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Aim: To compare the short- and long-term treatment outcomes of bisegmentectomy 7-8 vs. right hepatectomy for patients with hepatocellular carcinoma and cirrhosis. Methods: Thirty six cirrhotic HCC patients with infiltration of right hepatic vein in segments 7-8 underwent bisegmentectomy 7-8 for small-for-size remanant liver under right hemi-hepatectomy. Its outcome was compared with a case-matched control group of cirrhotic HCC patients who underwent right hemi-hepatectomy during the study period. Results: The study group consisted of 36 patients and the control group 36 patients selected from 1,526 patients matched with age, tumor size, tumor location, and Pugh-Child staging. There were no significant differences between the two groups in operative parameters and in perioperative main complications which included hemorrhage, bile leakage, ascites, pleural effusion, and liver failure. The overall morbidity rate and morbidity rate classified according to Clavien's classification were similar. There was no in-hospital mortality or 90 day post-operative mortality. The mean follow-up was 30 and 32 months for the study group and control group, respectively. The disease free survival rate (DFS) for the study group was just significantly better than the control group. The median DFS was 24 months for the study group and 8 months for the control group (P = 0.049). Meanwhile, the median cumulative overall survival was 35 months for the study group and 27 months for the control group (P = 0.494). Conclusion: Bisegmentectomy 7-8 was safe and feasible for selected cirrhosis patients, and did not increase the perioperative risk and inferior long-term overall survival outcomes. It extended the indications for liver resection in patients with borderline volumes of future liver remnant for HCC cirrhotic liver.
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Hepatocellular carcinoma is the second leading cause of cancer-related death worldwide. Neural regulation plays an important role in the development of hepatocellular carcinoma, and activation of sympathetic nervous system can promote the migration and invasion of cancer cells. However, little research has been conducted on how the vagus nerve influences hepatocellular carcinoma. In this study, we found that the expression of vesicular acetylcholine transporter, a biomarker of vagus nerve, was associated with hepatocellular carcinoma patients' clinicopathological characteristics by immunohistochemistry. Further, activation of muscarinic acetylcholine receptor 1 (M1R) promoted HepG2 and SMMC-7721 cells migration and invasion and epithelial-mesenchymal transition via PI3K/Akt pathway. Moreover, inhibition of M1R by antagonist or shRNA suppressed hepatocellular carcinoma cells migration and invasion in vitro and in vivo, inhibited epithelial-mesenchymal transition and PI3K/Akt pathway. Therefore, these results indicate that activation of M1R promotes invasion of hepatocellular carcinoma through epithelial-mesenchymal transition and PI3K/Akt pathway.
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Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Receptor Muscarínico M1/metabolismo , Animales , Línea Celular Tumoral , Movimiento Celular/fisiología , Transición Epitelial-Mesenquimal , Femenino , Células Hep G2 , Xenoinjertos , Humanos , Inmunohistoquímica , Masculino , Ratones , Ratones Desnudos , Persona de Mediana Edad , Invasividad Neoplásica , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal , Nervio Vago/patologíaRESUMEN
Hepatocellular carcinoma (HCC) is a highly malignant liver tumor. The presence of cancer stem cells (CSCs) figures prominently in tumor invasion, therapeutic resistance and tumor recurrence resulting in poor outcome and limited therapeutic options. Wnt/ß-catenin signaling is essential for cancer stem cell regulation and tumorigenesis in HCC, but its molecular mechanisms are not fully understood. Here, we demonstrate that ß-catenin is overexpressed in liver CSCs, and its expression level is positively correlated with SIRT1 in HCC specimens. SIRT1 regulates the protein stability of ß-catenin, thereby affecting the transcriptional activity of Wnt/ß-catenin signaling in liver CSCs. Mechanistically, we show that nuclear accumulation of ß-catenin results from deacetylation mediated by SIRT1. Further, nuclear ß-catenin promotes the transcription of Nanog to help maintain self-renewal of liver CSCs. Taken together, our findings indicate that the deacetylation of ß-catenin by SIRT1 represents a critical mechanism for regulating liver CSCs self-renewal and tumorigenesis. It provides an improved understanding of molecular mechanisms underlying ß-catenin activation and tumorigenesis in HCC.
