce tumour xenografts in nude mice (n=8), reduction in tumour sizes was observed (P=0.027). Furthermore, immunohistochemical studies showed that decreased expression of DKK4 was associated with ß-catenin accumulation in HCC tissues. Additionally, inhibition of the proteasome using specific inhibitor in DKK4-expressing 97L stable cells masked the effect of ß-catenin. Our findings suggest a potential tumour suppressive role of DKK4 as well as that of an important regulator of HCC.
Assuntos
Carcinoma Hepatocelular/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Neoplasias Hepáticas/metabolismo , Transdução de Sinais , Proteínas Wnt/metabolismo , beta Catenina/metabolismo , Animais , Carcinoma Hepatocelular/genética , Linhagem Celular Tumoral , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Regulação Neoplásica da Expressão Gênica , Genes Reporter , Quinase 3 da Glicogênio Sintase/metabolismo , Glicogênio Sintase Quinase 3 beta , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Neoplasias Hepáticas/genética , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Complexo de Endopeptidases do Proteassoma/metabolismo , ProteóliseRESUMO
BACKGROUND: There is a trend to offer liver transplantation to patients with hepatocellular carcinoma (HCC) with tumour status within the Milan criteria but with preserved liver function. This study aimed to evaluate the outcome of such patients following partial hepatectomy as primary treatment. METHODS: A retrospective analysis was performed on all adult patients with HCC and tumour status within the Milan criteria undergoing partial hepatectomy at a single centre from 1995 to 2008. Their outcomes were compared with those of similar patients having right-lobe living donor liver transplantation (LDLT) as primary treatment. RESULTS: A total of 408 patients with HCC were enrolled. Some 384 patients with a solitary tumour 5 cm or less in diameter had a better 5-year survival rate than 24 patients with oligonodular tumours (2-3 nodules, each 3 cm or less in size) (70·7 versus 46 per cent; P = 0·025). Multivariable analysis identified younger age (65 years or less), lack of postoperative complications, negative resection margin, absent microvascular invasion and non-cirrhotic liver as predictors of favourable overall survival. The 5-year survival rate of 287 younger patients with chronic liver disease and R0 hepatectomy was 72·8 per cent, comparable to that of 81 per cent in 50 similar patients treated by LDLT (P = 0·093). CONCLUSION: Partial hepatectomy for patients with HCC and tumour status within the Milan criteria achieved a satisfactory 5-year survival rate, particularly in younger patients with solitary tumours and R0 hepatectomy. Patients with oligonodular tumours have a worse survival and might benefit from liver transplantation.
Assuntos
Carcinoma Hepatocelular/cirurgia , Hepatectomia/métodos , Neoplasias Hepáticas/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Hepatocelular/mortalidade , Doença Crônica , Intervalo Livre de Doença , Feminino , Hepatectomia/mortalidade , Hepatite/mortalidade , Hepatite/cirurgia , Humanos , Cirrose Hepática/mortalidade , Cirrose Hepática/cirurgia , Neoplasias Hepáticas/mortalidade , Transplante de Fígado/mortalidade , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/mortalidade , Estudos Retrospectivos , Resultado do Tratamento , Adulto JovemRESUMO
Stress protein mortalin is a multifunctional protein and is highly expressed in cancers. It has been shown to interact with tumor suppressor protein-p53 (both wild and mutant types) and inactivates its transcriptional activation and apoptotic functions in cancer cells. In the present study, we found that, unlike most of the cancer cells, HepG2 hepatoma lacked mortalin-p53 interaction. We demonstrate that the mortalin-p53 interaction exists in cancer cells that are either physiologically stressed (frequently associated with p53 mutations) or treated with stress-inducing chemicals. Targeting mortalin-p53 interaction with either mortalin small hairpin RNA or a chemical or peptide inhibitor could induce p53-mediated tumor cell-specific apoptosis in hepatocellular carcinoma; p53-null hepatoma or normal hepatocytes remain unaffected.
