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Aims/Background The combination of lenvatinib and programmed cell death protein 1 (PD-1) inhibitor has demonstrated significant efficacy in treating unresectable hepatocellular carcinoma. Our study aimed to evaluate the safety and efficacy of triple therapy that includes hepatic arterial infusion chemotherapy, lenvatinib and PD-1 inhibitor for treating unresectable hepatocellular carcinoma. Methods Patients with a primary diagnosis of advanced hepatocellular carcinoma between June 2020 and August 2023 were included in this study. Initially, 53 patients with hepatocellular carcinoma were enrolled. Then, 13 patients were excluded based on the inclusion criteria, resulting in 40 patients included for analysis. Among them, 31 patients received triple therapy, including 16 Barcelona Clinic Liver Cancer C stage, 12 Barcelona Clinic Liver Cancer-B, and 3 Barcelona Clinic Liver Cancer-A hepatocellular carcinoma patients. The primary endpoint was the objective response rate, while the secondary endpoints included the conversion resection rate, pathological complete response rate, pathological partial response rate, and treatment-related adverse events. Results The objective response rate was 80.65% at a median follow-up of 24.5 months (range: 12.6-55.8 months). Of the 14 patients (45.2%) who underwent conversion therapy and were eligible for surgery, 7 patients underwent liver resection and the remaining 7 patients underwent liver transplantation. The median interval between the start of triple therapy and surgery was 117 days, ranging from 25 to 215 days. The pathological complete response was observed in six patients (19.4%) and the pathological partial response rate in eight patients (25.8%). All adverse events occurred in 77.4% of the patients. Conclusion In patients with unresectable hepatocellular carcinoma, the combination of hepatic arterial infusion chemotherapy, lenvatinib, and PD-1 inhibitor exhibits favourable efficacy and well tolerability, achieving a desirable pathological complete response rate while maintaining manageable drug toxicity.
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Carcinoma Hepatocelular , Infusiones Intraarteriales , Neoplasias Hepáticas , Compuestos de Fenilurea , Quinolinas , Humanos , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/patología , Compuestos de Fenilurea/uso terapéutico , Compuestos de Fenilurea/administración & dosificación , Quinolinas/uso terapéutico , Quinolinas/administración & dosificación , Masculino , Femenino , Persona de Mediana Edad , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Adulto , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/administración & dosificación , Resultado del Tratamiento , Arteria HepáticaRESUMEN
BACKGROUND AND AIMS: Lymph node metastasis is a significant risk factor for patients with cholangiocarcinoma, but the mechanisms underlying cholangiocarcinoma colonization in the lymph node microenvironment remain unclear. We aimed to determine whether metabolic reprogramming fueled the adaptation and remodeling of cholangiocarcinoma cells to the lymph node microenvironment. APPROACH AND RESULTS: Here, we applied single-cell RNA sequencing of primary tumor lesions and paired lymph node metastases from patients with cholangiocarcinoma and revealed significantly reduced intertumor heterogeneity and syntropic lipid metabolic reprogramming of cholangiocarcinoma after metastasis to lymph nodes, which was verified by pan-cancer single-cell RNA sequencing analysis, highlighting the essential role of lipid metabolism in tumor colonization in lymph nodes. Metabolomics and in vivo CRISPR/Cas9 screening identified PPARγ as a crucial regulator in fueling cholangiocarcinoma colonization in lymph nodes through the oleic acid-PPARγ-fatty acid-binding protein 4 positive feedback loop by upregulating fatty acid uptake and oxidation. Patient-derived organoids and animal models have demonstrated that blocking this loop impairs cholangiocarcinoma proliferation and colonization in the lymph node microenvironment and is superior to systemic inhibition of fatty acid oxidation. PPARγ-regulated fatty acid metabolic reprogramming in cholangiocarcinoma also contributes to the immune-suppressive niche in lymph node metastases by producing kynurenine and was found to be associated with tumor relapse, immune-suppressive lymph node microenvironment, and poor immune checkpoint blockade response. CONCLUSIONS: Our results reveal the role of the oleic acid-PPARγ-fatty acid-binding protein 4 loop in fueling cholangiocarcinoma colonization in lymph nodes and demonstrate that PPARγ-regulated lipid metabolic reprogramming is a promising therapeutic target for relieving cholangiocarcinoma lymph node metastasis burden and reducing further progression.
