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The heterogeneity of the tumour immune microenvironment (TIME), organized by various immune and stromal cells, is a major contributing factor of tumour metastasis, relapse and drug resistance1-3, but how different TIME subtypes are connected to the clinical relevance in liver cancer remains unclear. Here we performed single-cell RNA-sequencing (scRNA-seq) analysis of 189 samples collected from 124 patients and 8 mice with liver cancer. With more than 1 million cells analysed, we stratified patients into five TIME subtypes, including immune activation, immune suppression mediated by myeloid or stromal cells, immune exclusion and immune residence phenotypes. Different TIME subtypes were spatially organized and associated with chemokine networks and genomic features. Notably, tumour-associated neutrophil (TAN) populations enriched in the myeloid-cell-enriched subtype were associated with an unfavourable prognosis. Through in vitro induction of TANs and ex vivo analyses of patient TANs, we showed that CCL4+ TANs can recruit macrophages and that PD-L1+ TANs can suppress T cell cytotoxicity. Furthermore, scRNA-seq analysis of mouse neutrophil subsets revealed that they are largely conserved with those of humans. In vivo neutrophil depletion in mouse models attenuated tumour progression, confirming the pro-tumour phenotypes of TANs. With this detailed cellular heterogeneity landscape of liver cancer, our study illustrates diverse TIME subtypes, highlights immunosuppressive functions of TANs and sheds light on potential immunotherapies targeting TANs.
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Neoplasias Hepáticas , Neutrófilos , Microambiente Tumoral , Animales , Humanos , Ratones , Inmunoterapia , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/inmunología , Recurrencia Local de Neoplasia , Neutrófilos/citología , Neutrófilos/inmunología , Microambiente Tumoral/inmunología , Linfocitos T/inmunología , Macrófagos/inmunología , Pronóstico , Progresión de la EnfermedadRESUMEN
BACKGROUND & AIMS: Intrahepatic cholangiocarcinoma (iCCA) has two main histological subtypes: large and small duct-type iCCA, which are characterized by different clinicopathological features. This study was conducted with the purpose of expanding our understanding of their differences in molecular features and immune microenvironment. METHODS: We selected 132 patients who underwent radical surgery at our department between 2015 and 2021 for clinical and survival analyses. Whole-exome sequencing was performed to analyse mutational landscapes. Bulk RNA sequencing and single-cell RNA sequencing data were used for pathway enrichment and immune infiltration analyses based on differentially expressed genes. The function of PPP1R1B was analysed both in vitro and in vivo and the gene mechanism was further investigated. RESULTS: We found that large duct-type iCCA had worse overall survival and recurrence-free survival rates than small duct-type iCCA. Mutations in ARID1A, DOT1L and ELF3 usually occur in large duct-type iCCA, whereas mutations in IDH1 and BAP1 occur in small duct-type iCCA. Among the differentially expressed genes, we found that PPP1R1B was highly expressed in large duct-type iCCA tumour tissues. Expression of PPP1R1B promoted cell proliferation, migration and invasion and indicated a worse prognosis. A combination of USF2 with the promoter of PPP1R1B can enhance gene expression in iCCA, which may further affect the expression of genes such as AHNAK, C4BPA and activating the PI3K/AKT pathway. CONCLUSIONS: Our findings extend our understanding of large and small duct-type iCCA. In addition, PPP1R1B may serve as a potential marker and therapeutic target for large duct-type iCCA.
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BACKGROUND: Hepatocellular carcinoma (HCC) continues to play a substantial role in cancer-related morbidity and mortality, largely owing to its pronounced tumor heterogeneity and propensity for recurrence. This underscores the pressing need for in-depth examination of its highly malignant mechanisms. Annexin A5 (ANXA5), recognized as a hallmark tumor protein, has emerged as a focal point of interest because of its ambiguous function and mechanism in HCC prognosis. This study aimed to provide a comprehensive understanding of the role of ANXA5 in the malignant progression of human HCC cells by employing an integrative approach that combines conventional experimental methods with RNA sequencing. METHODS: Differences in ANXA5 expression between HCC tissues and corresponding nontumor tissues were evaluated using immunofluorescence (n = 25). Correlation analysis was subsequently performed to assess the association between ANXA5 expression and clinicopathological features (n = 65). The role of ANXA5 in human HCC cell lines with ANXA5 gene knockout and overexpression was explored in vitro using migration and invasion assays and Ki-67 indices and in vivo based on node mice xenograft model. A tube formation assay using human umbilical vein endothelial cells (HUVECs) was conducted to demonstrate the angiogenic effects of ANXA5 in HCC. Single-cell and bulk RNA sequencing was used to further investigate the underlying mechanisms involved. RESULTS: This study revealed that ANXA5 is highly expressed in patients with HCC and correlates with poor prognosis. Assays for migration, invasion, and proliferation based on ANXA5 gene knockout and overexpression systems in human HCC cell lines have demonstrated that ANXA5 enhances HCC malignancy in vitro and in vivo. Tube formation assays of HUVECs indicated that ANXA5 facilitates angiogenesis and recruits endothelial cells to HCC cells. Single-cell and bulk RNA sequencing data analysis further confirmed that ANXA5 expression in HCC is associated with hepatocyte metabolism, immune response activation, and various oncogenic signaling pathways. CONCLUSIONS: This study revealed a meaningful association between elevated ANXA5 expression in tumor tissues and an unfavorable prognosis in patients with HCC. In addition, ANXA5 promotes HCC malignancy by promoting invasion and angiogenesis. Thus, ANXA5 has emerged as a promising therapeutic target for HCC and has the potential to improve patient outcomes.