Assuntos
Apoptose , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/metabolismo , Proteínas de Choque Térmico HSP70/metabolismo , Estresse Fisiológico , Proteína Supressora de Tumor p53/metabolismo , Carcinoma Hepatocelular/genética , Proteínas de Choque Térmico HSP70/antagonistas & inibidores , Células Hep G2 , Hepatócitos/metabolismo , Humanos , Mutação , Peptídeos/farmacologia , Transcrição Gênica/genética , Proteína Supressora de Tumor p53/genéticaRESUMO
Yes-associated protein (YAP) is a downstream effector of the Hippo signaling pathway, which controls organ expansion and tissue development. We have recently defined the tumorigenic potential and clinical significance of the YAP1 oncogene in human hepatocellular carcinoma (HCC). The present study aims to define the tumorigenic properties of YAP in HCC and elucidate the related downstream signaling mechanism. In a gain-of-function study, we demonstrated that ectopic increased expression of YAP in the immortalized non-tumorigenic hepatocyte cell line MIHA confers tumorigenic and metastatic potentials, as evidenced by (1) enhanced aptitudes in cell viability, anchorage-independent growth, migration and invasion; (2) tumor formation in a xenograft mouse model; and (3) induction of HCC biomarker α-fetoprotein and activation of mitogen-activated protein kinase. Furthermore, we have identified AXL, a receptor tyrosine kinase, as a key downstream target that drives YAP-dependent oncogenic functions. RNAi-mediated knockdown of AXL expression decreased the ability of YAP-expressing MIHA cells and of the primary HCC cell line to proliferate and invade. These results indicate that AXL is a mediator of YAP-dependent oncogenic activities and implicates it as a potential therapeutic target for HCC.
Assuntos
Carcinoma Hepatocelular/metabolismo , Transformação Celular Neoplásica/metabolismo , Neoplasias Hepáticas/metabolismo , Proteínas Nucleares/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Transdução de Sinais/fisiologia , Fatores de Transcrição/metabolismo , Animais , Carcinoma Hepatocelular/genética , Proteínas de Ciclo Celular , Linhagem Celular , Movimento Celular/genética , Proliferação de Células , Transformação Celular Neoplásica/genética , Expressão Gênica , Regulação Neoplásica da Expressão Gênica/genética , Técnicas de Silenciamento de Genes , Humanos , Immunoblotting , Neoplasias Hepáticas/genética , Masculino , Camundongos , Camundongos Nus , Proteínas Nucleares/genética , Análise de Sequência com Séries de Oligonucleotídeos , Proteínas Proto-Oncogênicas/genética , RNA Interferente Pequeno , Receptores Proteína Tirosina Quinases/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Transcrição/genética , Transfecção , Transplante Heterólogo , Receptor Tirosina Quinase AxlRESUMO
In this study, we aimed to investigate the significance of hepatic stellate cells (HSCs) activation in small-for-size fatty liver graft injury and to explore the underlying molecular mechanism in a rat liver transplantation model. A rat orthotopic liver transplantation model using fatty grafts (40% of fatty changes) and cirrhotic recipients was applied. Intragraft gene expression profiles, ultrastructure features and HSCs activation were compared among the rats received different types of grafts (whole vs. small-for-size, normal vs. fatty). The distinct molecular signature of small-for-size fatty graft injury was identified by cDNA microarray screening and confirmed by RT-PCR detection. In vitro functional studies were further conducted to investigate the direct effect of specific molecular signature on HSCs activation. HSCs activation was predominantly present in small-for-size fatty grafts during the first 2 weeks after transplantation, and was strongly correlated with progressive hepatic sinusoidal damage and significant upregulation of intragraft Wnt4 signaling pathway. In vitro suppression of Wnt4 expression could inhibit HSC activation directly. In conclusion, upregulation of Wnt4 signaling led to direct HSC activation and subsequently induced small-for-size fatty liver grafts injury. Discovery of this distinct mechanism may lay the foundation for prophylactic treatment for marginal graft injury in living donor liver transplantation.