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Neoplasias de los Conductos Biliares , Colangiocarcinoma , Proteínas de Unión a Ácidos Grasos , Metástasis Linfática , Ácido Oléico , PPAR gamma , Microambiente Tumoral , Colangiocarcinoma/patología , Colangiocarcinoma/metabolismo , PPAR gamma/metabolismo , Humanos , Neoplasias de los Conductos Biliares/patología , Neoplasias de los Conductos Biliares/metabolismo , Animales , Proteínas de Unión a Ácidos Grasos/metabolismo , Ratones , Ganglios Linfáticos/patología , Metabolismo de los LípidosRESUMEN
Perihilar cholangiocarcinoma is a refractory malignancy with an unfavorable prognosis and a high probability of recurrence. Systemic chemotherapy is critical for palliative treatment, but effective therapeutic strategies for perihilar cholangiocarcinoma after first-line chemotherapy failure are scarce. Here, we introduced a sustained benefit following sintilimab combined with lenvatinib plus S-1 in a patient with recurrent perihilar cholangiocarcinoma. A 52-year-old female patient was admitted to our hospital due to yellow skin and sclera, and further radiological examination revealed perihilar cholangiocarcinoma. The patient underwent surgery and histopathological results confirmed moderately differentiated adenocarcinoma with metastatic lymph nodes. Postoperative adjuvant chemotherapy with gemcitabine and S-1 was given. One year after surgery, the patient experienced hepatic recurrence. Then, she received radiofrequency ablation combined with gemcitabine and cisplatin. Unfortunately, radiological assessment revealed progressive disease with multiple liver metastases after treatment. Subsequently, she received sintilimab combined with lenvatinib plus S-1 and the lesions were completely regressed following 14 cycles of combination therapy. The patient recovered well without disease recurrence at the last follow-up. Sintilimab combined with lenvatinib plus S-1 may be an alternative therapeutic option for chemotherapy-refractory perihilar cholangiocarcinoma, and further evaluation in a larger number of patients is needed.
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Neoplasias de los Conductos Biliares , Colangiocarcinoma , Tumor de Klatskin , Femenino , Humanos , Persona de Mediana Edad , Tumor de Klatskin/tratamiento farmacológico , Tumor de Klatskin/patología , Tumor de Klatskin/cirugía , Gemcitabina , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Colangiocarcinoma/tratamiento farmacológico , Colangiocarcinoma/patología , Respuesta Patológica Completa , Conductos Biliares Intrahepáticos/patología , Conductos Biliares Intrahepáticos/cirugía , Neoplasias de los Conductos Biliares/tratamiento farmacológico , Neoplasias de los Conductos Biliares/cirugía , Neoplasias de los Conductos Biliares/patologíaRESUMEN
Patients with cholangiocarcinoma (CCA) with lymph node metastasis (LNM) have the worst prognosis, even after complete resection; however, the underlying mechanism remains unclear. Here, we established CAF-derived PDGF-BB as a regulator of LMN in CCA. Proteomics analysis revealed upregulation of PDGF-BB in CAFs derived from patients with CCA with LMN (LN+CAFs). Clinically, the expression of CAF-PDGF-BB correlated with poor prognosis and increased LMN in patients with CCA, while CAF-secreted PDGF-BB enhanced lymphatic endothelial cell (LEC)-mediated lymphangiogenesis and promoted the trans-LEC migration ability of tumor cells. Co-injection of LN+CAFs and cancer cells increased tumor growth and LMN in vivo. Mechanistically, CAF-derived PDGF-BB activated its receptor PDGFR-ß and its downstream ERK1/2-JNK signaling pathways in LECs to promote lymphoangiogenesis, while it also upregulated the PDGFR-ß-GSK-P65-mediated tumor cell migration. Finally, targeting PDGF-BB/PDGFR-ß or the GSK-P65 signaling axis prohibited CAF-mediated popliteal lymphatic metastasis (PLM) in vivo. Overall, our findings revealed that CAFs promote tumor growth and LMN via a paracrine network, identifying a promising therapeutic target for patients with advanced CCA.