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Anexina A5 , Carcinoma Hepatocelular , Neoplasias Hepáticas , Invasividad Neoplásica , Neovascularización Patológica , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/metabolismo , Humanos , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neovascularización Patológica/genética , Neovascularización Patológica/metabolismo , Animales , Ratones , Anexina A5/metabolismo , Línea Celular Tumoral , Masculino , Femenino , Movimiento Celular/genética , Persona de Mediana Edad , Células Endoteliales de la Vena Umbilical Humana , Proliferación Celular , Pronóstico , Regulación Neoplásica de la Expresión Génica , AngiogénesisRESUMEN
OBJECTIVE: Immune checkpoint blockade (ICB) has improved cancer treatment, yet why most hepatocellular carcinoma (HCC) patients are resistant to PD-1 ICB remains elusive. Here, we elucidated the role of a programmed cell death protein 1 (PD-1) isoform, Δ42PD-1, in HCC progression and resistance to nivolumab ICB. DESIGN: We investigated 74 HCC patients in three cohorts, including 41 untreated, 28 treated with nivolumab and 5 treated with pembrolizumab. Peripheral blood mononuclear cells from blood samples and tumour infiltrating lymphocytes from tumour tissues were isolated for immunophenotyping. The functional significance of Δ42PD-1 was explored by single-cell RNA sequencing analysis and validated by functional and mechanistic studies. The immunotherapeutic efficacy of Δ42PD-1 monoclonal antibody was determined in HCC humanised mouse models. RESULTS: We found distinct T cell subsets, which did not express PD-1 but expressed its isoform Δ42PD-1, accounting for up to 71% of cytotoxic T lymphocytes in untreated HCC patients. Δ42PD-1+ T cells were tumour-infiltrating and correlated positively with HCC severity. Moreover, they were more exhausted than PD-1+ T cells by single T cell and functional analysis. HCC patients treated with anti-PD-1 ICB showed effective PD-1 blockade but increased frequencies of Δ42PD-1+ T cells over time especially in patients with progressive disease. Tumour-infiltrated Δ42PD-1+ T cells likely sustained HCC through toll-like receptors-4-signalling for tumourigenesis. Anti-Δ42PD-1 antibody, but not nivolumab, inhibited tumour growth in three murine HCC models. CONCLUSION: Our findings not only revealed a mechanism underlying resistance to PD-1 ICB but also identified anti-Δ42PD-1 antibody for HCC immunotherapy.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Ratones , Animales , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/patología , Leucocitos Mononucleares , Terapia de Inmunosupresión , Tolerancia Inmunológica , Inmunoterapia , Nivolumab/uso terapéutico , Linfocitos T CD8-positivosRESUMEN
BACKGROUND: Portal vein tumour thrombus (PVTT) is the main pathway of HCC intrahepatic metastasis and is responsible for the poor prognosis of patients with HCC. However, the molecular mechanisms underlying PVTT vascular metastases have not been fully elucidated. METHODS: NDRG1 expression was assessed by immunohistochemistry and immunoblotting in clinical specimens obtained from curative surgery. The functional relevance of NDRG1 was evaluated using sphere formation and animal models of tumorigenicity and metastasis. The relationship between NDRG1 and EpCAM was explored using molecular biological techniques. RESULTS: NDRG1 protein was upregulated in HCC samples compared to non-tumorous tissues. Furthermore, NDRG1 expression was enhanced in the PVTT samples. Our functional study showed that NDRG1 was required for the self-renewal of tumour-initiating/cancer stem cells (CSCs). In addition, NDRG1 knockdown inhibited the proliferation and migration of PVTT-1 cells in vitro and in vivo. NDRG1 was found to stabilise the functional tumour-initiating cell marker EpCAM through protein-protein interactions and inhibition of EpCAM ubiquitination. CONCLUSION: Our findings suggest that NDRG1 enhances CSCs expansion, PVTT formation and growth capability through the regulation of EpCAM stability. NDRG1 may be a promising target for the treatment of patients with HCC and PVTT.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Trombosis , Animales , Neoplasias Hepáticas/patología , Carcinoma Hepatocelular/patología , Molécula de Adhesión Celular Epitelial/genética , Molécula de Adhesión Celular Epitelial/metabolismo , Células Madre Neoplásicas/patología , Línea Celular TumoralRESUMEN