Assuntos
Transdução de Sinais/genética , Animais , Fígado Gorduroso/patologia , Perfilação da Expressão Gênica , Células Estreladas do Fígado , Transplante de Fígado/fisiologia , Doadores Vivos , Masculino , Análise de Sequência com Séries de Oligonucleotídeos , Ratos , Ratos Sprague-Dawley , Procedimentos de Cirurgia Plástica , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Regulação para Cima , Proteínas Wnt , Proteína Wnt4RESUMO
BACKGROUND/AIMS: Hepatic fibrosis is a consequence of severe liver damage that occurs in many patients with chronic liver diseases. TCM 319 recipe is a Chinese Medicine formula which consists of six Chinese herbs. In this study, we investigated the anti-fibrotic efficacy and mechanisms of TCM 319 recipe. METHODS: Hepatic fibrosis in rats was induced by carbon tetrachloride (CCl4). 34 male adult SD rats were allocated into five groups (group 1-concomitant CCl4 and TCM 319 recipe for 8 weeks; group 2-CCl4 for 4 weeks and then CCl4 and TCM 319 recipe for 4 weeks; group 3-CCl4 alone for 8 weeks; group 4-TCM 319 recipe only for 8 weeks; group 5-untreated controls). After 8 weeks of treatment, serum ALT assay, liver tissue histological examination and immunostaining were carried out to examine the liver function and fibrosis degree. The expression levels of platelet derived growth factor (PDGF-B), PDGF-Rbeta, and transforming growth factor-beta 1 (TGF-beta1) were measured by quantitative RT-PCR and western blot. RESULTS: TCM 319 recipe reduced liver injury and attenuated hepatic fibrosis in group 1 compared with that in group 3. TCM 319 recipe suppressed the mRNA expression of tissue inhibitor of metalloproteinase 1 (TIMP-1). In addition, treatment with TCM 319 recipe significantly down-regulated mRNA expression of PDGF-B and PDGF-Rbeta, and it also suppressed protein expression of PDGF-Rbeta and TGF-beta1. CONCLUSIONS: TCM 319 recipe extracts could attenuate hepatic fibrosis induced by CCl4 in rats. The anti-fibrotic effect of TCM 319 recipe is associated with the down-regulation of mRNA expression of TIMP-1, PDGF-B and PDGF-Rbeta, and with the suppression of protein expression of PDGF-Rbeta and TGF-beta1.
Assuntos
Medicamentos de Ervas Chinesas/uso terapêutico , Cirrose Hepática/prevenção & controle , Fígado/efeitos dos fármacos , Magnoliopsida , Fitoterapia , Actinas/metabolismo , Alanina Transaminase/metabolismo , Animais , Tetracloreto de Carbono , Colágeno/metabolismo , Regulação para Baixo , Combinação de Medicamentos , Medicamentos de Ervas Chinesas/farmacologia , Células Estreladas do Fígado/metabolismo , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/metabolismo , Masculino , Medicina Tradicional Chinesa , Fator de Crescimento Derivado de Plaquetas/genética , Fator de Crescimento Derivado de Plaquetas/metabolismo , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Inibidor Tecidual de Metaloproteinase-1/genética , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Fator de Crescimento Transformador beta1/metabolismoRESUMO
Human hepatocellular carcinoma (HCC) has an elevated requirement for arginine in vitro, and pegylated recombinant human arginase I (rhArg-PEG), an arginine-depleting enzyme, can inhibit the growth of arginine-dependent tumors. While supplementation of the culture medium with ornithine failed to rescue Hep3B cells from growth inhibition induced by rhArg-PEG, citrulline successfully restored cell growth. The data support the roles previously proposed for ornithine transcarbamylase (OTC) in the arginine auxotrophy and rhArg-PEG sensitivity of HCC cells. Expression profiling of argininosuccinate synthetase (ASS), argininosuccinate lyase (ASL) and OTC in 40 HCC tumor biopsy specimens predicted that 16 of the patients would be rhArg-sensitive, compared with 5 who would be sensitive to arginine deiminase (ADI), another arginine-depleting enzyme with anti-tumor activity. Furthermore, rhArg-PEG-mediated deprivation of arginine from the culture medium of different HCC cell lines produced cell cycle arrests at the G(2)/M or S phase, possibly mediated by transcriptional modulation of cyclins and/or cyclin dependent kinases (CDKs). Based on these results, together with further validation of the in vivo efficacy of rhArg-PEG against HCC, we propose that the application of rhArg-PEG alone or in combination with existing chemotherapeutic drugs may represent a specific and effective therapeutic strategy against HCC.