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Neoplasias de los Conductos Biliares , Fibroblastos Asociados al Cáncer , Colangiocarcinoma , Humanos , Becaplermina , Metástasis Linfática , Fibroblastos Asociados al Cáncer/metabolismo , Comunicación Paracrina , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/genética , Colangiocarcinoma/metabolismo , Conductos Biliares Intrahepáticos/metabolismo , Neoplasias de los Conductos Biliares/metabolismoRESUMEN
BACKGROUND: This study aimed to assess whether postoperative adjuvant chemoimmunotherapy could lead to better clinical outcomes for high-risk patients with perihilar cholangiocarcinoma (pCCA). METHODS: In the cohort study, we retrospectively reviewed patients who received surgical resection for pCCA with curative intent from January 2018 to December 2021 at the Sun Yat-sen Memorial Hospital. The patients at high risk for relapse were further analyzed. Among them, 20 patients received adjuvant chemoimmunotherapy, 28 patients received adjuvant chemotherapy, and 33 patients received surgery alone. The oncological outcomes and drug-associated adverse events were evaluated. RESULTS: The 2-year overall survival (OS) rates in patients treated with adjuvant chemoimmunotherapy, adjuvant chemotherapy, and surgery alone were 80.0%, 49.4% and 22.6%, respectively. Univariable and multivariable Cox analyses showed that the treatment regimen and TNM stage were associated with adverse OS. Adjuvant chemoimmunotherapy led to an increase in OS compared with adjuvant chemotherapy [hazard ratio (HR) = 3.253; 95% confidence interval (CI) 1.072-9.870; P = 0.037] or surgery alone (HR = 7.560; 95% CI 2.508-22.785; P < 0.001). The median recurrence-free survival was 22.0 months for the adjuvant chemoimmunotherapy group, 17.0 months for the adjuvant chemotherapy group, and 13.2 months for the surgery alone group (P = 0.177); these differences were not significant. The chemoimmunotherapy group was associated with more frequent hematological side effects than the chemotherapy group, but the difference was not statistically significant. CONCLUSION: Postoperative adjuvant chemoimmunotherapy for resected pCCA patients showed improved OS compared with adjuvant chemotherapy or surgery alone, and further prospectively randomized controlled trials are necessary to validate these results.
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Neoplasias de los Conductos Biliares , Colangiocarcinoma , Tumor de Klatskin , Humanos , Adyuvantes Inmunológicos , Neoplasias de los Conductos Biliares/cirugía , Quimioterapia Adyuvante/métodos , Estudios de Cohortes , Tumor de Klatskin/cirugía , Recurrencia Local de Neoplasia , Estudios RetrospectivosRESUMEN
The cellular origin of hepatocellular carcinomas (HCC) and the role of Notch1 signalling in HCC initiation are controversial. Herein, we establish Notch1 as a regulator of HCC development and progression. Clinically, high Notch1 expression correlates with enhanced cancer progression, elevated lung metastasis, increased cancer stem cell (CSC)-like cells' gene signature expression, and poor overall survival in HCC patients. Notch1 intracellular domain (N1ICD) overexpression spontaneously transforms rat liver progenitor cells (LPC) into CSC-like cells (WBN1ICD C5) under a selective growth environment, while orthotopic injection of these cells generates liver tumors and spontaneous pulmonary metastasis in an isogenic rat model. Mechanistically, the elevated Notch1 activity increases c-myc expression, which then transcriptionally upregulates VCAM1 expression to activate macrophage dependent HCC transendothelial migration. In vivo, silencing c-myc prohibits the tumorigenicity of WBN1ICD C5 cells, while depletion of VCAM1 reduces spontaneous lung metastasis without affecting primary WBN1ICD C5 orthotopic liver tumor growth. Importantly, depletion of macrophage or blockade of macrophage VCAM1 binding receptor α4ß1-integrin reduces the number of WBN1ICD C5 lung nodules in an experimental metastasis model. Overall, our work discovers that the Notch1-c-myc-VCAM1 signaling axis initiates LPC-driven hepatocarcinogenesis and metastasis, providing a preclinical model for HCC study and therapeutic targets for an improved HCC treatment.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Neoplasias Pulmonares , Animales , Carcinogénesis/genética , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Humanos , Neoplasias Hepáticas/patología , Neoplasias Pulmonares/genética , Ratas , Receptor Notch1/metabolismo , Células Madre/metabolismoRESUMEN
IgG4-related autoimmune cholangitis (IgG4-AIC) is often difficult to distinguish from cholangiocarcinoma (CCA). This study aimed to determine a practical clinical strategy for distinguishing between IgG4-AIC and CCA to avoid unnecessary surgical resection. We retrospectively collected and compared the clinicopathological data between IgG4-AIC and CCA patients, including the clinical, serological, and radiological characteristics, to follow up on these patients to investigate the prognosis. Among the 377 patients who received surgical resection for suspecting CCA at the Sun Yat-Sen Memorial Hospital between June 2004 and June 2014, 14 patients were diagnosed as IgG4-AIC through histochemistry after surgery. Immunohistochemistry revealed that IgG4 was up-regulated in the plasma cells of IgG4-AIC tissues in 13 out of 14 patients. The serum CA19-9 level was significantly lower than in the CCA group. Patients with IgG4-AIC can only see slight or no enhancement under the contrast enhancement CT scan, while there are no signs of ring-like or delayed enhancement that is unique to CCA. Thirteen patients were followed up, and the time was 12 to 92 months. Three of them were regularly treated with prednisone after surgery, and original symptoms disappeared. Our study demonstrated that the combination of imaging with serum CA19-9 could improve the preoperative diagnostic value and reduce the rate of unnecessary resection.
