RESUMO
RNA helicases are involved in the innate immune response against pathogens, including bacteria and viruses; however, their mechanism in the human airway epithelial cells is still not fully understood. Here, we demonstrated that DEAH (Asp-Glu-Ala-His) box polypeptide 35 (DHX35), a member of the DExD/H (Asp-Glu-x-Asp/His)-box helicase family, boosts antiviral innate immunity in human airway epithelial cells. DHX35 knockdown attenuated the production of interferon-ß (IFN-ß), IL6, and CXCL10, whereas DHX35 overexpression increased their production. Upon stimulation, DHX35 was constitutively expressed, but it translocated from the nucleus into the cytosol, where it recognized cytosolic poly(I:C) and poly(dA:dT) via its HELICc domain. Mitochondrial antiviral signaling protein (MAVS) acted as an adaptor for DHX35 and interacted with the HELICc domain of DHX35 using amino acids 360-510. Interestingly, DHX35 interacted with retinoic acid-inducible gene 1 (RIG-I), enhanced the binding affinity of RIG-I with poly(I:C) and poly(dA:dT), and formed a signalsome with MAVS to activate interferon regulatory factor 3 (IRF3), NF-κB-p65, and MAPK signaling pathways. These results indicate that DHX35 not only acted as a cytosolic nucleic acid sensor but also synergized with RIG-I to enhance antiviral immunity in human airway epithelial cells. Our results demonstrate a novel molecular mechanism for DHX35 in RIG-I-mediated innate immunity and provide a novel candidate for drug and vaccine design to control viral infections in the human airway.
Assuntos
Proteína DEAD-box 58 , RNA Helicases DEAD-box , Imunidade Inata , Receptores Imunológicos , Humanos , Proteína DEAD-box 58/metabolismo , Proteína DEAD-box 58/imunologia , RNA Helicases DEAD-box/metabolismo , RNA Helicases DEAD-box/imunologia , Receptores Imunológicos/metabolismo , Poli I-C/imunologia , Poli I-C/farmacologia , RNA Helicases/metabolismo , RNA Helicases/imunologia , Transdução de Sinais/imunologia , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/imunologia , Células Epiteliais/imunologia , Células Epiteliais/metabolismo , Células Epiteliais/virologia , Células HEK293RESUMO
Chemotherapeutic agents for treating colorectal cancer (CRC) primarily induce apoptosis in tumor cells. The ubiquitin-proteasome system is critical for apoptosis regulation. Deubiquitinating enzymes (DUBs) remove ubiquitin from substrates to reverse ubiquitination. Although over 100 DUB members have been discovered, the biological functions of only a small proportion of DUBs have been characterized. Here, we aimed to systematically identify the DUBs that contribute to the development of CRC. Among the DUBs, ubiquitin-specific protease 36 (USP36) is upregulated in CRC. We showed that the knockdown of USP36 induces intrinsic and extrinsic apoptosis. Through gene silencing and coimmunoprecipitation techniques, we identified survivin and cIAP1 as USP36 targets. Mechanistically, USP36 binds and removes lysine-11-linked ubiquitin chains from cIAP1 and lysine-48-linked ubiquitin chains from survivin to abolish protein degradation. Overexpression of USP36 disrupts the formation of the XIAP-second mitochondria-derived activator of caspase complex and promotes receptor-interacting protein kinase 1 ubiquitination, validating USP36 as an inhibitor to intrinsic and extrinsic apoptosis through deubiquitinating survivin and cIAP1. Therefore, our results suggest that USP36 is involved in CRC progression and is a potential therapeutic target.