Assuntos
Antineoplásicos/farmacologia , Arginase/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Ciclo Celular/efeitos dos fármacos , Neoplasias Hepáticas/tratamento farmacológico , Animais , Arginase/uso terapêutico , Carcinoma Hepatocelular/enzimologia , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Citrulina/metabolismo , Citrulinemia/epidemiologia , Quinase 2 Dependente de Ciclina/análise , Ciclinas/análise , Humanos , Neoplasias Hepáticas/enzimologia , Neoplasias Hepáticas/patologia , Camundongos , Doença da Deficiência de Ornitina Carbomoiltransferase/epidemiologia , Proteínas Recombinantes/farmacologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: The aim of this retrospective study was to determine the impact of postoperative complications on the long-term outcome of curative liver resection for hepatocellular carcinoma (HCC). METHODS: A total of 863 patients who had curative resection of HCC from December 1989 to December 2004 were included in the analysis. Median follow-up was 35.6 months. RESULTS: Some 288 patients (33.4 per cent) developed postoperative complications. The hospital mortality rate was 5.3 per cent (46 patients). Multiple logistic regression analysis showed that older age and massive intraoperative blood loss were related to a significantly higher complication rate. Demographics of patients with and without postoperative complications were comparable. The former had significantly more blood loss (median 1.1 versus 0.7 litres; P < 0.001) and required more transfused blood (P < 0.001). The overall survival rates of patients without complications at 1, 3, 5 and 10 years were 83.6, 62.8, 51.5 and 32.1 per cent respectively. Corresponding rates for those with complications were 67.8, 52.4, 41.5 and 26.6 per cent (P = 0.004). Cox proportional hazard model analysis revealed that the presence of postoperative complications was independently associated with poor overall survival. CONCLUSION: Postoperative complications can affect overall long-term survival after resection of HCC.
Assuntos
Carcinoma Hepatocelular/cirurgia , Neoplasias Hepáticas/cirurgia , Complicações Pós-Operatórias/etiologia , Carcinoma Hepatocelular/mortalidade , Feminino , Humanos , Estimativa de Kaplan-Meier , Tempo de Internação , Neoplasias Hepáticas/mortalidade , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/mortalidade , Estudos Retrospectivos , Fatores de Risco , Resultado do TratamentoRESUMO
Liver transplantation (LT) which is currently an established therapy for sma1l, early stage hepatocellular carcinoma (HCC) in patients with cirrhosis requires in most cases long waiting period. Tumor development during the waiting period may be associated with vascular invasion which is a strong factor of postoperative recurrence. Therefore, local treatment of the tumor including trans-arterial chemoembolization (TACE), percutaneous radiofrequency (RF) or partial liver resection can be used before transplantation. In the present paper we reviewed the efficacy of these treatments prior to LT. Although, TACE induced complete tumor necrosis in some patients there is no convincing arguments showing that this treatment reduces the rate of drop out before LT, nor improves the survival after LT. Although, RF can induce complete necrosis in the majority of small tumors (<2.5 cm), there is no data demonstrating that this treatment reduce the rate of drop out before LT, nor improves the survival after LT. It has been showed that both short and long term survival after LT was not compromised by previous partial liver resection of HCC. However, there is no data demonstrating that liver resection before LT, which can be used either as a bridge treatment or as a primary treatment, improves the survival after LT. The current data suggest that there is no role for pre-transplant therapy for HCC within Milano criteria transplanted within six months. On the opposite, if the waiting time is predicted to be prolonged, the risk of tumor progression and either drop-off from the list or interval dissemination with post-transplant tumor recurrence is recognized. In this setting, bridge therapy can reduce that risk but its efficacy has to be determined.