BACKGROUND: Non-small cell lung cancer (NSCLC) accounts for more than 80% of lung cancers, which is the most common malignant tumor worldwide. Polypeptide extract from scorpion venom (PESV) has been reported to inhibit NSCLC process. The present study aims to reveal the roles of PESV in NSCLC progression under hypoxia and the inner mechanism. METHODS: The expression levels of circular RNA 0016760 (circ_0016760) and microRNA-29b (miR-29b) were detected by quantitative real-time polymerase chain reaction (qRT-PCR). Protein expression was determined by western blot and immunohistochemistry assays. Cell migration, invasion, proliferation and tube formation were investigated by transwell, cell colony formation, 3-(4,5-Dimethylthazol-2-yl)-2,5-diphenyltetrazolium bromide and tube formation assays. The impacts between PESV and circ_0016760 overexpression on tumor growth in vivo were investigated by in vivo tumor formation assay. RESULTS: Circ_0016760 expression was dramatically upregulated in NSCLC tissues and cells, compared with adjacent lung tissues and cells, respectively. PESV treatment downregulated circ_0016760 expression. Circ_0016760 silencing or PESV treatment repressed cell migration, invasion, proliferation and tube formation under hypoxia in NSCLC cells. Circ_0016760 overexpression restored the effects of PESV treatment on NSCLC process under hypoxia. Additionally, circ_0016760 acted as a sponge of miR-29b, and miR-29b bound to HIF1A. Meanwhile, miR-29b inhibitor impaired the influences of circ_0016760 knockdown on NSCLC process under hypoxia. Further, ectopic circ_0016760 expression restrained the effects of PESV exposure on tumor formation in vivo. CONCLUSION: Circ_0016760 overexpression counteracted PESV-induced repression of NSCLC cell malignancy and angiogenesis under hypoxia through miR-29b/HIF1A axis.
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BACKGROUND: Anillin (ANLN) is required for tumor growth. It has been proven that knockdown of ANLN effectively reduces the occurrence of hepatocellular carcinoma (HCC) in transgenic mice. However, the functional role of ANLN in HCC patients remains to be elucidated. METHODS: Both microarray and TCGA project were used for the analyses of ANLN expression and regulation in HCC. The effect of ANLN on proliferation and cell cycle was detected by CCK-8, colony formation assay and flow cytometry. ANLN expression was measured by immunohistochemistry. Correlation between ANLN expression and clinicopathological features was assessed by Pearson Chi-square test and 5-year overall survival after liver resection was evaluated by Kaplan-Meier method. RESULTS: Increased copy number, decreased methylation levels in the CpG island and upregulated histone hypermethylation of ANLN were found in HCC. Knockdown of ANLN inhibited proliferation and induced G2/M phase arrest in SMMC-7721 cells. ANLN was mainly expressed in the nucleus and showed significantly higher expression levels in cancerous tissues than those in paired adjacent tissues. Moreover, nuclear ANLN expression levels in HCC metastases were significantly higher than those in primary HCC. The results of Cox proportional hazards regression model suggested that ANLN nuclear expression in HCC was an independent risk factor for poor 5-year overall survival of patients after liver resection. CONCLUSIONS: ANLN is a potential therapeutic target for HCC. Patients with nuclear ANLN overexpression in HCC tissue may need adjuvant therapy after liver resection.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Animales , Biomarcadores de Tumor/genética , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/cirugía , Línea Celular Tumoral , Proliferación Celular , Proteínas Contráctiles , Regulación Neoplásica de la Expresión Génica , Humanos , Estimación de Kaplan-Meier , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/cirugía , Ratones , PronósticoRESUMEN
INTRODUCTION: hepatocellular carcinoma (HCC) recurrence after liver resection remains a major threat for patients' survival. Sorafenib is recommended as an adjuvant treatment for patients after a liver resection. The objective of this meta-analysis was to estimate the therapeutic value of sorafenib in patients who underwent a HCC resection. MATERIALS AND METHODS: relevant reports were retrieved from electronic databases. All eligible studies were carefully reviewed and the required data were extracted. Outcome with regard to overall survival (OS), recurrence-free survival (RFS), recurrence rate, mortality rate, OS time (months) and RFS time (months) were analyzed. RESULTS: nine trials were