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Carcinogénesis/metabolismo , Carcinoma Hepatocelular/metabolismo , Regulación Neoplásica de la Expresión Génica/fisiología , Neoplasias Hepáticas/metabolismo , Células Madre Neoplásicas/fisiología , Sirtuina 1/fisiología , beta Catenina/metabolismo , Humanos , Sirtuina 1/metabolismo , Células Tumorales CultivadasRESUMEN
The gold standard endpoint to evaluate the effect of treatment for hepatocellular carcinoma (HCC) is overall survival (OS), but it requires a longer follow-up period to observe. This study aimed to identify whether disease-free survival (DFS) could be used as a surrogate endpoint for OS to assess the efficacy of adjuvant therapies after curative treatment (surgical resection and ablation) for HCC patients. A systematic review was conducted to identify trials about curative treatment combined with or without adjuvant therapies (interferon, IFN; or transarterial chemoembolization, TACE) for HCC. Total of 2211 patients' data from 17 trials were analyzed. At the individual study level, DFS was strongly correlated to OS (ρ = 0.988 and 0.930, 95% CI: 0.965-0.996 and 0.806-0.976 for the studies comparing Radiofrequency ablation (RFA) + TACE to RFA alone; and for the studies comparing curative treatment + IFN to curative treatment alone, respectively). At the trial level, the effects of treatment on DFS and OS were also strongly correlated to each other (R = 0.815 and 0.854, 95% CI: 0.536-0.934 and 0.621-0.948, respectively). In conclusion, DFS could be used as a potential surrogate endpoint for OS to assess the effect of adjuvant therapies after curative treatment for HCC.
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BACKGROUND: Homeobox B7 (HOXB7) has been identified associated with poor prognosis of hepatocellular carcinoma (HCC). However, the specific mechanism by which HOXB7 promotes the malignant progression of HCC remains to be determined. METHODS: Immunohistochemistry (IHC) was used to detect the expression level of HOXB7 in 77-paired HCC tissue samples, and the correlation between HOXB7 and HCC prognosis was assessed. The location of HOXB7 was confirmed by immunofluorescence. Cell Titer-Blue assay was used to assess the proliferation of hepatoma cells. The stem-like properties of hepatoma cells were analysed by sphere formation and clone formation assays. The effect of HOXB7 on expression of cancer stem cell markers was evaluated. Transwell and wound-healing assays were performed to estimate the invasion and migration abilities of hepatoma cells. A xenograft tumor model was established in nude mice to assess the role of HOXB7 in tumor growth. Bioluminescence imaging was used to survey the effect of HOXB7 on the metastatic ability of hepatoma cells in vivo. RESULTS: Higher expression of HOXB7 was detected in HCC tissues compared with noncancerous tissues and significantly associated with poor prognosis of HCC. In addition, HOXB7 knockdown suppressed the cell proliferation, clone formation, sphere formation, invasion and migration of hepatoma cells in vitro; conversely, these biological abilities of hepatoma cells were enhanced by HOXB7 overexpression. Moreover, the cancer stem cell markers EPCAM and NANOG were up-regulated by HOXB7. The role of HOXB7 in promoting tumor growth and metastasis was verified in vivo. Further investigation revealed that c-Myc and Slug expression was elevated by HOXB7 and the AKT pathway was activated. CONCLUSION: Overexpression of HOXB7 was significantly correlated with poor prognosis of HCC. HOXB7 up-regulated c-Myc and Slug expression via the AKT pathway to promote the acquisition of stem-like properties and facilitate epithelial-mesenchymal transition of hepatoma cells, accelerating the malignant progression of HCC.