Assuntos
Apoptose , Neoplasias Colorretais , Proteínas Inibidoras de Apoptose , Survivina , Ubiquitina Tiolesterase , Ubiquitinação , Humanos , Linhagem Celular Tumoral , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Neoplasias Colorretais/genética , Regulação Neoplásica da Expressão Gênica , Proteínas Inibidoras de Apoptose/metabolismo , Proteínas Inibidoras de Apoptose/genética , Survivina/metabolismo , Survivina/genética , Ubiquitina Tiolesterase/metabolismo , Ubiquitina Tiolesterase/genéticaRESUMO
Liver cancer is one of the most common malignancies, with severe morbidity and mortality. While considerable progress has been made in liver cancer treatment, the 5-year overall survival (OS) of patients has not improved significantly. Reasons include the inadequate capability of early screening and diagnosis, a high incidence of recurrence and metastasis, a high degree of tumor heterogeneity, and an immunosuppressive tumor microenvironment. Therefore, the identification and validation of specific and robust liver cancer biomarkers are of major importance for early screening, timely diagnosis, accurate prognosis, and the prevention of tumor progression. In this review, we highlight some of the latest research progress and potential applications of liver cancer biomarkers, describing hotspots and prospective directions in biomarker discovery.
Assuntos
Neoplasias Hepáticas , Humanos , Estudos Prospectivos , Prognóstico , Biomarcadores Tumorais , Microambiente TumoralRESUMO
Cyclic GMP-AMP synthase (cGAS) recognizes cytosolic DNA and catalyzes the formation of cyclic GMP-AMP, which upon activation triggers the induction of stimulator of interferon genes (STING), leading to type I interferons production; these events then promote the cross-priming of dendritic cells and the initiation of a tumor-specific CD8+ T cell response. However, cancer cells in the tumor microenvironment cannot trigger intrinsic cGAS-STING signaling, regardless of the expression of cGAS and STING. This dysfunctional cGAS-STING signaling enables cancer cells to evade immune surveillance, thereby promoting tumorigenesis. Here, we review recent advances in the current understanding of the activation of cGAS-STING signaling and immunotherapies based on this pathway and focus on the mechanisms for the inactivation of this pathway in tumor cells to promote the development of cancer immunotherapy. The discovery of inherent resistance and the selection of appropriate combination therapies are of great significance for tumor treatment development.
Assuntos
Proteínas de Membrana/imunologia , Neoplasias/terapia , Nucleotidiltransferases/imunologia , Evasão Tumoral , Animais , Humanos , Imunoterapia/métodos , Neoplasias/imunologia , Transdução de Sinais , Microambiente TumoralRESUMO
UNLABELLED: Hepatitis B virus X (HBx) protein is implicated in hepatitis B virus (HBV)-associated liver carcinogenesis. However, it remains unclear whether HBx-expressing hepatic progenitor cells (HPCs) are attributed to liver tumor formation. In this study, by using HBx transgenic mice and a 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-induced liver injury model, the relationship between HBx expression and tumorigenicity of HPCs was analyzed. Compared with control mice, an elevated number of EpCAM(+) cells with characteristics of HPCs was observed in HBx mice after 1 month and 4 months of DDC diet feeding. All HBx transgenic mice developed liver tumors characterized by histological features of both hepatocellular carcinoma (HCC) and cholangiocarcinoma after 7 months of DDC feeding. Notably, EpCAM(+) HPCs isolated from premalignant HBx mice exposed to a DDC diet for 4 months formed subcutaneous mixed-lineage tumors (four out of six) in nonobese diabetic/severe-combined immunodeficient (NOD/SCID) mice, and none of the cells from wildtype (WT) induced tumor, indicating that HBx may induce malignant transformation of HPCs that contributes to tumorigenesis. We also found higher titers of circulating interleukin (IL)-6, activities of IL-6/STAT3, and Wnt/ß-catenin signaling pathways in HBx transgenic mice, suggesting HBx may induce intrinsic changes in HPCs by way of the above signaling that enables HPCs with tumorigenicity potential. Finally, clinical evidence showed that high HBx expression in human HBV-related HCC was statistically associated with expansion of EpCAM(+) or OV6(+) tumor cells and aggressive clinicopathologic features. CONCLUSION: HBx induces intrinsic cellular transformation promoting the expansion and tumorigenicity of HPCs in DDC-treated mice, which may be a possible origin for liver cancer induced by chronic hepatitis infection.
