Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 189
Filtrar
1.
Hepatobiliary Pancreat Dis Int ; 23(2): 117-122, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38619051

RESUMO

Hepatectomy is still the major curative treatment for patients with liver malignancies. However, it is still a big challenge to remove the tumors in the central posterior area, especially if their location involves the retrohepatic inferior vena cava and hepatic veins. Ex vivo liver resection and auto-transplantation (ELRA), a hybrid technique of the traditional liver resection and transplantation, has brought new hope to these patients and therefore becomes a valid alternative to liver transplantation. Due to its technical difficulty, ELRA is still concentrated in a few hepatobiliary centers that have experienced surgeons in both liver resection and liver transplantation. The efficacy and safety of this technique has already been demonstrated in the treatment of benign liver diseases, especially in the advanced alveolar echinococcosis. Recently, the application of ELRA for liver malignances has gained more attention. However, standardization of clinical practice norms and international consensus are still lacking. The prognostic impact in these oncologic patients also needs further evaluation. In this review, we summarized the principles and recent progresses on ELRA.


Assuntos
Neoplasias Hepáticas , Transplante de Fígado , Humanos , Hepatectomia/efeitos adversos , Neoplasias Hepáticas/cirurgia , Transplante de Fígado/efeitos adversos , Consenso
2.
Hepatobiliary Pancreat Dis Int ; 21(5): 420-429, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35977874

RESUMO

Primary liver cancer, mainly hepatocellular carcinoma (HCC), is the sixth most diagnosed cancer and third leading cause of cancer-related death globally. Recently, immunotherapies such as immune checkpoint inhibitors (ICIs) have made great progress in the systemic treatment of HCC. However, anti-PD-1 therapy with pembrolizumab or nivolumab as a single agent did not meet their predefined end points of overall survival in the KEYNOTE-240 and CheckMate 459 trials. It is urgent to understand the immunological rationale and explore novel ways to improve the efficacy of immunotherapy. The combination of ICIs with other therapies, such as tyrosine kinase inhibitors (TKIs), monoclonal antibodies, or local therapy, has been demonstrated to improve overall response rate and survival. In addition, modulating tumor microenvironment is a potential way to overcome the primary and secondary resistance to immunotherapies. In this review, we summarized the latest findings in the immune microenvironment, the mechanisms of their synergistic effects when combined with anti-VEGF agents or TKIs, as well as other kinds of immune treatment.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Anticorpos Monoclonais/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Fatores Imunológicos/uso terapêutico , Imunoterapia/efeitos adversos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Nivolumabe/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Microambiente Tumoral
3.
Hepatobiliary Pancreat Dis Int ; 21(5): 413-419, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35973935

RESUMO

BACKGROUND: The advent of immune checkpoint inhibitors (ICIs) has revolutionized the therapeutic options of hepatobiliary malignancies. However, the clinical benefit provided by immunotherapy seems limited to a small subgroup of patients with hepatobiliary malignancies. The identification of reliable predictors of the response to immunotherapy is urgently needed. DATA SOURCES: Literature search was conducted in PubMed for relevant articles published up to May 2022. Information of clinical trials was obtained from https://clinicaltrials.gov/. RESULTS: Biomarkers for ICI response of hepatobiliary malignancies remain in the exploration stage and lack compelling evidence. Tumor programmed death-ligand 1 (PD-L1) expression is the most widely studied biomarker in hepatocellular carcinoma (HCC) and biliary tract cancers (BTCs), but there are conflicting results on its predictive potential. Tumor mutational burden (TMB) is generally low both in HCC and BTCs, and the clinical trials of TMB are rare in hepatobiliary malignancies. Promisingly, mismatch repair deficiency (dMMR)/high microsatellite instability (MSI-H) may be a predictive biomarker of response to anti-PD-1 therapy in BTCs. Furthermore, some emerging biomarkers, such as gut microbiota, show predictive potential in the preliminary studies. Radiomics and liquid-biopsy biomarkers, including circulating tumor cells, circulating tumor DNA (ctDNA) and exosomal PD-L1 provide a quick and non-invasive approach for monitoring the ICI response, showing a new promising direction. CONCLUSIONS: Multiple potential biomarkers for predicting ICI response of hepatobiliary malignancies have been explored and tried to apply in clinic. Yet there is no robust evidence to prove their clinical value in predicting immunotherapeutic response for patients with hepatobiliary malignancies. The identification of predictors for response to ICIs is an urgent need and major challenge. Further studies are warranted to validate the role of emerging biomarkers in predicting immunotherapeutic responses.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Antígeno B7-H1 , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Imunoterapia/métodos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética
4.
Int J Cancer ; 148(5): 1233-1244, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33205453