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Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patología , Transición Epitelial-Mesenquimal/genética , Proteínas de Homeodominio/genética , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Células Madre Neoplásicas/metabolismo , Adulto , Anciano , Animales , Carcinoma Hepatocelular/mortalidad , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Femenino , Expresión Génica , Técnicas de Silenciamiento del Gen , Genes myc , Xenoinjertos , Humanos , Neoplasias Hepáticas/mortalidad , Masculino , Ratones , Persona de Mediana Edad , Clasificación del Tumor , Metástasis de la Neoplasia/genética , Estadificación de Neoplasias , Neovascularización Patológica/genética , Neovascularización Patológica/metabolismo , Pronóstico , Factores de Transcripción de la Familia Snail/genética , Carga Tumoral/genéticaRESUMEN
The sympathetic nervous system (SNS) is known to play a significant role in tumor initiation and metastasis. Hepatocellular carcinoma (HCC) frequently occurs in cirrhotic livers after chronic inflammation, and the SNS is hyperactive in advanced liver cirrhosis. However, it remains unclear whether the SNS promotes hepatocarcinogenesis by modulating chronic liver inflammation. In this study, a retrospective pathological analysis and quantification of sympathetic nerve fiber densities (tyrosine hydroxylase, TH+) in HCC patients, and diethylnitrosamine (DEN)-induced hepatocarcinogenesis in rats were performed. Our data showed that high density of sympathetic nerve fibers and α1-adrenergic receptors (ARs) of Kupffer cells (KCs) were associated with a poor prognosis of HCC. Sympathetic denervation or blocking of α1-ARs decreased DEN-induced HCC incidence and tumor development. In addition, synergistic effects of interleukin-6 (IL-6) and transforming growth factor-beta (TGF-ß) in hepatocarcinogenesis were observed. The suppression of the SNS reduced IL-6 and TGF-ß expression, which suppressed hepatocarcinogenesis, and KCs play a key role in this process. After the ablation of KCs, IL-6 and TGF-ß expression and the development of HCC were inhibited. This study demonstrates that sympathetic innervation is crucial for hepatocarcinogenesis and that the SNS promotes hepatocarcinogenesis by activating α1-ARs of KCs to boost the activation of KCs and to maintain the inflammatory microenvironment. These results indicate that sympathetic denervation or α1-ARs blockage may represent novel treatment approaches for HCC.
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Carcinogénesis/patología , Carcinoma Hepatocelular/patología , Inflamación/patología , Macrófagos del Hígado , Neoplasias Hepáticas/patología , Receptores Adrenérgicos alfa 1 , Sistema Nervioso Simpático/patología , Adulto , Anciano , Animales , Femenino , Humanos , Interleucina-6/metabolismo , Neoplasias Hepáticas/inducido químicamente , Neoplasias Hepáticas Experimentales/inducido químicamente , Neoplasias Hepáticas Experimentales/patología , Masculino , Persona de Mediana Edad , Fibras Nerviosas/patología , Pronóstico , Ratas , Ratas Sprague-Dawley , Estudios Retrospectivos , Factor de Crecimiento Transformador beta/biosíntesisRESUMEN
Recellularized liver, as an approach for hepatic tissue engineering, is an effective alternative to orthotopic liver transplantation for end-stage hepatic failure. When compared with normal liver, recellularized liver has a disparity in hepatocyte viability and function, owing to the difficulty of fully simulating the microenvironment of liver. Although the sympathetic nervous system (SNS) is considered an important constituent of liver function, few studies have examined the effect of the SNS on hepatic tissue engineering. It is imperative to explore the regulation of the SNS on a tissue-like configuration to obtain an intact recellularized liver with better hepatic function. We have observed that various subtypes of adrenergic receptors (ARs) are expressed on the hepatocyte membrane. Salbutamol, an agonist of ß2-AR, promoted cell proliferation, albumin secretion and urea synthesis in the recellularized liver. Cytokines were screened in isoprenaline/salbutamol-treated recellularized liver, and the expression of IL-6 was significantly increased. Isoprenaline or salbutamol especially promoted the expression of Stat 3 and phosphorylated Stat 3, contributing to the activation of IL-6/Stat 3 signalling in promoting hepatocyte proliferation and recellularized liver function. This study suggests that activation of ß2-AR accelerated hepatocyte proliferation and improved recellularized liver function by mediating the IL-6/Stat 3 signalling pathway, indicating that nervous system regulation may be an essential component contributing to the complexity of recellularized liver in tissue engineering.