Assuntos
Carcinoma Hepatocelular/induzido quimicamente , Carcinoma Hepatocelular/virologia , Neoplasias Hepáticas Experimentais/induzido quimicamente , Neoplasias Hepáticas Experimentais/virologia , Piridinas/toxicidade , Transativadores/genética , Animais , Neoplasias dos Ductos Biliares/induzido quimicamente , Neoplasias dos Ductos Biliares/fisiopatologia , Neoplasias dos Ductos Biliares/virologia , Ductos Biliares Intra-Hepáticos , Carcinoma Hepatocelular/fisiopatologia , Transformação Celular Neoplásica/induzido quimicamente , Colangiocarcinoma/induzido quimicamente , Colangiocarcinoma/fisiopatologia , Colangiocarcinoma/virologia , Modelos Animais de Doenças , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/fisiologia , Humanos , Neoplasias Hepáticas Experimentais/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos SCID , Camundongos Transgênicos , Pessoa de Meia-Idade , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Células-Tronco/efeitos dos fármacos , Células-Tronco/fisiologia , Células-Tronco/virologia , Transativadores/metabolismo , Proteínas Virais Reguladoras e AcessóriasRESUMO
BACKGROUND & AIMS: Accumulating evidence suggests the involvement of tumor-initiating cells (T-ICs) in cancer genesis, but whether liver T-ICs contribute to HCC invasion and metastasis remains unclear. METHODS: OV6(+) T-ICs were isolated from SMMC7721 and HuH7 cell lines by magnetic sorting. Characteristics of T-ICs were assessed by in vitro and mouse xenograft assays. Expression of OV6 was determined by immunostaining in specimens from 218 HCC patients, and Kaplan-Meier survival analysis was used to determine the correlation of OV6 expression with prognosis. RESULTS: OV6(+) T-ICs isolated from HCC cell lines not only possess a higher capacity to form tumor spheroids in vitro, but also had a greater potential to form tumors when implanted in non-obese diabetic/severe combined immunodeficient mice, suggesting their elevated self-renewal capacity and tumorigenicity. Moreover, OV6(+) T-ICs exhibited more invasive and metastatic potentials both in vitro and in vivo. Patients with more OV6(+) tumor cells were associated with aggressive clinicopathologic features and poor prognosis. CXCR4 is expressed at higher levels in OV6(+) cells. Recombinant stromal cell-derived factor-1 (SDF-1) treatment expanded the OV6(+) HCC T-ICs population, by sustaining the stem cell property of OV6(+) cells. The SDF-1 effect was blocked by a specific CXCR4 inhibitor, AMD3100, or transfection of siRNA targeting CXCR4. CONCLUSIONS: OV6(+) HCC cells may represent a subpopulation of T-ICs with augmented invasion and metastasis potential, which contribute to progression and metastasis of HCC. The SDF-1/CXCR4 axis also provides therapeutic targets for elimination of liver T-ICs.
Assuntos
Antígenos de Diferenciação/metabolismo , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/secundário , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Neoplasias Pulmonares/metabolismo , Células-Tronco Neoplásicas/metabolismo , Antígeno AC133 , Animais , Antígenos CD/metabolismo , Antígenos de Neoplasias/metabolismo , Benzilaminas , Moléculas de Adesão Celular/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Quimiocina CXCL12/metabolismo , Ciclamos , Progressão da Doença , Intervalo Livre de Doença , Molécula de Adesão da Célula Epitelial , Feminino , Técnicas de Silenciamento de Genes , Glicoproteínas/metabolismo , Compostos Heterocíclicos/farmacologia , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/secundário , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Pessoa de Meia-Idade , Análise Multivariada , Invasividade Neoplásica , Peptídeos/metabolismo , Prognóstico , RNA Interferente Pequeno , Receptores CXCR4/efeitos dos fármacos , Receptores CXCR4/genética , Receptores CXCR4/metabolismo , Esferoides CelularesRESUMO
UNLABELLED: Increasing evidence suggests that the presence of endotoxemia is of substantial clinical relevance to patients with cirrhosis, but it is unclear whether and how gut-derived LPS amplifies the tumorigenic response of the liver. We found that the circulating levels of LPS were elevated in animal models of carcinogen-induced hepatocarcinogenesis. Reduction of LPS using antibiotics regimen in rats or genetic ablation of its receptor Toll-like receptor 4 (TLR4) in mice prevented excessive tumor growth and multiplicity. Additional investigation revealed that TLR4 ablation sensitizes the liver to carcinogen-induced toxicity via blocking NF-κB activation and sensitizing the liver to reactive oxygen species (ROS)-induced toxicity, but lessens inflammation-mediated compensatory proliferation. Reconstitution of TLR4-expressing myeloid cells in TLR4-deficient mice restored diethylnitrosamine (DEN)-induced hepatic inflammation and proliferation, indicating a paracrine mechanism of LPS in tumor promotion. Meanwhile, deletion of gut-derived endotoxin suppressed DEN-induced cytokine production and compensatory proliferation, whereas in vivo LPS pre-challenge promotes hepatocyte proliferation. CONCLUSION: Our data indicate that sustained LPS accumulation represents a pathological mediator of inflammation-associated hepatocellular carcinoma (HCC) and manipulation of the gut flora to prevent pathogenic bacterial translocation and endotoxin absorption may favorably influence liver function in patients with cirrhosis who are at risk of developing HCC.