RESUMO

Tumor-associated macrophages (TAMs) are crucial components of the tumor microenvironment. They play vital roles in hepatocellular carcinoma (HCC) progression. However, the interactions between TAMs and HCC cells have not been fully characterized. In this study, TAMs were induced using human monocytic cell line THP-1 cells in vitro to investigate their functions in HCC progression. S100 calcium-binding protein A9 (S100A9), an inflammatory microenvironment-related secreted protein, was identified to be significantly upregulated in TAMs. S100A9 expression in tumor tissues was associated with poor survival of HCC patients. It could enhance the stem cell-like properties of HepG2 and MHCC-97H cells by activating nuclear factor-kappa B signaling pathway through advanced glycosylation end product-specific receptor in a Ca2+ -dependent manner. Furthermore, we found that, after treatment with S100A9, HepG2 and MHCC-97H cells recruited more macrophages via chemokine (CC motif) ligand 2, which suggests a positive feedback between TAMs and HCC cells. Taken together, our findings reveal that TAMs could upregulate secreted protein S100A9 and enhance the stem cell-like properties of HCC cells and provide a potential therapeutic target for combating HCC.


Assuntos
Calgranulina B/fisiologia , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Células-Tronco Neoplásicas/fisiologia , Macrófagos Associados a Tumor/fisiologia , Animais , Linhagem Celular Tumoral , Humanos , Camundongos , Camundongos Endogâmicos BALB C , NF-kappa B/fisiologia , Receptor para Produtos Finais de Glicação Avançada/fisiologia
5.
Liver Transpl ; 27(1): 88-95, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32394500

RESUMO

We assess the safety and feasibility of the left hepatic vein preferential approach (LHVPA) based on left hepatic vein (LHV) anatomy for living donor laparoscopic left lateral sectionectomy (LLLS). Data from 50 donors who underwent LLLS in Huashan Hospital from October 2016 to November 2019 were analyzed retrospectively. On the basis of the classification of the LHV anatomy, the vein was defined as the direct import type, upper branch type, or indirect import type. A subgroup analysis was performed to compare the outcomes between the LHVPA and non-LHVPA groups. All 50 patients underwent pure LLLS. The mean operative duration was 157.5 ± 29.7 minutes. The intraoperative blood loss was 160.4 ± 97.5 mL. No complications more severe than grade 3 occurred. LHVPA was applied in 13 patients, whereas non-LHVPA was applied in 10 patients with the direct import type and upper branch type anatomy. The operative duration was shorter in the LHVPA group than the non-LHVPA group (142.7 ± 22.0 versus 173.0 ± 22.8 minutes; P = 0.01). Intraoperative blood loss was reduced in the LHVPA group compared with the non-LHVPA group (116.2 ± 45.6 versus 170.0 ± 63.3 mL; P = 0.02). The length of the LHV reserved extrahepatically in the LHVPA group was longer than in the non-LHVPA group (4.3 ± 0.2 versus 3.3 ± 0.3 mm; P = 0.01). Fewer reconstructions of the LHV in the direct import type anatomy were required for the LHVPA group than for the non-LHVPA group (0/8 versus 4/6). LHVPA based on the LHV anatomy is recommended in LLLS because it can further increase the safety and the efficiency of surgery for suitable donors.


Assuntos
Laparoscopia , Transplante de Fígado , Hepatectomia/efeitos adversos , Veias Hepáticas/diagnóstico por imagem , Veias Hepáticas/cirurgia , Humanos , Tempo de Internação , Transplante de Fígado/efeitos adversos , Doadores Vivos , Estudos Retrospectivos , Resultado do Tratamento
6.
Int J Cancer ; 146(6): 1754-1763, 2020 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-31456215

RESUMO

To explore whether plasma circular RNAs (circRNAs) can diagnose hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), microarray and qPCR were used to identify plasma circRNAs that were increased in HBV-related HCC patients compared to controls (including healthy controls, chronic hepatitis B and HBV-related liver cirrhosis). A logistic regression model was constructed using a training set (n = 313) and then validated using another two independent sets (n = 306 and 526, respectively). Area under the receiver operating characteristic curve (AUC) was used to evaluate diagnostic accuracy. We identified a plasma circRNA panel (CircPanel) containing three circRNAs (hsa_circ_0000976, hsa_circ_0007750 and hsa_circ_0139897) that could detect HCC. CircPanel showed a higher accuracy than AFP (alpha-fetoprotein) to distinguish individuals with HCC from controls in all three sets (AUC, 0.863 [95% confidence interval, CI: 0.819-0.907] vs. 0.790 [0.738-0.842], p = 0.036 in training set; 0.843 [0.796-0.890] vs. 0.747 [0.691-0.804], p = 0.011 in validation set 1 and 0.864 [0.830-0.898] vs. 0.769 [0.728-0.810], p < 0.001 in validation set 2). CircPanel also performed well in detecting Small-HCC (solitary, ≤3 cm), AFP-negative HCC and AFP-negative Small-HCC.