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In recent years, the deoxycytidine analogue gemcitabine (2',2',-difluorodeoxycytidine) has become the first-line chemotherapeutic agent for patients with pancreatic cancer. However, due to the intrinsic resistance of pancreatic cancer cells, gemcitabine-based chemotherapy yields limited disease control, with >85% disease progression at 6 months from diagnosis. Therefore, elucidating the mechanisms of chemoresistance is a critical step in improving cancer therapy, especially for the treatment of pancreatic cancer. We show PROM2, a transmembrane glycoprotein, is ubiquitously upregulated in pancreatic cancer cell. We also found higher PROM2 expression is associated with shortened overall and disease-free survival times in patients diagnosed with pancreatic cancer. We provide evidence that PROM2 promotes chemoresistance to gemcitabine both in vivo and in vitro. Mechanistically, we demonstrate that PROM2 could directly interacted with Akt and activates the Akt signaling pathway, which thus inhibiting gemcitabine-induced apoptosis. As further evidence, we show PROM2 expression and Akt phosphorylation both promote gemcitabine chemoresistance, and cause poorer survival in clinical samples with pancreatic cancer. Combining gemcitabine with the Akt inhibitor MK-2206 facilitated significant tumor shrinkage and dramatically elevated the survival status in mice xenografted with pancreatic cancer cells. Our findings not only establish PROM2 as a novel positive regulator of the Akt signaling pathway and a candidate prognostic indicator of gemcitabine response, but also provide a neo-therapeutic approach for patients resistant to gemcitabine treatment.
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Desoxicitidina/análogos & derivados , Resistencia a Antineoplásicos/genética , Glicoproteínas de Membrana/metabolismo , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/genética , Proteínas Proto-Oncogénicas c-akt/genética , Transducción de Señal/genética , Animales , Apoptosis/genética , Línea Celular Tumoral , Desoxicitidina/farmacología , Supervivencia sin Enfermedad , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Transducción de Señal/efectos de los fármacos , Regulación hacia Arriba/genética , Ensayos Antitumor por Modelo de Xenoinjerto/métodos , GemcitabinaRESUMEN
Dysregulation of dickkopf-related protein 1 (DKK1) expression has been reported in a variety of human cancers. We previously reported that DKK1 was upregulated in hepatocellular carcinoma (HCC). However, the role of DKK1 in HCC remains unclear. This study aimed to investigate the clinical significance and biological functions of DKK1 in HCC. The expression of DKK1 was examined in cirrhotic and HCC tissues by immunohistochemistry and quantitative real-time polymerase chain reaction (qRT-PCR). DKK1 was silenced or overexpressed in HCC cell lines, and in vitro and in vivo studies were performed. Immunohistochemistry revealed that DKK1 was weakly expressed in cirrhotic tissues (8/22, 36.4%) but upregulated in HCC tissues (48/53, 90.6%, cohort 1). Significant upregulation of DKK1 was observed in 57.6% (19/33, cohort 2) of HCC tissues by qRT-PCR, and the expression of DKK1 was associated with tumor size (P = 0.024) and tumor number (P = 0.019). Genetic depletion of DKK1 impaired the proliferation, colony-forming ability, invasion, and tumor formation of HCC cells (HepG2 and HUH-7). Conversely, forced expression of DKK1 increased the proliferation, colony-forming ability, and invasion of HepG2 and HUH-7 cells in vitro and enhanced tumor formation in vivo. Subsequent investigation revealed that the DKK1-mediated proliferation and tumorigenicity of HepG2 and HUH-7 cells is dependent on the Wnt/ß-catenin signaling pathway. These findings indicate that DKK1 plays an oncogenic role in HCC by activating the Wnt/ß-catenin signaling pathway.
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Pigment epithelium-derived factor (PEDF), a classic angiogenic inhibitor, has been reported to function as a tumor suppression protein and to downregulate in many types of solid tumors. However, the expression level of PEDF and its role in hepatocellular carcinoma (HCC) are contradictory. The present study investigates the expression and different activities of secreted and intracellular PEDF during HCC development, as well as the underlying mechanism of PEDF on HCC lipid disorders. We found that PEDF had no association with patients' prognosis, although PEDF was highly expressed and inhibited angiogenesis in HCC tumor tissues. The animal experiments indicated that full-length PEDF exhibited equalizing effects on tumor growth activation and tumor angiogenesis inhibition in the late stage of HCC progression. Importantly, the pro-tumor activity was mediated by the intracellular PEDF, which causes accumulation of free fatty acids (FFAs) in vivo and in vitro. Based on the correlation analysis of PEDF and lipid metabolic indexes in human HCC tissues, we demonstrated that the intracellular PEDF led to the accumulation of FFA and eventually promoted HCC cell growth by inhibiting the activation of AMPK via ubiquitin-proteasome-mediated degradation, which causes increased de novo fatty acid synthesis and decreased FFA oxidation. Our findings revealed why elevated PEDF did not improve the patients' prognosis as the offsetting intracellular and extracellular activities. This study will lead to a comprehensive understanding of the diverse role of PEDF in HCC and provide a new selective strategy by supplement of extracellular PEDF and downregulation of intracellular PEDF for the prevention and treatment of liver cancer.