Assuntos
Apoptose/efeitos dos fármacos , Carcinógenos/farmacologia , Carcinoma Hepatocelular/etiologia , Lipopolissacarídeos/farmacologia , Neoplasias Hepáticas/etiologia , Receptor 4 Toll-Like/fisiologia , Animais , Carcinoma Hepatocelular/patologia , Proliferação de Células/efeitos dos fármacos , Dietilnitrosamina/toxicidade , Intestinos/microbiologia , Lipopolissacarídeos/sangue , Cirrose Hepática/complicações , Masculino , Camundongos , NF-kappa B/antagonistas & inibidores , Neomicina/farmacologia , Polimixina B/farmacologia , Ratos , Espécies Reativas de Oxigênio/farmacologiaRESUMO
OBJECTIVE: To explore the mechanism of action of Zilongjin (ZLJ) in antagonizing multi-drug resistance (MDR) of tumor cells. METHODS: MDR tumor cells, including human breast cancer cell line MCF-7 and MCF-7/DOX, and human oral epithelial cancer cells KB and KBV200, were treated with ZLJ. The inhibition of ZLJ on cell proliferation was determined with MTT assay; cell cycle and fluorescence dye Rhodamine 123 intensity were detected by flow cytometry; and the expression of related proteins was examined by Western blot. RESULTS: IC50 values in MDR cells after ZLJ treatment were similar to those in sensitive cells; MDR cells showed no cross resistance to ZLJ. Flow cytometric analysis showed that the cell cycles of either sensitive or MDR cells were arrested at S phase after exposure to ZLJ. Using ZLJ singly showed a weak inhibition on MDR of MCF-7/ DOX and KBV200 cells, but when used in combining with doxorubicin or vincistine, it evidently increased their cytotoxicity. Expression of P-glycoprotein in MCF-7/DOX cells decreased after ZLJ treatment in a time-dependent manner. Western blot showed that ZLJ could cause the apoptosis marker protein PARP cleavage to initiate the apoptotic pathway. CONCLUSIONS: The proliferation of tumor cells with MDR could be inhibited by ZLJ and they show no cross resistance to ZLJ. The inhibitory effect is related to the activation of apoptotic pathway and the decrease of P-glycoprotein expression.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Apoptose/efeitos dos fármacos , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Humanos , Células MCF-7 , Neoplasias Bucais/patologiaRESUMO
Pattern recognition receptors (PRRs) are germline-encoded host sensors of the innate immune system. Some human cancer cells have been reported to express PRRs. However, nucleic acid sensors in human cancers have not been studied in detail. Therefore, we systematically analyzed the expression, molecular cascade, and functions of TLR3, RIG-I, MDA5, LGP2, cGAS, and STING in human cancer cells. TLR3, TRIF, RIG-I, MDA5, LGP2, and MAVS were expressed in 22 cell lines. The majority of cell lines responded to only RIG-I ligands 5'-ppp-dsRNA, Poly(I:C)-HMW, Poly(I:C)-LMW, and/or Poly(dA:dT), as revealed by IRF3 phosphorylation and IFN-ß secretion. IFN-ß secretion was inhibited by RIG-I and MAVS knockdown. cGAS and STING were co-expressed in 10 of 22 cell lines, but IFN-ß secretion was not induced by STING ligands ISD, HSV60, VACV70, Poly(dG:dC), and 3'3'-cGAMP in cGAS and STING intact cell lines. Further experiments revealed that the cGAS-STING pathway was activated, as revealed by TBK1 and IRF3 phosphorylation and IFN-ß and ISG mRNA expression. These results suggest that human epithelial cancer cells respond to cytosolic RNA through the RIG-I-MAVS pathway but only sense cytosolic DNA through the cGAS-STING pathway. These findings are relevant for cancer immunotherapy approaches based on targeting nucleic acid receptors.