included. The results of the meta-analysis revealed that sorafenib did not exert a significant superior effect on OS (sorafenib as reference: hazard ratio [HR] = 2.15; 95% CI, 0.91-5.08, p = 0.80; control as reference: HR = 0.56; 95% CI, 0.31-1.02; p = 0.059), OS time in months (weighted mean differences [WMD] = 4.96; 95% CI, -1.21-11.13; p = 0.115) and RFS time in months (WMD = 7.58; 95% CI, -1.36-16.53; p = 0.097). Nevertheless, the use of sorafenib was associated with a significantly higher RFS (HR = 0.53; 95% CI, 0.31-0.90; p = 0.018), and a lower recurrence rate (risk ratio [RR] = 0.72; 95% CI, 0.60-0.86; p < 0.001) and mortality rate (RR = 0.74; 95% CI, 0.57-0.95; p = 0.20). CONCLUSION: according to the present meta-analysis, sorafenib showed a significant benefit in RFS, recurrence rate and mortality rate. The effect of sorafenib for the prevention of HCC recurrence seems to be encouraging. However, more evidence is still needed before reaching a definitive conclusion.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/cirugía , Hepatectomía , Humanos , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/cirugía , Recurrencia Local de Neoplasia/prevención & control , Sorafenib/uso terapéutico , Resultado del TratamientoRESUMEN
BACKGROUND: To investigate the effects of retrograde reperfusion on the intraoperative internal environment and hemodynamics in classic orthotopic liver transplantation (OLT). METHODS: Thirty patients were undergone classic OLT using retrograde reperfusion in our center. Blood sampling was done at different time points including: Before blood venting via the portal vein (PV), 10 mL of blood was collected from the inferior vena cava (T0); During retrograde reperfusion through the inferior vena cava (IVC), 10 mL of blood was collected when the volume of blood venting reached 10 mL (T1), 100 mL (T2), and 200 mL (T3), respectively. 5 mL of blood was analyzed using a NOVA-f-type Blood Gas Analyzer. The remaining 5 mL was measured to determine the level of IL-1ß using an enzyme-linked immunosobent assay. RESULTS: All operations were completed successfully, and postreperfusion syndrome (PRS) occurred in 6 patients (20%). The most notable findings were significant changes at T1, T2 and T3, including pH value, PvO2, SvO2, BEecf, HCO3-, Lac, K+, Ca2+ and IL-1ß, compared with T0 (P < 0.05). Yet their levels at T3 were not back to the level at T0 (P < 0.05). CONCLUSION: This retrograde perfusion could eliminate some harmful metabolites inside the donor liver in time and reduce acid-base and electrolyte disorders as well as drastic hemodynamic fluctuations after recirculation during classic OLT.
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Hepatopatías/fisiopatología , Hepatopatías/cirugía , Trasplante de Hígado/métodos , Hígado/irrigación sanguínea , Reperfusión/métodos , Adulto , Femenino , Hemodinámica , Humanos , Hígado/fisiopatología , Trasplante de Hígado/efectos adversos , Masculino , Persona de Mediana Edad , Vena Porta/cirugía , Daño por Reperfusión/etiología , Daño por Reperfusión/prevención & control , Vena Cava Inferior/cirugíaRESUMEN
AIM: The purpose of this study was to investigate which inflammation-based marker more accurately predict recurrence in patients receiving hepatectomy for hepatocellular carcinoma (HCC). METHODS: A total of 1020 patients was included. The impacts of clinical variables and inflammation-based markers on disease-free survival (DFS) were measured by Kaplan-Meier method. Selected potential prognostic factors were further analyzed in multivariate model. To reduce influences of selection bias and possible confounders, clinical characteristics of patients were balanced by propensity score matching (PSM). RESULTS: Of the 1020 patients, 881 (86.4%) were male and 323 (31.7%) received major hepatectomy. In multivariate analysis, cirrhosis (HR: 1.49), tumor size (HR: 1.32), tumor number (HR: 1.57), portal vein tumor thrombus (HR: 1.66), microvascular invasion (HR: 1.60), histological grade (HR: 1.82), operation time (HR: 1.50), alpha foetal protein (HR: 1.29), neutrophil to lymphocyte ratio (NLR) (HR: 1.38), and lymphocyte to monocyte ratio (LMR) (HR: 1.51) were independently predictive of DFS. After PSM, 258 and 213 pairs of patients were generated for LMR and NLR, respectively. LMR and NLR were still independent predictors of recurrence for HCC patients receiving hepatectomy. CONCLUSION: Both LMR and NLR might be preferable independent prognostic factors for DFS in HCC patients undergoing hepatectomy.