Assuntos
Carcinoma Hepatocelular/terapia , Ablação por Cateter , Quimioembolização Terapêutica , Hepatectomia , Neoplasias Hepáticas/terapia , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Ablação por Cateter/estatística & dados numéricos , Quimioembolização Terapêutica/estatística & dados numéricos , Progressão da Doença , Hepatectomia/estatística & dados numéricos , Humanos , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Transplante de Fígado , Morbidade , Estadiamento de Neoplasias , Cuidados Pré-Operatórios , Análise de Sobrevida , Resultado do Tratamento , Listas de EsperaRESUMO
BACKGROUND/AIM: To examine the risks for hepatocellular carcinoma (HCC) with respect to hepatitis B virus (HBV) genotypes, specific viral mutations (MT), serum HBV DNA levels, and cirrhosis. METHODS: HBV genotypes, 1653/1753/core promoter (CP)/precore MT and HBV DNA levels were determined in 248 HBV patients with HCC and 248 HBV controls. RESULTS: Genotype C, CP-MT, T1653, HBV DNA levels >or=4 log(10) copies/ml and cirrhosis had a higher risk for HCC compared to patients with genotype B (p = 0.001, OR 1.9), CP wild-type (WT) (p<0.001, OR 4.1), C1653 (p = 0.028, OR 2.4), HBV DNA <4 log(10) copies/ml (p = 0.003, OR 2.1) and without cirrhosis (p<0.001, OR 4.0) respectively. Multivariate analysis showed that CP-MT, T1653, HBV DNA >or=4 log(10) copies/ml and cirrhosis were independent factors for HCC (all p<0.05). A receiver operating characteristics curve showed no cut-off HBV DNA level associated with minimal chance of HCC. Patients with CP-MT and cirrhosis had a 22.2-fold increased risk of HCC compared to patients with CP-WT and without cirrhosis. Patients with CP-MT and HBV DNA levels >or=4 log(10) copies/ml had a 7.2-fold increased risk of HCC compared to patients with CP-WT and HBV DNA levels <4 log(10) copies/ml. Patients with CP-MT and T1653 had a 9.9-fold increased risk of HCC compared to patients with wild-type for both regions. CONCLUSIONS: CP-MT, T1653, HBV DNA levels >or=4 log(10) copies/ml and cirrhosis are independent factors for development of HCC. The risks increased substantially in patients having these factors in combination.
Assuntos
Carcinoma Hepatocelular/virologia , Elementos Facilitadores Genéticos/genética , Vírus da Hepatite B/genética , Neoplasias Hepáticas/virologia , Mutação/genética , Regiões Promotoras Genéticas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , DNA Viral/sangue , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Curva ROCRESUMO
Understanding the precise molecular mechanisms that trigger liver cancer cell migration and invasion could develop novel therapeutic strategies targeting cancer cell invasion to increase the sensitivity to current treatment modalities. In the current study, 49 patients with hepatocellular carcinoma (HCC) were included prospectively. Liver tumour and adjacent non-tumour tissues were detected for the expression of Proline-rich tyrosine kinase 2 (Pyk2), focal adhesion kinase (FAK), ezrin and fibronectin at protein and/or gene levels. Correlation between the expressions of Pyk2/FAK with the clinical pathological data was analysed. Protein expression of Pyk2 was also examined in a nude mice orthotopic liver tumour model with higher metastatic potential. There were 59% (29 out of 49) and 57% (28 out of 49) of HCC patients with higher levels of Pyk2 and FAK protein/gene expression, respectively. We observed a positive correlation between the protein and gene expression levels of Pyk2 and FAK (P=0.000, r=0.875). Overexpression of Pyk2 and FAK was significantly correlated with shorter disease-free survival. Patients with higher levels of Pyk2/FAK had larger tumour size and advanced Edmonson grading. In the animal studies, Pyk2 overexpression was found in infiltrative tumour cells and lung metastatic nodules. In conclusion, overexpression of Pyk2 and FAK was found in nearly 60% of HCC patients and was significantly correlated with poor prognosis. The significance of Pyk2 in HCC invasiveness was confirmed by animal studies.