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Carcinoma Hepatocelular/metabolismo , Espacio Extracelular/metabolismo , Proteínas del Ojo/metabolismo , Espacio Intracelular/metabolismo , Neoplasias Hepáticas/metabolismo , Factores de Crecimiento Nervioso/metabolismo , Serpinas/metabolismo , Adenilato Quinasa/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Animales , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Proliferación Celular/genética , Proteínas del Ojo/genética , Ácidos Grasos/metabolismo , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Metabolismo de los Lípidos/genética , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Masculino , Ratones Endogámicos BALB C , Ratones Desnudos , Persona de Mediana Edad , Modelos Biológicos , Estadificación de Neoplasias , Factores de Crecimiento Nervioso/genética , Pronóstico , Complejo de la Endopetidasa Proteasomal/metabolismo , Proteolisis , Serpinas/genética , Ubiquitina/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Dickkopf-1 (DKK1) is involved in tumorigenesis and the invasion of several tumors. However, its biological function in human hilar cholangiocarcinoma (HCCA) has not yet been documented. This study was designed to investigate the clinical significance and biological function of DKK1 in HCCA. The expression of DKK1 was investigated in thirty-seven human HCCA biopsy samples by immunohistochemistry. To further explore the biological effects of DKK1 in HCCA, transient and stable knockdown of DKK1 in two human HCCA cells (QBC939 and FRH0201) were established using small interfering or short hairpin RNA expression vector. In the present study, immunohistochemistry revealed that DKK1 was up-regulated in human HCCA tissues (24/37, 64.9%). High levels of DKK1 in human HCCA correlated with metastasis to the hilar lymph nodes (P=0.038). Genetic depletion of DKK1 in HCCA cells resulted in significantly inhibited proliferation, colony formation and migration compared with controls. Most importantly, DKK1 down-regulation impaired tumor formation capacity of HCCA cells in vivo. Subsequent investigations revealed that ß-catenin is an important target of DKK1 and DKK1 exerts its pro-invasion function at least in part through the ß-catenin/ matrix metalloproteinase-7 (MMP-7) signaling pathway. Consistently, in human HCCA tissues, DKK1 level was positively correlated with ß-catenin and MMP-7 expression, as well as tumor hilar lymphatic metastasis. Taken together, our findings indicate that DKK1 may be a crucial regulator in the tumorigenicity and invasion of human HCCA, DKK1 exerts its pro-invasion function at least in part through the ß-catenin/ MMP-7 signaling pathway, suggesting DKK1 as a potential therapeutic target for HCCA.
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Neoplasias de los Conductos Biliares/etiología , Colangiocarcinoma/etiología , Péptidos y Proteínas de Señalización Intercelular/fisiología , Neoplasias de los Conductos Biliares/patología , Línea Celular Tumoral , Proliferación Celular , Colangiocarcinoma/patología , Femenino , Humanos , Metástasis Linfática , Masculino , Metaloproteinasa 7 de la Matriz/fisiología , Transducción de Señal/fisiología , beta Catenina/análisis , beta Catenina/fisiologíaRESUMEN
This study aims to investigate the biological function of microRNA-200b and BMI1, predicted target of microRNA-200b in human hepatocellular carcinoma (HCC). MicroRNA-200b and BMI1 expression in HCC tissues were evaluated by qPCR. A luciferase reporter assay was used to validate BMI1 as a direct target of microRNA-200b. The effect of microRNA-200b on HCC progression was studied in vitro and in vivo. Methylation specific PCR (MSP) and bisulfite sequencing PCR (BSP) were used to detect the methylation status of the microRNA-200b promoter. Significant downregulation of microRNA-200b was observed in 83.3% of HCC tissues. By contrast, BMI1 was significantly overexpressed in 66.7% of HCC tissues. The results of the luciferase assay confirmed BMI1 as a direct target gene of microRNA-200b. Forced expression of microRNA-200b in HCC cells dramatically repressed proliferation, colony formation, cell cycle progression, and invasion. Moreover, microRNA-200b synergized with 5-fluorouracil to induce apoptosis in vitro and suppressed tumorigenicity in vivo. In addition, MSP analysis and BSP revealed that CpG sites in the promoter region of microRNA-200b were extensively methylated in HCC, with concomitant downregulation of microRNA-200b expression. Furthermore, microRNA-200b was activated in HCC cells after treatment with 5-azacytidine, whereas BMI1 expression was clearly downregulated. Our results indicate that microRNA-200b is partially silenced by DNA hypermethylation and that it can repress tumor progression by directly targeting BMI1 in HCC.