Assuntos
Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/etiologia , Vírus da Hepatite B , Hepatite B/complicações , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/etiologia , RNA Circular/sangue , Biomarcadores Tumorais , Feminino , Perfilação da Expressão Gênica , Hepatite B/virologia , Humanos , Masculino , Reação em Cadeia da Polimerase , Curva ROC , Reprodutibilidade dos Testes
7.
Br J Cancer ; 122(2): 209-220, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31819189

RESUMO

BACKGROUND: Mitochondrial dynamics plays an important role in tumour progression. However, how these dynamics integrate tumour metabolism in hepatocellular carcinoma (HCC) metastasis is still unclear. METHODS: The mitochondrial fusion protein mitofusin-1 (MFN1) expression and its prognostic value are detected in HCC. The effects and underlying mechanisms of MFN1 on HCC metastasis and metabolic reprogramming are analysed both in vitro and in vivo. RESULTS: Mitochondrial dynamics, represented by constant fission and fusion, are found to be associated with HCC metastasis. High metastatic HCC displays excessive mitochondrial fission. Among genes involved in mitochondrial dynamics, MFN1 is identified as a leading downregulated candidate that is closely associated with HCC metastasis and poor prognosis. While promoting mitochondrial fusion, MFN1 inhibits cell proliferation, invasion and migration capacity both in vitro and in vivo. Mechanistically, disruption of mitochondrial dynamics by depletion of MFN1 triggers the epithelial-to-mesenchymal transition (EMT) of HCC. Moreover, MFN1 modulates HCC metastasis by metabolic shift from aerobic glycolysis to oxidative phosphorylation. Treatment with glycolytic inhibitor 2-Deoxy-D-glucose (2-DG) significantly suppresses the effects induced by depletion of MFN1. CONCLUSIONS: Our results reveal a critical involvement of mitochondrial dynamics in HCC metastasis via modulating glucose metabolic reprogramming. MFN1 may serve as a novel potential therapeutic target for HCC.


Assuntos
Carcinoma Hepatocelular/metabolismo , Desoxiglucose/farmacologia , GTP Fosfo-Hidrolases/genética , Glucose/metabolismo , Neoplasias Hepáticas/metabolismo , Proteínas de Transporte da Membrana Mitocondrial/genética , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Proliferação de Células/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , GTP Fosfo-Hidrolases/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glicólise/efeitos dos fármacos , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Mitocôndrias/genética , Mitocôndrias/metabolismo , Dinâmica Mitocondrial/genética , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Metástase Neoplásica , Fosforilação Oxidativa/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos
8.
Gut ; 68(9): 1653-1666, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-30902885

RESUMO

OBJECTIVE: In the tumour microenvironment, critical drivers of immune escape include the oncogenic activity of the tumour cell-intrinsic osteopontin (OPN), the expression of programmed death ligand 1 (PD-L1) and the expansion of tumour-associated macrophages (TAMs). We investigated the feasibility of targeting these pathways as a therapeutic option in hepatocellular carcinoma (HCC) mouse models. DESIGN: We analysed the number of tumour-infiltrating immune cells and the inflammatory immune profiles in chemically induced liver tumour isolated from wild-type and OPNknockout (KO) mice. In vitro cell cocultures were further conducted to investigate the crosstalk between TAMs and HCC cells mediated by OPN, colony stimulating factor-1 (CSF1) and CSF1 receptor (CSF1R). The in vivo efficacy of anti-PD-L1 and CSF1/CSF1R inhibition was evaluated in OPN overexpressing subcutaneous or orthotopic mouse model of HCC. RESULTS: The numbers of TAMs, as well as the expression levels of M2 macrophage markers and PD-L1 were significantly decreased, but the levels of cytokines produced by T-helper 1 (Th1) cells were upregulated in tumour tissues from OPN KO mice compared with that from the controls. In addition, we observed a positive association between the OPN and PD-L1 expression, and OPN expression and TAM infiltration in tumour tissues from patients with HCC. We further demonstrated that OPN facilitates chemotactic migration, and alternative activation of macrophages, and promotes the PD-L1 expression in HCC via activation of the CSF1-CSF1R pathway in macrophages. Combining anti-PD-L1 and CSF1R inhibition elicited potent antitumour activity and prolonged survival of OPNhigh tumour-bearing mice. Histological, flow cytometric and ELISA revealed increased CD8+ T cell infiltration, reduced TAMs and enhanced Th1/Th2 cytokine balance in multiple mouse models of HCC. CONCLUSIONS: OPN/CSF1/CSF1R axis plays a critical role in the immunosuppressive nature of the HCC microenvironment. Blocking CSF1/CSF1R prevents TAM trafficking and thereby enhances the efficacy of immune checkpoint inhibitors for the treatment of HCC.