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Carcinoma Hepatocelular/sangre , Inflamación/sangre , Neoplasias Hepáticas/sangre , Linfocitos/patología , Monocitos/patología , Recurrencia Local de Neoplasia/sangre , Neutrófilos/patología , Adolescente , Adulto , Anciano , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/cirugía , Supervivencia sin Enfermedad , Femenino , Humanos , Inflamación/patología , Estimación de Kaplan-Meier , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/cirugía , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/patología , Adulto JovenRESUMEN
BACKGROUND: The aim of this study was to characterize the disorder of lipid metabolism in hepatocellular carcinoma (HCC). HCC is a worldwide disease. The research into the disorder of lipid metabolism in HCC is very limited. Study of lipid metabolism in liver cancer tissue may have the potential to provide new insight into HCC mechanisms. METHODS: A lipidomics study of HCC based on Ultra high performance liquid chromatography-electronic spray ionization-QTOF mass spectrometer (UPLC-ESI-QTOF MS) and Matrix assisted laser desorption ionization-fourier transform ion cyclotron resonance mass spectrometer (MALDI-FTICR MS) was performed. RESULTS: Triacylglycerols (TAGs) with the number of double bond (DB) > 2 (except 56:5 and 56:4 TAG) were significantly down-regulated; conversely, others (except 52:2 TAG) were greatly up-regulated in HCC tissues. Moreover, the more serious the disease was, the higher the saturated TAG concentration and the lower the polyunsaturated TAG concentration were in HCC tissues. The phosphatidylcholine (PC), phosphatidylethanolamine (PE) and phosphatidylinositol (PI) were altered in a certain way. Sphingomyelin (SM) was up-regulated and ceramide (Cer) were down-regulated in HCC tissues. CONCLUSIONS: To our knowledge, this is the first such report showing a unique trend of TAG, PC, PE and PI. The use of polyunsaturated fatty acids, like eicosapentanoic and docosahexanoic acid, as supplementation, proposed for the treatment of Non-alcoholic steatohepatitis (NASH), may also be effective for the treatment of HCC.
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Carcinoma Hepatocelular/metabolismo , Ceramidas/metabolismo , Metabolismo de los Lípidos/fisiología , Neoplasias Hepáticas/metabolismo , Espectrometría de Masas , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción , Triglicéridos/metabolismoRESUMEN
BACKGROUND: Recent studies have demonstrated that transducin (beta)-like 1 X-linked receptor 1 (TBLR1) is involved in tumor progression. However, the exact role and clinical significance of TBLR1 in hepatocellular carcinoma (HCC) are poorly understood. AIM: In this study, we aimed to investigate the expression and clinical significance of TBLR1 in HCC. METHODS: Quantitative polymerase chain reaction and immunohistochemical staining were performed to detect the expression levels of TBLR1 in HCC tissue and adjacent noncancerous tissue (ANT). The relationships between TBLR1 expression and clinicopathological factors were examined in this study. The effects of TBLR1 on epithelial-mesenchymal transition (EMT) of HCC cells were investigated in vitro. RESULTS: The expression levels of TBLR1 were elevated in HCC cell lines. TBLR1 mRNA in HCC tissue was markedly higher (P < 0.001) than that in ANT. High expression of TBLR1 is closely related to serum alpha fetoprotein (P = 0.047), BCLC stage (P < 0.001), maximum size of tumors (P < 0.001), tumor embolus (P < 0.001), and histological grade (P < 0.001). The disease-free survival and overall survival of HCC patients with high expression of TBLR1 were significantly shorter. Furthermore, we found that EMT of HCC cells could be induced by up-regulating TBLR1 and be inhibited by down-regulating TBLR1. ICG-001, the inhibitor of Wnt/ß-catenin signaling, could suppress induction of EMT mediated by TBLR1. CONCLUSIONS: Our finding suggested that TBLR1 is likely to be a potential prognostic indicator and therapeutic target for HCC and that TBLR1 may be implicated in EMT of HCC cells.