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Carcinoma Hepatocelular/genética , Metilación de ADN , Neoplasias Hepáticas/genética , MicroARNs/metabolismo , Complejo Represivo Polycomb 1/genética , Animales , Apoptosis/fisiología , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Progresión de la Enfermedad , Células Hep G2 , Xenoinjertos , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Ratones , Ratones Desnudos , MicroARNs/genética , Complejo Represivo Polycomb 1/metabolismo , Regiones Promotoras Genéticas , TransfecciónRESUMEN
Autoimmune pancreatitis (AIP) is a rare type of chronic pancreatitis that is often misdiagnosed as pancreatic cancer (PaC). This study was undertaken to investigate the clinicopathological characteristics of AIP, in order to improve the diagnosis and treatment of the disease. Among the 271 patients with PaC who underwent pancreatoduodenectomy between January 2003 and December 2012 at the Sun Yat-Sen Memorial Hospital, chronic pancreatitis was identified and tissue samples obtained from 16 patients. The clinicopathological and imaging characteristics of 16 of the patients with chronic pancreatitis were analyzed retrospectively. The expression of immunoglobulin G4 (IgG4) in the pancreas tissue was detected by immunohistochemistry. Immunohistochemistry showed that IgG4 was highly expressed in 12 out of the 16 patients, and those 12 patients were diagnosed with AIP. Among those 12 patients, 6 presented with emaciation and 7 with jaundice and abdominal pain, respectively. Among the 16 included patients, 12 had an elevated level of serum γ-glutamyltransferase and 9 had an elevated level of serum carbohydrate antigen 19-9. The imaging features were as follows: Pancreatic enlargement in 11 patients (particularly pancreatic head enlargement), pancreatic miniature in 1, 'sausage-like' pancreatic changes in 4 and 'halo' sign pancreatic changes in 5. Massive plasma cell infiltration (11/12) and parenchymal fibrosis (8/12) were observed in the pancreatic tissues through pathology. These results suggest that combining imaging with IgG4 expression for the purpose of diagnosis can enhance the preoperative diagnostic value and reduce the rate of AIP misdiagnosis.
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Notch signaling has been reported to be activated to promote biliary epithelial cell differentiation and tubulogenesis during bile duct development. In this study, clinicopathological significance of aberrant expression of Notch receptors in intrahepatic cholangiocarcinoma (ICC) was investigated. Thus, forty-one ICC specimens were examined by immunohistochemistry using anti-Notch1-4 antibodies, respectively. Expression of Notch receptors was scored by percentage of positive tumor cells and intensity of immunostaining. Clinicopathological parameters and survival data were compared with the expression of Notch receptors, respectively. Expression of Notch receptors was identified in cancer cells, as well as in non-neoplastic cells. Compared with adjacent non-tumor liver tissues, Notch1 and 4 were up regulated, and Notch2 and 3 were relatively weaker. Positive immunostaining of Notch1 in ICC cells was detected in 34 cases (82.9%), Notch2 in 23 (56.1%), Notch3 in 16 (39.0%) and Notch4 in 14 (34.1%). Notch1 was overexpressed in cases with tumor size > 5 cm (P = 0.036). Expression of Notch2 was correlated inversely with histological grade (P = 0.016). Overexpression of Notch4 was more common in cases with serum CA125 > 35 U/ml than cases with CA125 ≤ 35 U/ml (P = 0.048). Expression of Notch3 was not correlated with any other clinicopathological parameters. Moreover, Notch4 was related to poor survival (P < 0.001). To conclude, this study reveals that aberrant expression of Notch receptors 1 and 4 might play important roles during ICC progression.
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Neoplasias de los Conductos Biliares/patología , Conductos Biliares Intrahepáticos/patología , Biomarcadores de Tumor/análisis , Colangiocarcinoma/patología , Receptores Notch/biosíntesis , Adulto , Anciano , Neoplasias de los Conductos Biliares/metabolismo , Neoplasias de los Conductos Biliares/mortalidad , Conductos Biliares Intrahepáticos/metabolismo , Colangiocarcinoma/metabolismo , Colangiocarcinoma/mortalidad , Femenino , Humanos , Inmunohistoquímica , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Receptores Notch/análisisRESUMEN
The Bmi1 gene has been reported to play important roles in cancer initiation and progression. The aim of this study was to investigate the effects of RNA interference (RNAi)-mediated silencing of Bmi1 gene expression on the proliferation and invasiveness of hepatocellular carcinoma (HCC) cells and on the efficacy of chemotherapy in HCC patients. The Bmi1 gene was silenced by Bmi1-siRNA (small interfering RNA) in the human HCC cell lines HepG2 and Bel-7402, and the gene expression levels were assayed by real-time quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and western blotting. The proliferation and migration of Bmi1-silenced tumor cells and their sensitivity to 5-FU treatment were determined by Cell Counting Kit-8 (CCK-8), transwell assays and 4',6-diamidino-2-phenylindole (DAPI) staining and flow cytometry, respectively. Bmi1-siRNA inhibited the Bmi1 expression at both the mRNA and protein levels in HCC cells. Proliferation and migration of HCC cells treated with Bmi1-siRNA was significantly lower compared to that of the control cells. Moreover, Bmi1 gene silencing increased the percentage of apoptotic cells treated by 5-FU and decreased the IC50 values of 5-FU to a greater extent. Downregulation of the Bmi1 gene by RNAi can inhibit the proliferation and invasivesness of HCC cells and increase their sensitivity to 5-FU treatment.