Assuntos
Carcinoma Hepatocelular/genética , Quinase 2 de Adesão Focal/metabolismo , Neoplasias Hepáticas/genética , Adulto , Animais , Carcinoma Hepatocelular/enzimologia , Linhagem Celular Tumoral , Proliferação de Células , Proteínas do Citoesqueleto/metabolismo , Progressão da Doença , Fibronectinas/metabolismo , Quinase 1 de Adesão Focal/metabolismo , Humanos , Neoplasias Hepáticas/enzimologia , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/secundário , Camundongos , Camundongos Nus , Invasividade Neoplásica , Metástase Neoplásica , Recidiva Local de Neoplasia , Transplante de Neoplasias , Prognóstico , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
Both Secreted Protein Acidic and Rich in Cysteine (SPARC) and Hevin are multifunctional matricellular glycoproteins. Recent experimental studies suggested that Hevin and SPARC together diminish angiogenesis, but their significance in hepatocellular carcinoma (HCC) remains unclear. This study aimed to correlate SPARC and Hevin expression with angiogenesis and clinicopathological features in HCC. SPARC and Hevin protein and mRNA expression in HCC specimens were assessed by immunostaining, immunoblotting, and quantitative reverse transcriptase-polymerase chain reaction. Tumour microvessel density (MVD) was assessed by CD34 immunostaining. The role of SPARC and Hevin in HCC was further assessed in an in vivo nude mice xenograft model. Both SPARC and Hevin mRNA levels were significantly higher in tumours than in non-tumourous livers. A significant correlation between tumour SPARC and Hevin mRNA levels was found. Moreover, SPARC protein localized in the tumour sinusoidal area correlated significantly with Hevin protein localized in HCC cells. Truncated forms of SPARC and Hevin proteins were detected in clinical samples. Truncated SPARC protein localized in the tumour sinusoidal area correlated significantly with tumour MVD. On the other hand, overexpression of full-length SPARC in tumour xenografts in athymic nude mice significantly delayed tumour growth, and this delay was related to a decrease in tumour angiogenesis. Expression of Hevin protein within HCC cells was related to the presence of tumour encapsulation and the absence of hepatitis B surface antigen in clinical samples. Overexpression of Hevin in tumour xenografts also significantly delayed tumour growth. In conclusion, this study has shown that SPARC and Hevin are upregulated in HCC compared with non-tumourous liver, and that they are inter-related at both mRNA and protein levels. Moreover, both SPARC and Hevin were related to HCC angiogenesis and tumour progression.
Assuntos
Proteínas de Ligação ao Cálcio/genética , Carcinoma Hepatocelular/genética , Proteínas da Matriz Extracelular/genética , Neoplasias Hepáticas/genética , Neovascularização Patológica/genética , Osteonectina/genética , Animais , Antígenos CD34/análise , Carcinoma Hepatocelular/irrigação sanguínea , Carcinoma Hepatocelular/patologia , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Imuno-Histoquímica/métodos , Fígado/química , Neoplasias Hepáticas/irrigação sanguínea , Neoplasias Hepáticas/patologia , Camundongos , Camundongos Nus , Proteínas de Neoplasias/genética , RNA Mensageiro/genética , RNA Neoplásico/genética , Regulação para Cima/genéticaRESUMO
Tumour recurrence and metastases of hepatocellular carcinoma (HCC) after hepatectomy are the major obstacles of long-term survival. The present study investigated the clinicopathological significance of a possible metastasis regulator Six1 in HCC patients who were undergone hepatectomy. Seventy-two pairs of RNA and 103 pairs of protein from tumour and adjacent nontumour liver tissues of HCC patients were examined. About 85 and 60% of HCC tumour tissues were found to overexpress Six1 mRNA and protein, respectively, compared with nontumour liver tissues. No Six1 protein was detected in HCC nontumour liver tissues and normal liver tissues. Increased Six1 protein expression in HCC patients was significantly correlated with pathologic tumour-node-metastasis (pTNM) stage (P=0.002), venous infiltration (P=0.004) and poor overall survival (P=0.0423). We concluded that Six1 is frequently overexpressed in HCC patients and elevated Six1 protein in HCC patients may be an indication of advanced stage and poor overall survival after hepatectomy.