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Carcinoma Hepatocelular/metabolismo , Transición Epitelial-Mesenquimal/fisiología , Neoplasias Hepáticas/metabolismo , Proteínas Nucleares/metabolismo , Receptores Citoplasmáticos y Nucleares/metabolismo , Proteínas Represoras/metabolismo , Carcinoma Hepatocelular/genética , Línea Celular Tumoral , Regulación hacia Abajo , Femenino , Regulación Neoplásica de la Expresión Génica/fisiología , Humanos , Neoplasias Hepáticas/genética , Masculino , Persona de Mediana Edad , Proteínas Nucleares/genética , ARN Mensajero/genética , ARN Mensajero/metabolismo , Receptores Citoplasmáticos y Nucleares/genética , Proteínas Represoras/genética , Regulación hacia Arriba , Proteínas Wnt , beta CateninaRESUMEN
BACKGROUND: Lysyl oxidase (LOX) is frequently overexpressed in a variety of malignancies and involved in tumor invasion and metastasis. Furthermore, it has been shown that LOX is closely related to vascular endothelial growth factor (VEGF). AIMS: In this study, we aimed to investigate the exact role of LOX and the correlation between LOX and VEGF in hepatocellular carcinoma (HCC). METHODS: The expression levels of LOX in HCC tissue and adjacent noncancerous tissue were evaluated by quantitative reverse transcription polymerase chain reaction and immunohistochemical analysis. The effect of LOX knockdown on cell proliferation, migration, and invasion was investigated in vitro. The role of LOX in the regulation of VEGF was further characterized in HCC cells that had been treated with transforming growth factor beta (TGF-ß). RESULTS: Our study showed that LOX was up-regulated in HCC cell lines and tissue. HCC patients with elevated expression of LOX had relatively shorter disease-free survival and overall survival. Knockdown of LOX reduced the proliferation, migration, and invasion of HCC cells. Additionally, the expression level of LOX positively correlated with that of VEGF. After treatment with TGF-ß, the levels of LOX and VEGF were both up-regulated in a dose-dependent manner. In the cells treated with siRNA of LOX, levels of VEGF and phosphorylated p38 were significantly decreased and could not be up-regulated by TGF-ß. Inhibition of p38 MAPK signaling abrogated TGF-ß-mediated up-regulation of VGEF but did not affect LOX expression. CONCLUSIONS: LOX appears to be a predictor of less favorable outcomes and may regulate the expression of VEGF via p38 MAPK signaling.
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Carcinoma Hepatocelular/mortalidad , Regulación Neoplásica de la Expresión Génica , Neoplasias Hepáticas/mortalidad , Proteína-Lisina 6-Oxidasa/genética , Factor A de Crecimiento Endotelial Vascular/genética , Anciano , Biopsia con Aguja , Western Blotting , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patología , Proliferación Celular/genética , Supervivencia sin Enfermedad , Femenino , Humanos , Inmunohistoquímica , Estimación de Kaplan-Meier , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Masculino , Persona de Mediana Edad , Análisis Multivariante , Valor Predictivo de las Pruebas , Pronóstico , Modelos de Riesgos Proporcionales , Muestreo , Transducción de Señal/genética , Estadísticas no Paramétricas , Análisis de Supervivencia , Células Tumorales Cultivadas , Regulación hacia ArribaRESUMEN
BACKGROUND/AIMS: To evaluate short-term outcomes and long-term survival after pancreaticoduodenectomy for malignancy in elderly Chinese patients (aged 70 years or older) compared with younger patients. METHODOLOGY: Between January 2005 and December 2013, 216 consecutive patients who underwent a PD with pancreatic cancer or periampullary cancers in our institution were recruited in this study. Sixty-eight patients aged 70 years or older when they underwent PD, while 148 patients younger than 70. RESULTS: There were no significant differences in postoperative mortality (p = 0.104), overall morbidity (p = 0.057) and surgical complications (p = 0.200) between the elderly patients and the younger patients. Elderly patients had a significantly higher incidence of cardiac events (p = 0.008) and pneumonia (p = 0.041) postoperatively. The postoperative hospital stay in the older age group was significantly longer (p = 0.013). The overall survival did not differ between the two age groups both when patients with pancreatic cancer were analyzed (p = 0.836) and when patients with periampullary cancers were analyzed (p = 0.817). CONCLUSIONS: Our results showed that pancreaticoduodenectomy for malignancy in Chinese patients over 70 years old could be performed safely. Age should not be considered as a contraindication to pancreaticoduodenectomy.