Assuntos
Antígeno B7-H1/antagonistas & inibidores , Carcinoma Hepatocelular/imunologia , Neoplasias Hepáticas/imunologia , Fator Estimulador de Colônias de Macrófagos/imunologia , Macrófagos/imunologia , Aminopiridinas/farmacologia , Aminopiridinas/uso terapêutico , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antígeno B7-H1/metabolismo , Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/tratamento farmacológico , Quimiotaxia/imunologia , Citocinas/biossíntese , Deleção de Genes , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Linfócitos do Interstício Tumoral/imunologia , Fator Estimulador de Colônias de Macrófagos/antagonistas & inibidores , Masculino , Camundongos Knockout , Terapia de Alvo Molecular/métodos , Osteopontina/genética , Osteopontina/imunologia , Prognóstico , Pirróis/farmacologia , Pirróis/uso terapêutico , Células Tumorais Cultivadas , Evasão Tumoral/imunologia , Microambiente Tumoral/imunologia
9.
Cell Biol Toxicol ; 35(5): 407-421, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-30680600

RESUMO

The goal of cancer eradication has been overshadowed despite the continuous improvement in research and generation of novel cancer therapeutic drugs. One of the undeniable existing problems is drug resistance due to which the paradigm of killing all cancer cells is ineffective. Tumor microenvironment plays a crucial role in inducing drug resistance besides cancer development and progression. Recently, many efforts have been devoted to understand the role of tumor microenvironment in cancer drug resistance as it provides the shelter, nutrition, and paracrine niche for cancer cells. Cancer-associated fibroblasts (CAFs), one major component of tumor microenvironment, reside in symbiotic relationship with cancer cells, supporting them to survive from cancer drugs. The present review summarizes the recent understandings in the role of CAFs in drug resistance in various tumors. Acknowledging the fact that drug resistance depends not only upon cancer cells but also upon the microenvironment niche could guide us to formulate novel cancer drugs and provide the optimal cancer treatment.


Assuntos
Fibroblastos Associados a Câncer/metabolismo , Resistencia a Medicamentos Antineoplásicos/fisiologia , Microambiente Tumoral/fisiologia , Antineoplásicos , Fibroblastos Associados a Câncer/fisiologia , Progressão da Doença , Fibroblastos/patologia , Humanos
10.
Cancer Sci ; 109(3): 710-723, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29285854

RESUMO

In the hepatocellular carcinoma (HCC) microenvironment, chemokine receptors play a critical role in tumorigenesis and metastasis. Our previous studies have found that osteopontin (OPN) is a promoter for HCC metastasis. However, the role of chemokine receptors in OPN-induced HCC metastasis remains unclear. In this study, we demonstrate that OPN is dramatically elevated in HCC tissues with metastasis and that high expression of OPN correlates with poorer overall survival and higher recurrence rate. OPN upregulates chemokine receptor expression, migration, invasion and pulmonary metastasis in HCC. We find that C-C chemokine receptor type 1 (CCR1) and C-X-C chemokine receptor type 6 (CXCR6) are the most upregulated chemokine receptors induced by OPN. CCR1 knockdown results in reduction of migration, invasion and pulmonary metastasis induced by OPN in vitro and in vivo, whereas CXCR6 knockdown does not reverse OPN-promoted migration and invasion. Moreover, OPN upregulates the expression of CCR1 through activating phosphoinositide 3-kinase (PI3K)/AKT and hypoxia-inducible factor 1α (HIF-1α) in HCC cells. Furthermore, blockade of OPN-CCR1 axis with CCR1 antagonist significantly restrains the promoting effects of OPN on HCC progression and metastasis. In human HCC tissues, OPN expression shows significantly positive correlation with CCR1 expression, and the patients with high levels of both OPN and CCR1 have the most dismal prognosis. Collectively, our results indicate that the OPN-CCR1 axis in HCC is important for accelerating tumor metastasis and that CCR1 is a potential therapeutic target for controlling metastasis in HCC patients with high OPN.


Assuntos
Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Osteopontina/genética , Osteopontina/metabolismo , Receptores CCR1/metabolismo , Regulação para Cima , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Feminino , Regulação Neoplásica da Expressão Gênica , Células Hep G2 , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Masculino , Metástase Neoplásica , Prognóstico , Transdução de Sinais , Análise de Sobrevida
11.
Cell Physiol Biochem ; 47(3): 1152-1166, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29913454

RESUMO

BACKGROUND/AIMS: Effective drug treatment for intrahepatic cholangiocarcinoma (ICC) is currently lacking. Therefore, there is an urgent need for new targets and new drugs that can prolong patient survival. Recently targeting the ubiquitin proteasome pathway has become an attractive anti-cancer strategy. In this study, we aimed to evaluate the therapeutic effect of and identify the potential mechanisms involved in targeting the proteasome subunit ADRM1 for ICC. METHODS: The expression of ADRM1 and its prognostic value in ICC was analyzed using GEO and TCGA datasets, tumor tissues, and tumor tissue arrays. The effects of RA190 on the proliferation and survival of both established ICC cell lines and primary ICC cells were examined in vitro. Annexin V/propidium iodide staining, western blotting and immunohistochemical staining were performed. The in vivo anti-tumor effect of RA190 on ICC was validated in subcutaneous xenograft and patient-derived xenograft (PDX) models. RESULTS: ADRM1 levels were significantly higher in ICC tissues than in normal bile duct tissues. ICC patients with high ADRM1 levels had worse overall survival (hazard ratio [HR] = 2.383, 95% confidence interval [CI] =1.357 to 4.188) and recurrence-free survival (HR = 1.710, 95% CI =1.045 to 2.796). ADRM1 knockdown significantly inhibited ICC growth in vitro and in vivo. The specific inhibitor RA190 targeting ADRM1 suppressed proliferation and reduced cell vitality of ICC cell lines and primary ICC cells significantly in vitro. Furthermore, RA190 significantly inhibited the proteasome by inactivating ADRM1, and the consequent accumulation of ADRM1 substrates decreased the activating levels of NF-κB to aggravate cell apoptosis. The therapeutic benefits of RA190 treatment were further demonstrated in both subcutaneous implantation and PDX models. CONCLUSIONS: Our findings indicate that up-regulated ADRM1 was involved in ICC progression and suggest the potential clinical application of ADRM1 inhibitors (e.g., RA190 and KDT-11) for ICC treatment.