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Antimetabolitos Antineoplásicos/farmacología , Carcinoma Hepatocelular/tratamiento farmacológico , Fluorouracilo/farmacología , Neoplasias Hepáticas/tratamiento farmacológico , Complejo Represivo Polycomb 1/genética , Interferencia de ARN , Antígenos CD/metabolismo , Apoptosis/efectos de los fármacos , Cadherinas/metabolismo , Carcinoma Hepatocelular/metabolismo , Movimiento Celular , Proliferación Celular , Resistencia a Antineoplásicos , Técnicas de Silenciamiento del Gen , Células Hep G2 , Humanos , Neoplasias Hepáticas/metabolismo , Complejo Represivo Polycomb 1/metabolismo , ARN Interferente Pequeño/genética , Vimentina/metabolismoRESUMEN
BACKGROUND/AIMS: Hepatocellular carcinoma (HCC) with bile duct tumor thrombi (BDTT) is a rare event. The Bmi1 gene has been reported to play important roles in cancer initiation and progression. In this study, the expression of Bmi1 in HCC with BDTT was investigated. METHODOLOGY: The expression of Bmi1 was examined immunohistochemically in HCC patients with BDTT (B+ group), HCC patients with vascular invasion (V+ group) and combined hepatocellular carcinoma and cholangiocarcinoma (C+ group), respectively. Besides, the Bmi1 mRNA level was investigated by real time PCR in the fresh samples obtained from 13 cases in B+ group, 10 cases in V+ group, and 6 cases in C+ group, respectively. RESULTS: Immunohistochemical staining for Bmi1 showed Bmi1 was highly expressed in the B+ group in comparison with the C+ group and the V+ group, respectively. The Bmi1 mRNA level by real time PCR also showed that it was significantly up-regulated in B+ group compared with those of C+ group and V+ group, respectively. However, there was no statistically significant difference in Bmi1 levels between the subjects with vascular invasion and the subjects without vascular invasion. CONCLUSIONS: Bmi1 might play important roles in the development of BDTT in HCC.
Asunto(s)
Conductos Biliares Intrahepáticos/química , Biomarcadores de Tumor/análisis , Carcinoma Hepatocelular/química , Neoplasias Hepáticas/química , Complejo Represivo Polycomb 1/análisis , Neoplasias de los Conductos Biliares/química , Neoplasias de los Conductos Biliares/patología , Conductos Biliares Intrahepáticos/patología , Biopsia , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patología , Colangiocarcinoma/química , Colangiocarcinoma/patología , Femenino , Humanos , Inmunohistoquímica , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Masculino , Persona de Mediana Edad , Mucina-1/análisis , Invasividad Neoplásica , Complejo Represivo Polycomb 1/genética , ARN Mensajero/análisis , Reacción en Cadena en Tiempo Real de la Polimerasa , Estudios Retrospectivos , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Regulación hacia ArribaRESUMEN
BACKGROUND: Combined hepatocellular carcinoma and cholangiocarcinoma (cHCC-CC) is an uncommon subtype of primary hepatic carcinoma, and its prognosis is poor. This study was undertaken to investigate the prognosis and the clinicopathological characteristics of cHCC-CC, including their possible cellular origin. METHODS: Among 852 patients with a primary hepatic carcinoma who underwent hepatectomy from January 1998 to April 2008 at our hospital, cHCC-CC was identified in 14 patients. The clinicopathological characteristics of the 14 patients were analyzed retrospectively. The expression of the liver stem cell markers (c-kit, CD90, CD133 and CK19) in the tumor tissue was detected by immunohistochemistry, and the Kaplan-Meier method was used to evaluate survival. RESULTS: Among the 14 patients, 9 presented with abdominal pain, 3 with anorexia and debilitation, and the remaining two patients were asymptomatic. The mean age was 53.6+/-3.0 (range 38-74) years. Among the included patients, 11 had an elevated serum alpha-fetoprotein level, 13 were infected with hepatitis B virus, 9 had vascular invasion and 1 had lymph node metastasis. The average diameter of the tumors was 9.9+/-1.1 (range 5.0-16.0) cm. The median overall survival time was 7.9+/-1.0 months. In addition, the presence of the liver stem cell markers, c-kit, CD90, CD133 and CK19 was 71.4%, 85.7%, 92.9% and 78.6%, respectively. All four markers were simultaneously expressed in eight cases. CONCLUSIONS: cHCC-CC has aggressive characteristics and the prognosis is extremely dismal. The high expression of liver stem cell markers in the tumor tissue suggests that these tumors may derive from liver stem cells.