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Interleucina-6/metabolismo , Hígado/efectos de los fármacos , Neurotransmisores/química , Factor de Transcripción STAT3/metabolismo , Albúminas/química , Albuterol/química , Animales , Membrana Celular/metabolismo , Proliferación Celular , Citocinas/metabolismo , Matriz Extracelular/metabolismo , Hepatocitos/citología , Hepatocitos/metabolismo , Humanos , Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Fosforilación , Receptores Adrenérgicos/metabolismo , Transducción de Señal , Ingeniería de Tejidos , Urea/químicaRESUMEN
AIM: To investigate the efficacy and safety of adjuvant sorafenib after curative resection for patients with Barcelona Clinic Liver Cancer (BCLC)-stage C hepatocellular carcinoma (HCC). METHODS: Thirty-four HCC patients, classified as BCLC-stage C, received adjuvant sorafenib for high-risk of tumor recurrence after curative hepatectomy at a tertiary care university hospital. The study group was compared with a case-matched control group of 68 patients who received curative hepatectomy for HCC during the study period in a 1:2 ratio. RESULTS: The tumor recurrence rate was markedly lower in the sorafenib group (15/34, 44.1%) than in the control group (51/68, 75%, P = 0.002). The median disease-free survival was 12 mo in the study group and 10 mo in the control group. Tumor number more than 3, macrovascular invasion, hilar lymph nodes metastasis, and treatment with sorafenib were significant factors of disease-free survival by univariate analysis. Tumor number more than 3 and treatment with sorafenib were significant risk factors of disease-free survival by multivariate analysis in the Cox proportional hazards model. The disease-free survival and cumulative overall survival in the study group were significantly better than in the control group (P = 0.034 and 0.016, respectively). CONCLUSION: Our study verifies the potential benefit and safety of adjuvant sorafenib for both decreasing HCC recurrence and extending disease-free and overall survival rates for patients with BCLC-stage C HCC after curative resection.
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Carcinoma Hepatocelular/terapia , Hepatectomía , Neoplasias Hepáticas/terapia , Recurrencia Local de Neoplasia/tratamiento farmacológico , Niacinamida/análogos & derivados , Compuestos de Fenilurea/uso terapéutico , Adolescente , Adulto , Anciano , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/cirugía , Quimioterapia Adyuvante , Terapia Combinada , Supervivencia sin Enfermedad , Femenino , Humanos , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/cirugía , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Niacinamida/efectos adversos , Niacinamida/uso terapéutico , Compuestos de Fenilurea/efectos adversos , Estudios Prospectivos , Estudios Retrospectivos , Factores de Riesgo , Sorafenib , España , Tasa de Supervivencia , Resultado del Tratamiento , Adulto JovenRESUMEN
Hepatocellular carcinoma is associated with high mortality, and tumor metastasis is an important reason for poor prognosis. However, metastasis has not been effectively prevented in clinical therapy and the mechanisms underlying metastasis have not been fully characterized. CCAAT/enhancer-binding protein-α (C/EBPα) is a transcriptional regulator with an essential role in tumor metastasis. We used short-activating RNAs (saRNA) to enhance expression of C/EBPα. Intravenous injection of C/EBPα-saRNA in a nude mouse liver orthotopic xenograft tumor model inhibited intrahepatic and distant metastasis. C/EBPα-saRNA-treated mice showed increased serum levels of albumin and decreased alanine aminotransferase (ALT), glutamic-oxalacetic transaminase (AST), indicating a role of C/EBPα in improving liver function. Migration and invasion were inhibited in hepatoma cell lines transfected with C/EBPα-saRNA. We also observed an inhibition of epithelial-mesenchymal transition (EMT) and suppression of epidermal growth factor receptor (EGFR), EGFR phosphorylation, and ß-catenin in C/EBPa-saRNA-transfected cells. Our results suggested that C/EBPα-saRNA successfully inhibited HCC metastasis by inhibiting EGFR/ß-catenin signaling pathway mediated EMT in vitro and in vivo.