Assuntos
Carcinoma Hepatocelular/patologia , Proteínas de Homeodomínio/genética , Neoplasias Hepáticas/patologia , Adulto , Idoso , Western Blotting , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica , Proteínas de Homeodomínio/metabolismo , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Masculino , Pessoa de Meia-Idade , Análise Multivariada , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
The phospho-Ser/Thr-Pro specific prolyl-isomerase PIN1 is over-expressed in more than 50% of hepatocellular carcinomas (HCCs). To investigate its potential oncogenicity, we over-expressed PIN1 in a non-transformed human liver cell line MIHA. This resulted in up-regulation of beta-catenin and cyclin D1, leading to anchorage-independent growth in soft agar and tumorigenicity in nude mice. To further validate the role of PIN1 in hepatocarcinogenesis, PIN was suppressed by RNA interference (siRNA) in the HCC cell line PLC/PRF/5. siRNA-PIN1 transfection of PLC/PRF/5 cells led to repression of PIN1 expression, resulting in decreased levels of beta-catenin and cyclin D1. siRNA-PIN1 transfectants showed lower cell proliferation rates, reduced colony formation, and retarded cell cycle progression, with an increase in cells residing in G0/G1. Furthermore, soft agar colony formation was depressed, and tumorigenicity in nude mice was abrogated. These findings implicate PIN1 expression as an important step in hepatic carcinogenesis.
Assuntos
Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , Proteínas de Neoplasias/genética , Peptidilprolil Isomerase/genética , Animais , Linhagem Celular , Linhagem Celular Tumoral , Ciclina D1/genética , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Camundongos , Camundongos Nus , Peptidilprolil Isomerase de Interação com NIMA , Interferência de RNA , RNA Neoplásico/genética , Transfecção/métodos , Regulação para Cima/genética , beta Catenina/genéticaRESUMO
It is uncertain whether occult hepatitis B virus co-infection will hasten progressive liver disease in chronic hepatitis C patients after liver transplantation. This study evaluated fibrosis progression and severe fibrosis in 118 consecutive hepatitis B surface antigen-negative patients with virological and histological evidence of recurrent chronic hepatitis C infection co-infected with occult hepatitis B virus after liver transplantation. HBV DNA was detected from serum at the time of recurrent chronic hepatitis C infection by polymerase chain reaction. Each subject underwent a repeat liver biopsy 5 years post-liver transplantation. Occult hepatitis B virus co-infection was present in 41 of the 118 (34.7%) patients. At 5 years post-liver transplantation, 13 of the 41 occult hepatitis B virus co-infected patients compared with 16 of the 77 patients without occult hepatitis B virus co-infection developed fibrosis progression (31.7% vs. 20.8%, respectively, p = 0.39). Eight of 41 the occult hepatitis B virus co-infected patients compared with 13 of the 77 patients without occult hepatitis B virus co-infection had severe fibrosis (19.5% vs. 16.9%, respectively, p = 0.97). In conclusion, occult hepatitis B virus co-infection in patients with recurrent chronic hepatitis C infection was not associated with accelerated fibrosis progression or severe fibrosis after liver transplantation.