Assuntos
Apoptose/efeitos dos fármacos , Compostos de Benzilideno/farmacologia , Neoplasias dos Ductos Biliares/tratamento farmacológico , Colangiocarcinoma/tratamento farmacológico , Glicoproteínas de Membrana/antagonistas & inibidores , NF-kappa B/metabolismo , Proteínas de Neoplasias , Idoso , Neoplasias dos Ductos Biliares/metabolismo , Neoplasias dos Ductos Biliares/patologia , Linhagem Celular Tumoral , Colangiocarcinoma/metabolismo , Colangiocarcinoma/patologia , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Masculino , Glicoproteínas de Membrana/metabolismo , Pessoa de Meia-Idade , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/metabolismo
12.
Biochim Biophys Acta Mol Basis Dis ; 1864(6 Pt B): 2360-2368, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29408647

RESUMO

BACKGROUND: Primary liver cancer (PLC) is the third largest contributor to cancer mortality in the world. PLC is a heterogeneous disease that encompasses several biologically distinct subtypes including hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (ICC) and combined hepatocellular-cholangiocarcinoma (CHC). CHC is a distinct, albeit rare, subtype of PLC and is comprised of cells with histopathological features of both HCC and ICC. Several studies have focused on the mutation and expression landscapes of HCC and ICC. However, studies of CHC were rare. OBJECTIVE: The aim of the current study was to identify genetic and gene expression alterations in the carcinogenesis and development of CHC and ICC in the Chinese population. Unraveling both similar and differing patterns among these subtypes may help to identify personalized medicine approaches that could improve patient survival. METHODS: Whole genome sequencing (WGS), whole exome sequencing (WES) and RNA-seq were performed on 10 ICC and 10 CHC samples, matched with adjacent non-tumor liver tissue specimens. Comparative analysis was performed using HCC datasets from The Cancer Genome Atlas (TCGA). RESULTS: Mutational and transcriptional landscapes of CHC and ICC were clearly delineated. TP53 and CTNNB1 were identified as exhibiting mutations in CHC. ARID1A, PBRM1, and IDH1 were frequently mutated in ICC. RYR3, FBN2, and KCNN3 are associated with cell migration and metastasis and might be driver genes in CHC. KCNN3 was identified as also exhibiting mutations in ICC. The ECM-receptor interaction pathway associated fibrogenic hepatic progenitor cell differentiation and liver fibrosis may play an important role in carcinogenesis of PLC. Chromatin remodeling and chromosome organization are key processes in carcinogenesis and development in PLC. P53 related pathways showed alterations in CHC and HCC. Inflammation may be a key factor involved in ICC carcinogenesis. CONCLUSION: CHC and ICC are different subtypes of PLC. This study discusses predominantly the molecular genetic details of PLC subtypes and highlights the need for an accurate diagnosis and treatment of specific PLC subtypes to optimize patient management.


Assuntos
Neoplasias dos Ductos Biliares , Carcinoma Hepatocelular , Colangiocarcinoma , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Genoma Humano , Neoplasias Hepáticas , Transcriptoma , Neoplasias dos Ductos Biliares/genética , Neoplasias dos Ductos Biliares/metabolismo , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Colangiocarcinoma/genética , Colangiocarcinoma/metabolismo , Estudo de Associação Genômica Ampla , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo
13.
Hepatology ; 66(6): 1894-1909, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28646551

RESUMO

Angiogenesis has been proven to play an important role in the progression of hepatocellular carcinoma (HCC). However, the molecular mechanism underlying HCC angiogenesis is not well understood. In this study, Prospero-related homeobox 1 (PROX1) was identified as a novel proangiogenic factor in HCC cell lines and tissues. A strong positive correlation was found between the levels of PROX1 and microvessel density in HCC tissues. Knockdown of PROX1 expression in HCC cells significantly inhibited the in vitro capillary tube formation by human vascular endothelial cells and in vivo angiogenesis of HCC, while overexpression of PROX1 in HCC cells induced the opposite effects. PROX1 and nuclear factor κB p65 expression levels were positively correlated in both HCC tissues and cell lines. PROX1 enhances the nuclear accumulation of p65 and stabilizes p65 by recruiting ubiquitin-specific protease 7 to prevent p65 ubiquitination. Consequently, PROX1 activated nuclear factor κB signaling and selectively promoted expression of the proangiogenic interleukin-8 (IL-8) by epigenetically stimulating the IL-8 promoter. Finally, progression of high PROX1 expression HCC in tumor xenograft mice could be effectively contained by an anti-IL-8 monoclonal antibody. CONCLUSIONS: We have identified PROX1 as a crucial promoter of HCC angiogenesis; our study provides an insight into PROX1's function in HCC progression and the potential therapeutic application of anti-IL-8 antibody in high PROX1 expression HCC patients. (Hepatology 2017;66:1894-1909).