RESUMO
Octreotide is a crucial drug used for treating patients with chylous ascites; however, there have been few reports related to octreotide that are being used in cirrhotic patients. Thus, this thesis is designed to determine the effects of octreotide on patients with chylous ascites after liver cirrhosis. Eight patients were diagnosed with chylous ascites, on the basis of laboratory findings on ascites samples, between January 2003 and May 2008. Octreotide was given to the six patients, while the remaining two were treated as a control. All patients had persistent peritoneal drainage with the quantity and quality of the drainage fluid observed once every other day. All the necessary care was individually given to the patients during the therapy. All patients properly received combined therapy including a low-fat and low-sodium diet, and diuretic and peritoneal drainage. The volume of the peritoneal drainage was reduced to zero in one of the six patients who received octreotide therapy, while the other five had the drainage volumes decreased from 2,000 to 50 ml with a clear appearance and negative qualitative analysis of chyle. For those two patients who did not receive octreotide therapy, the conditions of peritoneal drainage seldom changed both from the qualitative and quantitative aspects. In conclusion, Octreotide, along with combined therapy, can rapidly relieve portal hypertension and reduce triglyceride levels in ascites. It appears to be an effective therapy available for the treatment of chylous ascites caused by liver cirrhosis.
Assuntos
Ascite Quilosa/tratamento farmacológico , Ascite Quilosa/etiologia , Fármacos Gastrointestinais/uso terapêutico , Cirrose Hepática/complicações , Octreotida/uso terapêutico , Ascite Quilosa/sangue , Drenagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Triglicerídeos/sangueRESUMO
Long noncoding RNAs (lncRNAs) refer to a group of noncoding RNAs (ncRNAs) that has a transcript of more than 200 nucleotides in length in eukaryotic cells. The lncRNAs regulate gene expression at epigenetic, transcriptional, and post-transcriptional levels by multiple action modes. In this review, we describe the diverse roles reported for lncRNAs, and discuss how they could mechanistically be involved in the development of central nervous system (CNS) and neurodegenerative diseases. Further studies on the function of lncRNAs and their mechanism will help deepen our understanding of the development, function, and diseases of the CNS, and provide new ideas for the design and development of some therapeutic drugs.
RESUMO
The importance of non-coding RNA involved in biological processes has become apparent in recent years and the mechanism of transcriptional regulation has also been identified. MicroRNAs (miRNAs) represent a class of small regulatory non-coding RNAs of 22bp in length that mediate gene silencing by identifying specific sequences in the target messenger RNAs (mRNAs). Many miRNAs are highly expressed in the central nervous system in a spatially and temporally controlled manner in normal physiology, as well as in certain pathological conditions. There is growing evidence that a considerable number of specific miRNAs play important roles in synaptic plasticity, learning and memory function. In addition, the dysfunction of these molecules may also contribute to the etiology of several neurodegenerative diseases. Here we provide an overview of the current literatures, which support non-coding RNA-mediated gene function regulation represents an important but underappreciated, layer of epigenetic control that facilitates learning and memory functions.