Assuntos
Hepacivirus/fisiologia , Vírus da Hepatite B/fisiologia , Hepatite C Crônica/diagnóstico , Hepatite C Crônica/cirurgia , Transplante de Fígado , Adulto , Biópsia , DNA Viral/sangue , Progressão da Doença , Feminino , Rejeição de Enxerto/imunologia , Hepatite C Crônica/imunologia , Hepatite C Crônica/virologia , Humanos , Transplante de Fígado/imunologia , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
PURPOSE: The purposes of this study were to investigate a treatment strategy to increase liver tumor necrosis and minimize complications with ultrasound-guided percutaneous radiofrequency (RF) ablation and to evaluate its therapeutic efficacy. MATERIALS AND METHODS: A total of 332 patients with 503 liver malignancies underwent RF ablation according to a mathematical protocol with adjunctive measures. In the 332 patients, 205 had 308 hepatocellular carcinomas (HCCs) with a mean largest diameter of 4.1 cm and 127 had 195 metastatic liver carcinomas (MLCs) with a mean largest diameter of 3.9 cm. In patients with HCC, 60 (29.3%) had stage I/II disease and 145 (70.7%) had stage III/IV disease. Depending on tumor size, shape, and location, a defined treatment strategy was adopted that consisted of a mathematical protocol, an individualized protocol, and adjunctive measures. The mathematical protocol was followed for tumors larger than 3.5 cm. The individualized protocol was used for tumors located adjacent to the diaphragm, gastrointestinal tract, or gallbladder. Some adjunctive measures such as supplementary fine needle localization, local saline solution injection, and feeding vessel ablation were used to deal with different features of these liver tumors. Patients were followed regularly to assess treatment efficiency, and the tumor was considered to have early complete necrosis if no viability was found on enhanced computed tomography 1 month after RF ablation. RESULTS: In this series, the early necrosis rates were 95.8% for HCC (295 of 308 tumors), 94.9% for MLC (185 of 195 tumors), 91.3% for tumors larger than 3.5 cm (189 of 207 tumors), 90.7% for tumors near the gastrointestinal tract (49 of 54 tumors), 91.5% for tumors near the diaphragm (86 of 94 tumors), and 90.6% for tumors near the gallbladder (48 of 53 tumors). The local recurrence rates were 10.7% for HCC (33 of 308 tumors) and 14.9% for MLC (29 of 195 tumors). The 1-, 2-, and 3-year overall survival rates were 89.6%, 69.4%, and 59.6%, respectively, for HCC and 80.3%, 52.8%, and 30.9%, respectively, for MLC. The 1-, 2-, and 3-year survival rates in 60 patients with stage I/II HCC were 93.7%, 87.1%, and 76.2%, respectively. The incidence of major complications was 1.4% (eight of 574 sessions), which included of three hemorrhages, four injuries to adjacent structures, and one case of needle tract seeding. CONCLUSION: In RF ablation of hepatic tumors, application of a proper protocol and adjunctive measures play important roles in improving tumor necrosis rate and minimizing potential complications.
Assuntos
Carcinoma Hepatocelular/cirurgia , Ablação por Cateter/métodos , Neoplasias Hepáticas/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Hepatocelular/diagnóstico por imagem , Carcinoma Hepatocelular/patologia , Distribuição de Qui-Quadrado , Feminino , Humanos , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Taxa de Sobrevida , Resultado do Tratamento , Ultrassonografia Doppler em Cores , Ultrassonografia de IntervençãoRESUMO
BACKGROUND: The role of radiofrequency ablation (RFA) for perivascular (up to 5 mm from the major intrahepatic portal vein or hepatic vein branches) hepatocellular carcinoma (HCC) is unclear because of possible incomplete tumour ablation and potential vascular damage. This study aimed to evaluate the safety and efficacy of RFA for perivascular HCC without hepatic inflow occlusion. METHODS: Between May 2001 and November 2003, RFA using an internally cooled electrode was performed on 52 patients with perivascular HCC (group 1) through open (n = 39), percutaneous (n = 9), laparoscopic (n = 2) and thoracoscopic (n = 2) approaches. Hepatic inflow occlusion was not applied during the ablation procedure. The perioperative and postoperative outcomes were compared with those of 90 patients with non-perivascular HCC (group 2) treated by RFA during the same period. RESULTS: The morbidity rate was similar between groups 1 and 2 (25 versus 28 per cent; P = 0.844). One patient in group 1 (2 per cent) and two in group 2 (2 per cent) had developed thrombosis of major intrahepatic blood vessels on follow-up computed tomography scan. There were no significant differences between groups 1 and 2 in mortality rate (2 versus 0 per cent; P = 0.366), complete ablation rate for small HCC (92 versus 98 per cent; P = 0.197), local recurrence rate (11 versus 9 per cent; P = 0.762) and overall survival (1-year: 86 versus 87 per cent; 2-year: 75 versus 75 per cent; P = 0.741). CONCLUSION: RFA without hepatic inflow occlusion is a safe and effective treatment for perivascular HCC.