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Neoplasias del Sistema Digestivo/cirugía , Pancreaticoduodenectomía , Factores de Edad , Anciano , China , Neoplasias del Sistema Digestivo/mortalidad , Neoplasias del Sistema Digestivo/patología , Femenino , Humanos , Estimación de Kaplan-Meier , Tiempo de Internación , Masculino , Persona de Mediana Edad , Pancreaticoduodenectomía/efectos adversos , Pancreaticoduodenectomía/mortalidad , Selección de Paciente , Complicaciones Posoperatorias/mortalidad , Complicaciones Posoperatorias/terapia , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND: Esophagogastric variceal hemorrhage is a life-threatening complication of portal hypertension. In this study, we compared the therapeutic effect of a novel surgical procedure, esophagogastric devascularization without splenectomy (EDWS), with the widely used modified esophagogastric devascularization (MED) with splenectomy for the treatment of portal hypertension. METHODS: Fifty-five patients with portal hypertension were included in this retrospective study. Among them, 27 patients underwent EDWS, and the other 28 patients underwent MED. Patients' characteristics, perioperative parameters and long-term follow-up were analyzed. RESULTS: The portal venous pressure was decreased by 20% postoperatively in both groups. The morbidity rate of portal venous system thrombosis in the EDWS group was significantly lower than that in the MED group (P=0.032). The 1- and 3-year recurrence rates of esophagogastric variceal hemorrhage were 0% and 4.5% in the EDWS group, and 0% and 8.7% in the MED group, respectively (P=0.631). CONCLUSIONS: EDWS is a safe and effective treatment for esophagogastric varices secondary to portal hypertension in selected patients. Patients treated with EDWS had a lower complication rate of portal venous system thrombosis compared with those treated with conventional MED.
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Várices Esofágicas y Gástricas/cirugía , Hemorragia Gastrointestinal/cirugía , Técnicas Hemostáticas , Hipertensión Portal/cirugía , Esplenectomía , Procedimientos Quirúrgicos Vasculares , Adulto , Supervivencia sin Enfermedad , Várices Esofágicas y Gástricas/diagnóstico , Várices Esofágicas y Gástricas/etiología , Femenino , Hemorragia Gastrointestinal/diagnóstico , Hemorragia Gastrointestinal/etiología , Técnicas Hemostáticas/efectos adversos , Humanos , Hipertensión Portal/complicaciones , Hipertensión Portal/diagnóstico , Hipertensión Portal/fisiopatología , Masculino , Persona de Mediana Edad , Recurrencia , Estudios Retrospectivos , Esplenectomía/efectos adversos , Factores de Tiempo , Resultado del Tratamiento , Procedimientos Quirúrgicos Vasculares/efectos adversos , Presión Venosa , Trombosis de la Vena/etiologíaRESUMEN
BACKGROUND: Glypican-3 (GPC-3) is frequently overexpressed in hepatocellular carcinoma (HCC). Recent studies have shown that GPC-3 is a highly efficient diagnostic biomarker of HCC and an indicator of poor prognosis in HCC patients who have undergone hepatectomy. However, its prognostic value in patients with HBV-associated HCC after liver transplantation (LT) is not clear. The present study is to evaluate the prognostic value of GPC-3 in patients with HBV-associated HCC after LT. METHODS: A cohort of 104 HCC patients with HBV-associated cirrhosis who had undergone LT at our hospital between 2002 and 2011 were enrolled in this study. Samples of HCC were taken from these patients. GPC-3 protein expression was detected in paraffin-embedded specimens using immunohistochemistry. All related clinical data were obtained from the China Liver Transplant Registry. The relationship between GPC-3 expression and clinicopathological parameters was analyzed. Univariate and multivariate Cox-regression analyses were used to identify risk factors for poor prognosis. RESULTS: GPC-3 was expressed in samples from 74 (71.2%) of the 104 patients. GPC-3 was expressed only in HCC cells. Positive staining was correlated with tumor size (P=0.004), encapsulation (P=0.018), pathological stage (P=0.027), portal vein invasion (P=0.043), tumor differentiation (P=0.002) and the Milan criteria (P=0.016). The 5-year survival rate and disease-free survival rate of patients with GPC-3-positive were lower than those (38.2% vs 75.4%, P<0.001; 30.8% vs 69.7%, P=0.001) of patients with GPC-3-negative. Multivariate Cox-regression analysis revealed that GPC-3 was an independent risk factor for 5-year survival rate (P=0.031) and disease-free survival rate (P=0.047), together with tumor differentiation, Milan criteria and pre-operative alpha-fetoprotein. CONCLUSION: GPC-3 is a potential biomarker for poor prognosis after LT in HCC patients with HBV-associated cirrhosis.