Asunto(s)
Neoplasias de los Conductos Biliares/patología , Conductos Biliares Intrahepáticos , Carcinoma Hepatocelular/patología , Colangiocarcinoma/patología , Neoplasias Hepáticas/patología , Estadificación de Neoplasias , Neoplasias Primarias Múltiples , Adulto , Anciano , Neoplasias de los Conductos Biliares/mortalidad , Neoplasias de los Conductos Biliares/terapia , Carcinoma Hepatocelular/mortalidad , Carcinoma Hepatocelular/terapia , China/epidemiología , Colangiocarcinoma/mortalidad , Colangiocarcinoma/terapia , Terapia Combinada , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/terapia , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Tasa de Supervivencia/tendenciasRESUMEN
A hepatic artery aneurysm is an unusual but life-threatening hepatobiliary complication occurring in patients with systemic lupus erythematosus (SLE), and early diagnosis and treatment of this complication are essential. A 31-year-old man with SLE presented with recurring epigastric pain and jaundice for 2 months; he was diagnosed with choledocholithiasis and underwent surgery. Hemobilia was found intraoperatively, and two hepatic artery aneurysms were identified in the left lateral lobe during postoperative arteriography. Major hemobilia occurred 6 days after the operation, and the patient was immediately treated with selective embolization of the hepatic artery. However, the major hemobilia recurred 2 days later, and he was treated with a left lateral lobectomy and ligation of the proximal hepatic artery. The patient recovered uneventfully and is in good condition. A histological analysis revealed small- and medium-sized arteritis as well as hepatic artery aneurysm. Systemic lupus erythematosus complicated by a hepatic artery aneurysm should be considered in the differential diagnosis of patients showing symptoms of abdominal pain, jaundice, or gastrointestinal bleeding.
Asunto(s)
Aneurisma/diagnóstico , Aneurisma/terapia , Hemobilia/cirugía , Hepatectomía/métodos , Arteria Hepática , Lupus Eritematoso Sistémico/complicaciones , Adulto , Biopsia con Aguja , Colangiopancreatografia Retrógrada Endoscópica/métodos , Embolización Terapéutica/efectos adversos , Embolización Terapéutica/métodos , Estudios de Seguimiento , Hemobilia/etiología , Humanos , Inmunohistoquímica , Hepatopatías/diagnóstico , Hepatopatías/cirugía , Lupus Eritematoso Sistémico/diagnóstico , Imagen por Resonancia Magnética/métodos , Masculino , Medición de Riesgo , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
BACKGROUND: Hepatocellular carcinoma (HCC) with bile duct tumor thrombi (BDTT) is a rare type of primary liver cancer, and its clinical and pathological characteristics remain to be defined. AIMS: To investigate the clinical and pathological characteristics of HCC with BDTT. METHODS: Among 676 HCC patients who underwent surgical treatment from Dec. 2002 to Dec. 2008 at the author's hospital, HCC with BDTT was identified in 20 patients. The clinical and pathological characteristics of the 20 patients were measured or analyzed retrospectively. The integrity of the involved bile duct was examined macroscopically and microscopically, the expression of liver stem cell markers was investigated by immunohistochemistry, and the Kaplan-Meier method was adopted for evaluating survival. RESULTS: Among the 20 patients, the diameter of the primary tumor was less than 5 cm in 13 patients (range: 0.5-10 cm, mean 4.47±0.68 cm). Most of the primary tumors lacked an intact tumor capsule (15/20, 75%), had simultaneous blood vessel invasion (12/20, 60%), and were poorly differentiated (13/20, 65%). There was no evidence of bile duct wall infiltration by the tumor cells macroscopically or microscopically. The positive rate of the liver stem cell markers c-kit, CD90, CD133, and EpCAM was 90, 90, 85 and 85%, respectively. Postoperative overall survival rates at 1, 2, and 3 years were 73.1, 41.1, and 20.6%, respectively. The log-rank test showed that the overall survival rates were significantly worse for HCC patients with BDTT than for HCC patients without BDTT (P=0.016). CONCLUSIONS: HCC with BDTT has aggressive characteristics and the long-term prognosis is extremely dismal.