Assuntos
Carcinoma Hepatocelular/metabolismo , Proteínas de Homeodomínio/metabolismo , Interleucina-8/metabolismo , Neoplasias Hepáticas/metabolismo , Neovascularização Patológica , Proteínas Supressoras de Tumor/metabolismo , Animais , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Humanos , Interleucina-8/antagonistas & inibidores , Neoplasias Hepáticas Experimentais/tratamento farmacológico , Camundongos , Camundongos Nus , Terapia de Alvo Molecular , Estabilidade Proteica , Distribuição Aleatória , Fator de Transcrição RelA/metabolismo , Ativação Transcricional , Peptidase 7 Específica de Ubiquitina/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Tumour Biol ; 39(6): 1010428317699111, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28618948

RESUMO

BAP1 is an emerging tumor suppressor whose inactivating mutations have been found to play critical roles in tumor development. This study was conducted to elucidate the potential value of BAP1 mutation in guiding prognostic prediction and clinical stratification. We conducted a comprehensive analysis of relevant studies from multiple databases, to determine the impact of BAP1 mutation on the overall survival and disease-free survival of patients in various cancers. A total of 2457 patients from 21 studies were included in the final analysis. Although the pooled results demonstrated that BAP1 mutation was a negative indicator of overall survival (hazard ratio = 1.73; 95% confidence interval = 1.23-2.42) and disease-free survival (hazard ratio = 2.25; 95% confidence interval = 1.47-3.45), this prognostic value was only applicable to uveal melanoma and clear cell renal cell carcinoma, but not to malignant pleural mesothelioma or cholangiocarcinoma. Consistently, BAP1 mutation was correlated with critical clinicopathological features only in uveal melanoma and clear cell renal cell carcinoma. In uveal melanoma, BAP1 mutation and SF3B1/EIF1AX mutations were negatively correlated, and BAP1-mutant tumors indicated significant worse prognosis than SF3B1/EIF1AX-mutant tumors ( p = 0.028). While in clear cell renal cell carcinoma, BAP1 mutation was mutually exclusive with PBRM1 mutations, and BAP1-mutant clear cell renal cell carcinomas also showed significantly worse prognosis than PBRM1-mutant clear cell renal cell carcinomas ( p = 0.001). Our study revealed a unique tissue-specific significance of BAP1 mutation in prognostic prediction among different types of cancer. Clinically, combining detection of BAP1 mutation and other driver mutations may further allow for a more precise molecular taxonomy to stratify patients into distinct subgroups in uveal melanoma and clear cell renal cell carcinoma.


Assuntos
Carcinoma de Células Renais/genética , Melanoma/genética , Prognóstico , Proteínas Supressoras de Tumor/genética , Ubiquitina Tiolesterase/genética , Neoplasias Uveais/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Renais/patologia , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Melanoma/patologia , Pessoa de Meia-Idade , Mutação , Especificidade de Órgãos , Neoplasias Uveais/patologia
16.
Hepatology ; 59(5): 1874-85, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24259426

RESUMO

UNLABELLED: MicroRNA (miR)-26a can suppress tumor growth and metastasis of hepatocellular carcinoma (HCC). Since angiogenesis is important for tumor growth and metastasis, we investigated the possible roles of miR-26a in tumor angiogenesis. Down-regulation of miR-26a was found to correlate with an increased angiogenic potential of HCC. Through gain- and loss-of-function studies, miR-26a was demonstrated to significantly inhibit vascular endothelial growth factor A (VEGFA) expression in HCC cells and then suppress the promoting effects of HCC cells on in vitro proliferation, migration, and capillary tube formation of endothelial cells, as well as in vivo tumor angiogenesis of HCC. Hepatocyte growth factor (HGF) was identified as a target of miR-26a. HGF simulation antagonized the effects induced by miR-26a up-regulation. In contrast, silencing HGF induced similar effects to miR-26a. We further found that miR-26a exerted its antiangiogenesis function, at least in part, by inhibiting HGF-hepatocyte growth factor receptor (cMet) and its downstream signaling pathway, in turn, suppressing VEGFA production in HCC cells and impairing VEGFR2-signaling in endothelial cells. HCC patients who had high miR-26a, low HGF, low VEGFA, or low microvessel density (MVD) in tumor tissues had a better prognosis with longer overall survival (OS) and time to recurrence (TTR). In multivariate analysis, miR-26a, or in combination with HGF, was demonstrated to be an independent prognostic indicator for OS and TTR of HCC patients. CONCLUSION: miR-26a could suppress tumor angiogenesis of HCC through HGF-cMet signaling, and it is a new hopeful therapeutic target and prognostic marker for HCC.