Asunto(s)
Carcinoma Hepatocelular/química , Carcinoma Hepatocelular/patología , Glipicanos/análisis , Neoplasias Hepáticas/química , Neoplasias Hepáticas/patología , Adulto , Carcinoma Hepatocelular/cirugía , Carcinoma Hepatocelular/virología , Técnicas de Apoyo para la Decisión , Supervivencia sin Enfermedad , Complejo IV de Transporte de Electrones , Femenino , Hepatitis B Crónica/complicaciones , Humanos , Neoplasias Hepáticas/cirugía , Neoplasias Hepáticas/virología , Trasplante de Hígado , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Pronóstico , Estudios Retrospectivos , Factores de Riesgo , Tasa de Supervivencia , alfa-Fetoproteínas/metabolismoRESUMEN
BACKGROUND/AIMS: To confirm the relationship between hepatitis B recurrence and Hepatocellular carcinoma recurrence. METHODOLOGY: Data from 340 patients undergoing liver transplantation for HBV-related liver disease were retrospectively evaluated. Clinically relevant variables were analyzed using univariate models. Significant variables were subjected to multivariate logistic regression analysis to identify the independent predictors for HBV recurrence. Fifteen samples removed from HCC recurrence patients were stained for HBsAg and HBcAg. RESULTS: The analyzed population included 283 male and 57 female patients. The mean age was 48.5±9.33 years and median follow-up was 47 months. Hepatitis B relapsed in 16 patients (4.7%). Univariate analysis indicated that HCC (P=0.022) and HCC recurrence (P=0.000) were associated to post transplantation HB. Multivariate analysis identified HCC recurrence as an independent risk factor for HB recurrence (hazard ratio: 23.262 (95% CI: 3.752, 144.216); P <0.001). Three of 15 metastatic lesions were positive for HBsAg and 1 lesion was positive for HBcAg. Conclusion: HCC recurrence is an independent risk factor for post transplantation recurrence of hepatitis.
Asunto(s)
Carcinoma Hepatocelular/cirugía , Virus de la Hepatitis B/patogenicidad , Hepatitis B/complicaciones , Neoplasias Hepáticas/cirugía , Trasplante de Hígado/efectos adversos , Recurrencia Local de Neoplasia , Activación Viral , Adolescente , Adulto , Anciano , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/virología , Femenino , Hepatitis B/diagnóstico , Antígenos del Núcleo de la Hepatitis B/análisis , Antígenos de Superficie de la Hepatitis B/análisis , Virus de la Hepatitis B/inmunología , Humanos , Inmunohistoquímica , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/virología , Modelos Logísticos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Estudios Retrospectivos , Factores de Riesgo , Factores de Tiempo , Resultado del Tratamiento , Adulto JovenAsunto(s)
Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Anilidas/uso terapéutico , Carcinoma Hepatocelular/mortalidad , Carcinoma Hepatocelular/patología , Ensayos Clínicos Fase III como Asunto , Femenino , Humanos , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/patología , Masculino , Compuestos de Fenilurea/uso terapéutico , Pronóstico , Piridinas/uso terapéutico , Quinolinas/uso terapéutico , Medición de Riesgo , Sorafenib/uso terapéutico , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
Background: The incidence of intrahepatic cholangiocarcinoma (ICC) is increasing globally, and its prognosis has not improved substantially in recent years. Understanding the pathogenesis of ICC may provide a theoretical basis for its treatment. In this study, we investigated the effects and underlying mechanisms of fucosyltransferase 5 (FUT5) on the malignant progression of ICC. Methods: FUT5 expression in ICC samples and adjacent nontumor tissues was compared using quantitative real-time polymerase chain reaction and immunohistochemical assays. We performed cell counting kit-8, colony formation, and migration assays to determine whether FUT5 influenced the proliferation and mobility of ICC cells. Finally, mass spectrometry was performed to identify the glycoproteins regulated by FUT5. Results: FUT5 mRNA was significantly upregulated in most ICC samples compared with corresponding adjacent nontumor tissues. The ectopic expression of FUT5 promoted the proliferation and migration of ICC cells, whereas FUT5 knockdown significantly suppressed these cellular properties. Mechanistically, we demonstrated that FUT5 is essential for the synthesis and glycosylation of several proteins, including versican, ß3 integrin, and cystatin 7, which may serve key roles in the precancer effects of FUT5. Conclusions: FUT5 is upregulated in ICC and promotes ICC development by promoting glycosylation of several proteins. Therefore, FUT5 may serve as a therapeutic target for the treatment of ICC.