Assuntos
Aprendizagem/fisiologia , Memória/fisiologia , MicroRNAs/genética , MicroRNAs/fisiologia , Plasticidade Neuronal/genética , Plasticidade Neuronal/fisiologia , Animais , HumanosRESUMO
BACKGROUND: Postoperative cognitive dysfunction is a postoperative severe complication caused by many factors. However, its specific pathogenesis remains unclear. MicroRNAs (miRNAs), which are involved in the pathogenesis of neurodegenerative diseases, may also affect POCD. METHODS: In this research, microarray technology was used to screen 26 miRNAs that had a differential expression in the hippocampus of mouse between the surgery group and control group. The qRT-PCR verification on the hippocampuses of 10 pairs of mouse testifies the high expression of miR-7684-5p in the surgery group (identical with the result of chip). RESULTS: Surgical trauma was found to induce the expression of miR-7684-5p with the accumulation of Aß in the hippocampus. Furthermore, miR-7684-5p knockdown effectively reduced the levels of Aß triggered by surgery, and attenuated hippocampal-dependent memory impairment. Moreover, we testify that sorLA is a target gene of miR-7684-5p through bioinformatics prediction and dual-luciferase report gene experiment. CONCLUSIONS: Our data indicate that decreased postoperative cognitive function may be caused by the increased generation of Aß by reducing sorLA expression. Our work implicates miR-7684-5p as a potential biomarker and a novel therapeutic target.
RESUMO
This study was designed to identify and verify hepatocellular carcinoma (HCC)-associated human carcinoma antigens (HCAs) that may be useful as tumor markers for HCC. We found that BCE075 and BCD021 anti-HCA antibodies were immunostained in the liver tissue samples and showed specific staining. Their expression was increased in HCC compared with normal liver tissues (P = 0.008). Immunoprecipitation and mass spectrometry analyses of the proteins precipitated by these two antibodies were identified to be cytoskeleton-associated protein 4 (CLIMP63) and brain-type glycogen phosphorylase (PYGB). This study demonstrated that HCC tissues expressed specific HCA glycoproteins, suggesting that our mouse monoclonal anti-HCA antibodies could be useful for immunohistochemical analysis of HCA expression as potential biomarkers for HCC diagnosis.
Assuntos
Antígenos de Neoplasias/análise , Biomarcadores Tumorais , Carcinoma Hepatocelular/patologia , Glicogênio Fosforilase Encefálica/análise , Neoplasias Hepáticas/patologia , Proteínas de Membrana/análise , Animais , Anticorpos Monoclonais , Humanos , Imuno-Histoquímica , Imunoprecipitação , Espectrometria de Massas , CamundongosRESUMO
ß-Catenin plays many critical roles during various liver physiological and pathological processes. However, the role of ß-Catenin in acute liver failure remains unclear. Using hepatocyte specific ß-Catenin knockout mice, we found that loss of ß-Catenin in hepatocyte significantly reduced GalN/LPS-induced liver damage and hepatocyte apoptosis, but exacerbated Jo2-mediated liver injury. Mechanistically, the dual effects of ß-Catenin attributes on its function of inhibiting NF-κB signaling, which aggravates oxidative stress but decreases Fas expression under injury conditions. In conclusion, ß-Catenin plays an important role in regulating the balance between TNF-α and Fas-induced liver injury via its effect on NF-κB.
Assuntos
Lesão Pulmonar Aguda/metabolismo , Fator de Necrose Tumoral alfa/fisiologia , beta Catenina/fisiologia , Receptor fas/fisiologia , Lesão Pulmonar Aguda/imunologia , Lesão Pulmonar Aguda/patologia , Alanina Transaminase/sangue , Animais , Apoptose , Aspartato Aminotransferases/sangue , Linhagem Celular Tumoral , Técnicas de Inativação de Genes , Lipopolissacarídeos/farmacologia , Fígado/metabolismo , Fígado/patologia , Camundongos , Camundongos Transgênicos , NF-kappa B/metabolismo , Estresse OxidativoRESUMO