Assuntos
Carcinoma Hepatocelular/irrigação sanguínea , Fator de Crescimento de Hepatócito/genética , Neoplasias Hepáticas/irrigação sanguínea , MicroRNAs/fisiologia , Neovascularização Patológica/prevenção & controle , Proteínas Proto-Oncogênicas c-met/genética , Animais , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Movimento Celular , Proliferação de Células , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Camundongos , Camundongos Endogâmicos BALB C , Prognóstico , Proteínas Proto-Oncogênicas c-met/metabolismo , Transdução de Sinais , Fator A de Crescimento do Endotélio Vascular/análise , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores
17.
Hepatology ; 60(3): 872-83, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24798303

RESUMO

UNLABELLED: Globally, hepatocellular carcinoma (HCC) accounts for 70%-85% of primary liver cancers and ranks as the second leading cause of male cancer death. Serum alpha-fetoprotein (AFP), normally highly expressed in the liver only during fetal development, is reactivated in 60% of HCC tumors and associated with poor patient outcome. We hypothesize that AFP+ and AFP- tumors differ biologically. Multivariable analysis in 237 HCC cases demonstrates that AFP level predicts poor survival independent of tumor stage (P<0.043). Using microarray-based global microRNA (miRNA) profiling, we found that miRNA-29 (miR-29) family members were the most significantly (P<0.001) down-regulated miRNAs in AFP+ tumors. Consistent with miR-29's role in targeting DNA methyltransferase 3A (DNMT3A), a key enzyme regulating DNA methylation, we found a significant inverse correlation (P<0.001) between miR-29 and DNMT3A gene expression, suggesting that they might be functionally antagonistic. Moreover, global DNA methylation profiling reveals that AFP+ and AFP- HCC tumors have distinct global DNA methylation patterns and that increased DNA methylation is associated with AFP+ HCC. Experimentally, we found that AFP expression in AFP- HCC cells induces cell proliferation, migration, and invasion. Overexpression of AFP, or conditioned media from AFP+ cells, inhibits miR-29a expression and induces DNMT3A expression in AFP- HCC cells. AFP also inhibited transcription of the miR-29a/b-1 locus, and this effect is mediated through c-MYC binding to the transcript of miR-29a/b-1. Furthermore, AFP expression promotes tumor growth of AFP- HCC cells in nude mice. CONCLUSION: Tumor biology differs considerably between AFP+ HCC and AFP- HCC; AFP is a functional antagonist of miR-29, which may contribute to global epigenetic alterations and poor prognosis in HCC.


Assuntos
Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/mortalidade , Epigenômica , Regulação Neoplásica da Expressão Gênica , Neoplasias Hepáticas/genética , MicroRNAs/antagonistas & inibidores , MicroRNAs/biossíntese , alfa-Fetoproteínas/biossíntese , Adulto , Animais , Carcinoma Hepatocelular/enzimologia , Linhagem Celular Tumoral , Estudos de Coortes , Metilação de DNA/genética , DNA Metiltransferase 3A , Regulação para Baixo/genética , Feminino , Humanos , Neoplasias Hepáticas/enzimologia , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas Experimentais/enzimologia , Neoplasias Hepáticas Experimentais/genética , Neoplasias Hepáticas Experimentais/mortalidade , Masculino , Camundongos , Camundongos Nus , MicroRNAs/genética , Pessoa de Meia-Idade , alfa-Fetoproteínas/genética
18.
Gastroenterology ; 144(5): 1066-1075.e1, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23376425

RESUMO

BACKGROUND & AIMS: We combined gene expression and metabolic profiling analyses to identify factors associated with outcomes of patients with hepatocellular carcinoma (HCC). METHODS: We compared metabolic and gene expression patterns between paired tumor and nontumor tissues from 30 patients with HCC, and validated the results using samples from 356 patients with HCC. A total of 469 metabolites were measured using liquid chromatography/mass spectrometry and gas chromatography/mass spectrometry. Metabolic and genomic data were integrated, and Kaplan-Meier and Cox proportional hazards analyses were used to associate specific patterns with patient outcomes. Associated factors were evaluated for their effects on cancer cells in vitro and tumor formation in nude mice. RESULTS: We identified 28 metabolites and 169 genes associated with aggressive HCC. Lipid metabolites of stearoyl-CoA-desaturase (SCD) activity were associated with aberrant palmitate signaling in aggressive HCC samples. Expression of gene products associated with these metabolites, including SCD, were associated independently with survival times and tumor recurrence in the test and validation sets. Combined expression of SCD and α-fetoprotein were associated with outcomes of patients with early-stage HCC. Levels of monounsaturated palmitic acid, the product of SCD activity, were increased in aggressive HCCs; monounsaturated palmitic acid increased migration and invasion of cultured HCC cells and colony formation by HCC cells. HCC cells that expressed small interfering RNA against SCD had decreased cell migration and colony formation in culture and reduced tumorigenicity in mice. CONCLUSIONS: By using a combination of gene expression and metabolic profile analysis, we identified a lipogenic network that involves SCD and palmitate signaling and was associated with HCC progression and patient outcomes. The microarray platform and data have been submitted to the Gene Expression Omnibus public database at NCBI following MIAME guidelines. Accession numbers: GPL4700 (platform), and GSE6857 (samples).