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Proteína alfa Potenciadora de Unión a CCAAT/genética , Carcinoma Hepatocelular/patología , Transición Epitelial-Mesenquimal/fisiología , Receptores ErbB/fisiología , Neoplasias Hepáticas/patología , Metástasis de la Neoplasia/prevención & control , ARN/administración & dosificación , Transducción de Señal , beta Catenina/metabolismo , Animales , Carcinoma Hepatocelular/metabolismo , Línea Celular Tumoral , Xenoinjertos , Humanos , Neoplasias Hepáticas/metabolismo , Masculino , Ratones , Ratones DesnudosRESUMEN
Partial hepatectomy is still the treatment of choice aiming at a cure for patients with hepatocellular carcinoma (HCC), provided that the patient can tolerate the treatment. For patients with multiple recurrent HCC after partial hepatectomy which cannot be treated by re-hepatectomy or local ablative therapy, the prognosis is extremely poor. Sorafenib is a molecular-targeted agent which has been demonstrated in two global phase III randomized controlled trials to show survival benefit for advanced HCC. Here, we present a 56-year-old patient with HCC who showed complete clinical response after sorafenib was used for tumor recurrence which developed 3 mo after partial hepatectomy. There was no evidence of progression of disease for 60 mo till now after continuous treatment with sorafenib.
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Antineoplásicos/uso terapéutico , Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Niacinamida/análogos & derivados , Compuestos de Fenilurea/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Biopsia , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/cirugía , Hepatectomía , Humanos , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/cirugía , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Niacinamida/uso terapéutico , Inducción de Remisión , Sorafenib , Factores de Tiempo , Tomografía Computarizada por Rayos X , Resultado del TratamientoRESUMEN
BACKGROUND: The prognosis of hepatocellular carcinoma (HCC) patients with extrahepatic metastasis is extremely poor. However, what is the main risk factor for survival remains unclear for these patients. We aimed to find out the relative frequency, incidence and locations of extrahepatic metastases and the risk factors of long-term survival of the patients. METHODS: 132 HCC patients with extrahepatic metastasis diagnosed by 18F-FDG PET/CT and conventional workup were enrolled into this study. The incidence and locations of extrahepatic metastases were summarized, and the related risk factors of overall survival were analyzed. RESULTS: The most frequent extrahepatic metastatic sites were lymph nodes in 72 (54.5%), bone in 33 (25.0%) and lung in 28 (21.2%) patients. On univariate analysis, prothrombin time, Child-Pugh grade, portal/hepatic vein invasion and lymph node metastasis were independent risk factors of overall survival. On multivariate analysis, lymph node metastasis was the only independent risk factor of overall survival. The cumulative survival rates at 1- and 3-years after diagnosis of extrahepatic metastasis of HCC were 34.4% and 9.3%, respectively. The median survival time was 7 months (range 1 â¼38 months). The median survival time for patients with or without lymph node metastasis were 5 months (range 1â¼38 months) and 12 months (range 1â¼30 months), respectively (Pâ=â0.036). CONCLUSIONS: This study showed lymph nodes to be the most frequent site of extrahepatic metastases for primary HCC. Lymph node metastasis was the main risk factor of overall survival in patients with HCC with extrahepatic metastasis.