Robust clinical and epidemiologic data support the role of inflammation as a key player in hepatocellular carcinoma (HCC) development. Our previous data showed that gut-derived lipopolysaccharide (LPS) promote HCC development by activating Toll-like receptor 4 (TLR4) expressed on myeloid-derived cells. However, the effects of gut-derived LPS on other types of liver injury models are yet to be studied. The purpose of this study was to determine the importance of gut-derived LPS and TLR4 signaling in a T-cell-mediated hepatitis-Con A-induced hepatitis model, which mimic the viral hepatitis. Reduction of endotoxin using antibiotics regimen or genetic ablation of TLR4 in mice significantly alleviate Con A-induced liver injury by inhibiting the infiltration of T lymphocytes into the liver and the activation of CD4(+) T lymphocytes as well as the production of T helper 1 cytokines; in contrast, exogenous LPS can promote Con A-induced hepatitis and CD4(+) T cells activation in vivo and in vitro. Reconstitution of TLR4-expressing myeloid cells in TLR4-deficient mice restored Con A-induced liver injury and inflammation, indicating the major cell target of LPS. In addition, TLR4 may positively regulate the target hepatocellular apoptosis via the perforin/granzyme B pathway. These data suggest that gut-derived LPS and TLR4 play important positive roles in Con A-induced hepatitis and modulation of the gut microbiotia may represent a new avenue for therapeutic intervention to treat acute hepatitis induced by hepatitis virus infection, thus to prevent hepatocellular carcinoma.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Hepatite/imunologia , Lipopolissacarídeos/imunologia , Ativação Linfocitária/imunologia , Receptor 4 Toll-Like/imunologia , Animais , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/metabolismo , Modelos Animais de Doenças , Citometria de Fluxo , Intestinos/imunologia , Intestinos/microbiologia , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais/imunologia , Receptor 4 Toll-Like/metabolismoRESUMO
AIM: To study the prognostic factors for intrahepatic cholangiocarcinoma (ICC) and evaluate the impact of chronic hepatitis B virus (HBV) infection on survival rate of ICC patients. METHODS: A total of 155 ICC patients who underwent macroscopic curative resections (R0 and R1) were enrolled in this retrospective study and divided into group A with HBV infection and group B without HBV infection according to their chronic HBV infection, represented by positive hepatitis B surface antigen (HBsAg) in serum or in liver tissue. Clinicopathological characteristics and survival rate of the patients were evaluated. RESULTS: All patients underwent anatomical resection. Their 1- and 3-year survival rates were 60.6% and 32.1%, respectively. Multivariate analyses revealed that HBV infection, hepatolithiasis, microscopic satellite lesion, and lymphatic metastasis were the independent prognostic factors for the survival rate of ICC patients. The median disease-free survival time of the patients was 5.0 mo. The number of tumors, microscopic satellite lesion, and vascular invasion were the independent prognostic factors for the disease-free survival rate of the patients. The prognostic factors affecting the survival rate of ICC patients with HBV infection and those without HBV infection were not completely consistent. Alkaline phosphatase > 119 U/L, microscopic satellite lesion, vascular invasion, and lymphatic metastasis were the independent factors for the patients with HBV infection, while r-glutamyltransferase > 64 U/L, microscopic satellite lesion, and poor tumor differentiation were the independent factors for the patients without HBV infection. CONCLUSION: HBV infection is a valuable clinical factor for predicting tumor invasiveness and clinical outcome of ICC patients. ICC patients with HBV infection should be distinguished from those without HBV infection because they have different clinicopathological characteristics, prognostic factors and outcomes after surgical resection.
Assuntos
Antígenos de Superfície da Hepatite B/metabolismo , Hepatite B/diagnóstico , Hepatite B/virologia , Adulto , Idoso , Neoplasias dos Ductos Biliares/diagnóstico , Neoplasias dos Ductos Biliares/cirurgia , Neoplasias dos Ductos Biliares/virologia , Ductos Biliares Intra-Hepáticos , Colangiocarcinoma/diagnóstico , Colangiocarcinoma/cirurgia , Colangiocarcinoma/virologia , Feminino , Vírus da Hepatite B/metabolismo , Humanos , Fígado/virologia , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/cirurgia , Neoplasias Hepáticas/virologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Invasividade Neoplásica , Prognóstico , Estudos Retrospectivos , Resultado do TratamentoRESUMO
AIM: To investigate the prevalence, risk factors, and clinicopathologic characteristics of intrahepatic cholangiocarcinoma (ICC) in young patients. METHODS: A retrospective analysis was performed in ICC patients referred to the Eastern Hepatobiliary Surgery Hospital in Shanghai, China. Among 317 consecutively enrolled patients, 40 patients were aged