Assuntos
Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/genética , Regulação Neoplásica da Expressão Gênica , Metabolismo dos Lipídeos/genética , Neoplasias Hepáticas/genética , Animais , Biomarcadores Tumorais/biossíntese , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , China/epidemiologia , Progressão da Doença , Feminino , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas Experimentais/genética , Neoplasias Hepáticas Experimentais/metabolismo , Neoplasias Hepáticas Experimentais/mortalidade , Camundongos , Camundongos Nus , Transdução de Sinais/genética , Taxa de Sobrevida/tendências
19.
Hepatology ; 57(3): 1024-34, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23079960

RESUMO

UNLABELLED: Osteopontin (OPN) plays a crucial role in hepatocellular carcinoma (HCC) metastasis. However, little is known about the impact of OPN polymorphisms on cancer progression. In this study, we first identified the single nucleotide polymorphisms (SNPs) in the OPN promoter region by direct sequencing in 30 HCCs, and then evaluated the prognostic values of the selected ones in two large cohorts of 826 HCC patients. The identified SNPs were functionally analyzed using in vitro and in vivo assays and their correlations with OPN levels were also evaluated. Only SNP at locus -443 and their related haplotypes (Ht2: -1748A/-616G/-443T/-155* [*indicates base deletion]; Ht3: -1748A/-616G/-443C/-155*) were significantly associated with overall survival (OS) and time to recurrence (TTR). The patients with the -443TT/TC genotype or Ht2 had a shorter OS and TTR compared with those with -443CC genotype or Ht3. This was further confirmed in the validation cohort. Moreover, this correlation remained significant in patients with small HCCs (≤5 cm). Multivariate analyses indicated that the prognostic performance of the -443 genotypes (OS, P=0.031; TTR, P=0.005) and their related haplotypes (OS, P=0.002; TTR, P=0.001) was independent of other clinicopathological factors. The Ht2 and -443TT genotype could significantly increase the promoter transcriptional activity and expression level of OPN compared with the Ht3 or -443CC genotype, and lead to an obvious increase in both in vitro invasion and in vivo tumor growth and lung metastasis of HCC cells (P<0.05). CONCLUSION: The genetic variation at locus -443 of the OPN promoter plays important roles in the regulation of OPN expression and cancer progression of HCCs, which is a novel determinant and target for HCC metastasis and prognosis.


Assuntos
Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/secundário , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Osteopontina/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Testes Genéticos , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Prognóstico , Regiões Promotoras Genéticas/genética
20.
Hepatology ; 58(1): 158-70, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23389848

RESUMO

UNLABELLED: Down-regulation of microRNA-26a (miR-26a) is associated with poor prognosis of hepatocellular carcinoma (HCC), but its functional mechanism in HCC remains unclear. In this study, we investigated the roles of miR-26a in tumor growth and metastasis of HCC and found that miR-26a was frequently down-regulated in HCC tissues. Down-regulation of miR-26a correlated with HCC recurrence and metastasis. Through gain- and loss-of-function studies, miR-26a was demonstrated to significantly inhibit in vitro cell proliferation, migration, and invasion. In addition, miR-26a induced G1 arrest and promoted apoptosis of HCC cells. Importantly, miR-26a suppressed in vivo tumor growth and metastasis in nude mice models bearing human HCC. Interleukin-6 (IL-6) was identified as a target of miR-26a. Knockdown of IL-6 induced effects on HCC cells similar to those induced by miR-26a. In contrast, IL-6 treatment abrogated the effects induced by miR-26a up-regulation. Moreover, miR-26a dramatically suppressed expression of signal transducer and activator of transcription 3 (Stat3) target genes, including Bcl-2, Mcl-1, cyclin D1, and MMP2. IL-6 treatment antagonized this effect, while knockdown of IL-6 by IL-6 short hairpin RNA (shIL-6) induced inhibitory effects on the expression of p-Stat3 and its main target genes, similar to miR-26a. The messenger RNA and protein levels of IL-6 inversely correlated with miR-26a in HCCs. Patients with high miR-26a or low IL-6 in HCC tissues had a better prognosis with longer overall survival (OS) and time to recurrence (TTR). In multivariate analysis, miR-26a, IL-6, and their combination were demonstrated to be independent prognostic indicators for OS and TTR of HCC patients. CONCLUSION: miR-26a could suppress tumor growth and metastasis of HCC through IL-6-Stat3 signaling and is a novel prognostic marker and therapeutic target for HCC.


Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Interleucina-6/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , MicroRNAs/uso terapêutico , Animais , Carcinoma Hepatocelular/secundário , Regulação para Baixo , Feminino , Humanos , Interleucina-6/farmacologia , Neoplasias Hepáticas/secundário , Masculino , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Fator de Transcrição STAT3/fisiologia , Transdução de Sinais/efeitos dos fármacos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA