RESUMEN
BACKGROUND: Regulatory B cells (Bregs) is an indispensable element in inducing immune tolerance after liver transplantation. As one of the microRNAs (miRNAs), miR-29a-3p also inhibits translation by degrading the target mRNA, and yet the relationship between Bregs and miR-29a-3p has not yet been fully explored. This study aimed to investigate the impact of miR-29a-3p on the regulation of differentiation and immunosuppressive functions of memory Bregs (mBregs) and ultimately provide potentially effective therapies in inducing immune tolerance after liver transplantation. METHODS: Flow cytometry was employed to determine the levels of Bregs in peripheral blood mononuclear cells. TaqMan low-density array miRNA assays were used to identify the expression of different miRNAs, electroporation transfection was used to induce miR-29a-3p overexpression and knockdown, and dual luciferase reporter assay was used to verify the target gene of miR-29a-3p. RESULTS: In patients experiencing acute rejection after liver transplantation, the proportions and immunosuppressive function of mBregs in the circulating blood were significantly impaired. miR-29a-3p was found to be a regulator of mBregs differentiation. Inhibition of miR-29a-3p, which targeted nuclear factor of activated T cells 5 (NFAT5), resulted in a conspicuous boost in the differentiation and immunosuppressive function of mBregs. The inhibition of miR-29a-3p in CD19+ B cells was capable of raising the expression levels of NFAT5, thereby promoting B cells to differentiate into mBregs. In addition, the observed enhancement of differentiation and immunosuppressive function of mBregs upon miR-29a-3p inhibition was abolished by the knockdown of NFAT5 in B cells. CONCLUSIONS: miR-29a-3p was found to be a crucial regulator for mBregs differentiation and immunosuppressive function. Silencing miR-29a-3p could be a potentially effective therapeutic strategy for inducing immune tolerance after liver transplantation.
Asunto(s)
Antígenos CD19 , Linfocitos B Reguladores , Antígeno CD24 , Diferenciación Celular , Trasplante de Hígado , MicroARNs , Humanos , MicroARNs/metabolismo , MicroARNs/genética , Linfocitos B Reguladores/inmunología , Linfocitos B Reguladores/metabolismo , Antígenos CD19/metabolismo , Antígenos CD19/genética , Masculino , Antígeno CD24/metabolismo , Antígeno CD24/genética , Transducción de Señal , Rechazo de Injerto/inmunología , Rechazo de Injerto/genética , Femenino , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Persona de Mediana Edad , Tolerancia Inmunológica , Células Cultivadas , Adulto , Fenotipo , Memoria InmunológicaRESUMEN
Objectives: This study aimed to evaluate and update incidence trends of soft-tissue sarcoma (STS) and to develop a nomogram to predict cancer-specific survival (CSS) in patients diagnosed with primary STS of the liver.Methods: Patients with hepatic STS were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. Joinpoint regression analyses were performed to assess the incidence trends of STS. A nomogram was developed based on the independent risk factors chosen by Cox regression models. The calibration curve, area under the receiver operating characteristic curve (AUC), C-index, and decision curve analysis (DCA) were used to assess the predictive performance of the nomogram.Results: The incidence of STS increased between 1994 and 2012. There was a sudden decline in the incidence of STS from 2013. The incidence of STS was different in distinct races and genders. The nomogram for predicting the CSS of hepatic STS according to the independent factors was well calibrated and it displayed optimal discrimination power.Conclusion: This study highlights that age, sex, tumor size, quality of surgery, and histologic subtypes may contribute to the prognosis of hepatic STS, and STS may be etiologically distinct and should be considered separately in different races and genders.
Asunto(s)
Reglas de Decisión Clínica , Neoplasias Hepáticas/epidemiología , Nomogramas , Sarcoma/epidemiología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Área Bajo la Curva , Niño , Preescolar , Etnicidad , Femenino , Estudios de Seguimiento , Humanos , Incidencia , Lactante , Recién Nacido , Neoplasias Hepáticas/diagnóstico , Masculino , Persona de Mediana Edad , Pronóstico , Curva ROC , Análisis de Regresión , Factores de Riesgo , Programa de VERF , Sarcoma/diagnóstico , Factores Sexuales , Análisis de Supervivencia , Estados Unidos/epidemiología , Adulto JovenRESUMEN
BACKGROUND AND AIMS: The development and progression of hepatocellular carcinoma (HCC) is dependent on its local microenvironment. Tumor-associated macrophages (TAMs) are deemed a key factor for the tumor microenvironment and attribute to contribute to tumor aggressiveness. However, the detailed mechanism underlying the pro-metastatic effect of TAMs on HCC remains undefined. APPROACH AND RESULTS: The present study proved that TAMs were enriched in HCC. TAMs were characterized by an M2-polarized phenotype and accelerated the migratory potential of HCC cells in vitro and in vivo. Furthermore, we found that M2-derived exosomes induced TAM-mediated pro-migratory activity. With the use of mass spectrometry, we identified that integrin, αM ß2 (CD11b/CD18), was notably specific and efficient in M2 macrophage-derived exosomes (M2 exos). Blocking either CD11b and/or CD18 elicited a significant decrease in M2 exos-mediated HCC cell metastasis. Mechanistically, M2 exos mediated an intercellular transfer of the CD11b/CD18, activating the matrix metalloproteinase-9 signaling pathway in recipient HCC cells to support tumor migration. CONCLUSIONS: Collectively, the exosome-mediated transfer of functional CD11b/CD18 protein from TAMs to tumor cells may have the potency to boost the migratory potential of HCC cells, thus providing insights into the mechanism of tumor metastasis.
Asunto(s)
Antígeno CD11b/metabolismo , Antígenos CD18/metabolismo , Carcinoma Hepatocelular , Exosomas/metabolismo , Neoplasias Hepáticas , Macrófagos Asociados a Tumores/metabolismo , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/fisiopatología , Carcinoma Hepatocelular/secundario , Línea Celular Tumoral , Exosomas/fisiología , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/fisiopatología , Neoplasias Hepáticas/secundario , Metástasis de la Neoplasia/fisiopatología , Transducción de Señal , Microambiente Tumoral/fisiología , Macrófagos Asociados a Tumores/fisiologíaRESUMEN
BACKGROUND: The effect of tumor size on account of long-term survival results in perihilar cholangiocarcinoma (PCCA) patients has remained a controversial debate. It is urgent necessary to identify the optimal cutoff value of tumor size in PCCA and integrate tumor size with other prognostic factors into a nomogram to improve the predictive accuracy of prognosis of patients with PCCA. METHODS: Three hundred sixty-three PCCA patients underwent surgical resection were extracted from the Surveillance, Epidemiology and End Results (SEER) database. X-tile program was used to identify the optimal cutoff value of tumor size. A nomogram including tumor size was established to predict 1-, 3- and 5-year cancer-specific survival (CSS) based on the independent risk factors chosen by Kaplan-Meier methods and multivariable cox regression models. The precision of the nomogram for predicting survival was validated internally and externally. RESULTS: PCCA patients underwent surgical resection were classified into 1-19 mm, 20-33 mm and ≥ 34 mm subgroups based on the optimal cutoff for tumor size in terms of CSS. And we noticed that more larger tumor size group had worse tumor grade, advanced T stage, more positive regional lymph nodes and more frequent vascular invasion. The nomogram according to the independent factors was well calibrated and displayed better discrimination power than 7th Tumor-Node-Metastasis (TNM) stage systems. CONCLUSIONS: The results demonstrated that the larger tumor size of PCCA was, the worse survival would be. The proposed nomogram, which outperforms the conventional TNM staging system, showed relatively good performance and could be considered as convenient individualized predictive tool for prognosis of PCCA patients.
Asunto(s)
Neoplasias de los Conductos Biliares/mortalidad , Neoplasias de los Conductos Biliares/patología , Tumor de Klatskin/mortalidad , Tumor de Klatskin/patología , Nomogramas , Neoplasias de los Conductos Biliares/cirugía , Femenino , Estudios de Seguimiento , Humanos , Tumor de Klatskin/cirugía , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Factores de Riesgo , Programa de VERF , Tasa de SupervivenciaRESUMEN
BACKGROUND: Presence of inferior vena cava tumor thrombosis (IVCTT) is an unfavorable factor to prognosis for patients with hepatocellular carcinoma (HCC). CASE PRESENTATION: Herein we report a case of HCC with IVC tumor thrombosis extending from the right hepatic vein (RHV) to the IVC, but it had not infiltrated the right atrium. Anterior approach right hepatectomy combined with IVC thrombectomy using trans-diaphragmatic IVC occlusion was performed for this patient. The patient is alive with disease-free at 32 months after treatment. A literature review was also performed. This case was demonstrated with the details and concepts of surgery. CONCLUSION: This case suggested that surgical resection of HCC involving the IVC, but still outside the right atrium (RA), could offer satisfactory surgical outcomes in selected patients.
Asunto(s)
Carcinoma Hepatocelular/cirugía , Hepatectomía/métodos , Neoplasias Hepáticas/cirugía , Trombectomía/métodos , Venas Hepáticas/patología , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Vena Cava Inferior/cirugía , Trombosis de la Vena/patologíaRESUMEN
OBJECTIVES: Kita-Kyushu lung cancer antigen-1 (KK-LC-1) is a cancer/testis antigen reactivated in several human malignancies. So far, the major focus of studies on KK-LC-1 has been on its potential as diagnostic biomarker and immunotherapy target. However, its biological functions and molecular mechanisms in cancer progression remain unknown. MATERIALS AND METHODS: Expression of KK-LC-1 in HCC was analysed using RT-qPCR, Western blot and immunohistochemistry. The roles of KK-LC-1 on HCC progression were examined by loss-of-function and gain-of-function approaches. Pathway inhibitor DAPT was employed to confirm the regulatory effect of KK-LC-1 on the downstream Notch signalling. The interaction of KK-LC-1 with presenilin-1 was determined by co-immunoprecipitation. The association of CpG island methylation status with KK-LC-1 reactivation was evaluated by methylation-specific PCR, bisulphite sequencing PCR and 5-Aza-dC treatment. RESULTS: We identified that HCC tissues exhibited increased levels of KK-LC-1. High KK-LC-1 level independently predicted poor survival outcome. KK-LC-1 promoted cell growth, migration, invasion and epithelial-mesenchymal transition in vitro and in vivo. KK-LC-1 modulated the Notch1/Hes1 pathway to exacerbate HCC progression through physically interacting with presenilin-1. Upregulation of KK-LC-1 in HCC was attributed to hypomethylated CpG islands. CONCLUSIONS: This study identified that hypomethylation-induced KK-LC-1 overexpression played an important role in HCC progression and independently predicted poor survival. We defined the KK-LC-1/presenilin-1/Notch1/Hes1 as a novel signalling pathway that was involved in the growth and metastasis of HCC.
Asunto(s)
Antígenos de Neoplasias/metabolismo , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , Receptor Notch1/metabolismo , Factor de Transcripción HES-1/metabolismo , Animales , Antígenos de Neoplasias/genética , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Islas de CpG , Metilación de ADN , Progresión de la Enfermedad , Transición Epitelial-Mesenquimal , Técnicas de Silenciamiento del Gen , Células Hep G2 , Xenoinjertos , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Masculino , Ratones , Ratones Desnudos , Presenilina-1/metabolismo , Pronóstico , ARN Interferente Pequeño/genética , Transducción de Señal , Regulación hacia ArribaRESUMEN
Serotonin and its receptors have been shown to play critical regulatory roles in cancer biology. Nevertheless, the contributions of 5-hydroxytryptamine 1D (5-HT1D), an indispensable member of the serotonergic system, to hepatocellular carcinoma (HCC) remain unknown. The present study demonstrated that the 5-HT1D expression level was significantly up-regulated in HCC tissues and cell lines. The 5-HT1D expression level was closely correlated with unfavorable clinicopathological characteristics. Survival analyses show that elevated 5-HT1D expression level predicts poor overall survival and high recurrence probability in HCC patients. Functional studies revealed that 5-HT1D significantly promoted HCC proliferation, epithelial-mesenchymal transition, and metastasis in vitro and in vivo. Mechanistically, 5-HT1D could stabilize PIK3R1 by inhibiting its ubiquitin-mediated degradation. The interaction between 5-HT1D and phosphoinositide-3-kinase regulatory subunit 1 (PIK3R1) enhanced the expression of FoxO6 through the PI3K/Akt signaling pathway; FoxO6 could also be directly transcriptionally activated by 5-HT1D in an Akt-independent manner. MicroRNA-599 was found to be an upstream suppressive modulator of 5-HT1D. Additionally, 5-HT1D could attenuate tryptophan hydroxylase 1 expression through the PI3K/Akt/cut-like homeobox 1 axis in HCC. Conclusion: Herein, we uncovered the potent oncogenic effect of 5-HT1D on HCC by interacting with PIK3R1 to activate the PI3K/Akt/FoxO6 pathway, and provided a potential therapeutic target for HCC.
Asunto(s)
Carcinoma Hepatocelular/metabolismo , Factores de Transcripción Forkhead/metabolismo , Neoplasias Hepáticas Experimentales/metabolismo , Receptor de Serotonina 5-HT1D/metabolismo , Animales , Carcinoma Hepatocelular/mortalidad , Carcinoma Hepatocelular/patología , China/epidemiología , Transición Epitelial-Mesenquimal , Femenino , Células Hep G2 , Humanos , Neoplasias Hepáticas Experimentales/mortalidad , Neoplasias Hepáticas Experimentales/patología , Masculino , Ratones Endogámicos BALB C , Ratones Desnudos , MicroARNs/metabolismo , Persona de Mediana Edad , Metástasis de la Neoplasia , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Triptófano Hidroxilasa/metabolismoRESUMEN
OBJECTIVE: Intrahepatic cholangiocarcinoma is a rare disease whose etiology is far from clear, the Ser326Cys polymorphism in human 8-hydroxyguanine glycosylase (hOGG1) has been shown associated with various cancers, however, the association of Ser326Cys (rsl052133) polymorphism and intrahepatic cholangiocarcinoma susceptibility has not been clarified. The purpose of this study is to investigate whether this polymorphism is related to the genetic susceptibility of intrahepatic cholangiocarcinoma. METHODS: A total 150 patients and 150 normal people were included in this study, the Ser326Cys polymorphisms in each group were genotyped using PCR-RFLP method. RESULTS: We found that individuals carrying Cys/Cys genotype were exposed to higher riskof intrahepatic cholangiocarcinoma (OR=2.924, 95% CI=1.475-5.780) compared with the individuals with wild type genotype Ser/Ser. Further analysis revealed that male individuals carrying Cys/Cys genotype also had increased risk (OR=2.762, 95% CI=1.233-6.173), whereas no significant difference was observed in female group. CONCLUSIONS: Therefore, our data indicates that the Ser326Cys (rs1052133) polymorphism is associated with intrahepatic cholangiocarcinoma susceptibility, and it shows preference in male population.
RESUMEN
OBJECTIVE: To explore the impact of microwave dealing with cutting surface on perioperative liver function recovery and recurrence and metastasis after hepatectomy for HCC. METHODS: Clinical data of 133 patients with HCC from March 2009 to November 2010 were retrospectively analyzed. They were divided into the conventional surgery group (66 cases) and microwave treatment group (67 cases). A domestic ECO-100 microwave knife was inserted into the liver cutting surface 0.5 cm from the cutting edge, and repeated multi-point burning with an average time of 25 minutes in the microwave treatment group. Then the perioperative liver function recovery and recurrence and metastasis in the two groups were compared. RESULTS: The operation time of conventional surgery group was (158.0 ± 31.0) minutes, and that of microwave treatment group was significantly longer (181.0 ± 28.0) minutes (P=0.027). There were no significant differences in the liver function recovery between the two groups (P>0.05). There were 6 cases of recurrence and metastasis after 6 months and 9 cases after 12 months in the microwave treatment group, while there were 15 cases of recurrence and metastasis after 6 months and 20 cases after 12 months in the conventional surgery group, showing a significant difference (P=0.034 and 0.022, respectively). CONCLUSIONS: Microwave dealing with the cutting surface has no significant effect on perioperative liver function recovery in hepatectomy. However, microwave treatment can reduce the in situ recurrence in HCC patients within the first year after surgery, indicating a good clinical application value.
Asunto(s)
Carcinoma Hepatocelular/terapia , Hepatectomía , Neoplasias Hepáticas/terapia , Microondas/uso terapéutico , Carcinoma Hepatocelular/cirugía , Humanos , Hígado/fisiología , Neoplasias Hepáticas/cirugía , Recurrencia Local de Neoplasia/prevención & control , Tempo Operativo , Recuperación de la Función , Estudios RetrospectivosRESUMEN
Stromal interaction molecule 1 (STIM1), an endoplasmic reticulum luminal Ca(2+) sensor, activates Ca(2+) -release-activated Ca(2+) channels and migrates from the Ca(2+) store to the plasma membrane. Recently, STIM1 was shown be critical for the progression of several cancers, including breast cancer and cervical cancer. However, its role in hepatocellular carcinoma has remained unknown. The current study was aimed to evaluate the effect of STIM1 on the growth of hepatocellular cancer. Lentivirus-mediated short hairpin RNA targeting STIM1 was transduced into SMMC7721 cells to knock down STIM1 expression. Knockdown of STIM1 significantly inhibited cell proliferation and colony-forming ability and arrested the cell cycle at the G0/G1 phase. Moreover, the DNA synthesis progression was also decreased. Furthermore, lentiviral vector-mediated overexpression of STIM1 promoted the proliferation of SMMC7721 cells. Our findings suggest that STIM1 may play an important role in the development of hepatocellular cancer and may be a potential target for therapy.
Asunto(s)
Carcinoma Hepatocelular/patología , Puntos de Control del Ciclo Celular/genética , Neoplasias Hepáticas/patología , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Interferencia de ARN , Línea Celular Tumoral , Proliferación Celular/genética , Puntos de Control de la Fase G1 del Ciclo Celular/genética , Regulación Neoplásica de la Expresión Génica/genética , Técnicas de Silenciamiento del Gen , Humanos , Lentivirus/genética , Proteínas de la Membrana/deficiencia , Proteínas de Neoplasias/deficiencia , Fase de Descanso del Ciclo Celular/genética , Molécula de Interacción Estromal 1RESUMEN
We sought to evaluate the efficacy and effects of low-dose tacrolimus (FK506) to recipients with living donor liver transplantation (LDLT). A total of 66 patients who underwent LDLT between 2001 and 2007 were enrolled in this study. According to different doses of tacrolimus, the recipients were randomly divided into two groups: the low-dose tacrolimus group (group A) and the normal-dose tacrolimus group (group B). The blood concentration of tacrolimus and its side effects including infection, hyperglycemia, hypertension, high blood creatinine and jaundice were monitored once a week at the perioperative period, and once a month thereafter. Besides, the survival rates of the recipients were analyzed at the 1- and 3-year time point after operation. Among these patients, no significant acute rejection was detected after LDLT. The incidences of infection, hyperglycemia, liver dysfunction and renal impairment in group A were markedly lower than those in group B. However, no significant differences were detected in the incidence of hypertension between the two groups. Moreover, the recipients in each group had a similar survival rate according to the results of 1- and 3-year follow-up. The incidence of side effects that associated with tacrolimus positively correlated with tacrolimus blood concentration. In conclusion, long-term and low-dose administration of tacrolimus is a safe and effective treatment for LDLT recipients.
RESUMEN
BACKGROUND: Low-dose lipopolysaccharide (LPS) preconditioning-induced liver protection has been demonstrated during ischemia-reperfusion injury (IRI) in several organs but has not been sufficiently elucidated underlying causal mechanism. This study investigated the role of low-dose LPS preconditioning on ATF4-CHOP pathway as well as the effects of the pathway on tissue injury and inflammation in a mouse model of liver partial-warm IRI. METHODS: LPS (100 µg/kg/d) was injected intraperitoneally two days before ischemia. Hepatic injury was evaluated based on serum alanine aminotransferase levels, histopathology, and caspase-3 activity. The ATF4-CHOP pathway and its related apoptotic molecules were investigated after reperfusion. The role of LPS preconditioning on apoptosis and ATF4-CHOP pathway was examined in vitro. Moreover, the effects of the ATF4-CHOP pathway on apoptosis, Caspase-12, and Caspase-3 were determined with ATF4 small interfering RNA (siRNA). Inflammatory cytokine expression was also checked after reperfusion. Inflammatory cytokines and related signaling pathways were analyzed in vitro in macrophages treated by LPS preconditioning or ATF4 siRNA. RESULTS: LPS preconditioning significantly attenuated liver injury after IRI. As demonstrated by in vitro experiments, LPS preconditioning significantly reduced the upregulation of the ATF4-CHOP pathway and inhibited Caspase-12 and Caspase-3 activation after IRI. Later experiments showed that ATF4 knockdown significantly suppressed CHOP, cleaved caspase-12 and caspase-3 expression, as well as inhibited hepatocellular apoptosis. In addition, in mice pretreated with LPS, TNF-α and IL-6 were inhibited after reperfusion, whereas IL-10 was upregulated. Similarly, low-dose LPS significantly inhibited TNF-α, IL-6, ATF4-CHOP pathway, NF-κB pathway, and ERK1/2 in high-dose LPS-stimulated macrophages, whereas IL-10 and cytokine signaling (SOCS)-3 suppressor were induced. Importantly, ATF4 siRNA is consistent with results of LPS preconditioning in macrophages. CONCLUSIONS: This work is the first time to provide evidence for LPS preconditioning protects hepatocytes from IRI through inhibiting ATF4-CHOP pathway, which may be critical to reducing related apoptosis molecules and modulating innate inflammation.
Asunto(s)
Factor de Transcripción Activador 4/metabolismo , Hepatocitos/efectos de los fármacos , Precondicionamiento Isquémico , Lipopolisacáridos/farmacología , Daño por Reperfusión/prevención & control , Transducción de Señal/efectos de los fármacos , Factor de Transcripción CHOP/metabolismo , Factor de Transcripción Activador 4/deficiencia , Factor de Transcripción Activador 4/genética , Animales , Apoptosis/efectos de los fármacos , Caspasa 12/metabolismo , Caspasa 3/metabolismo , Relación Dosis-Respuesta a Droga , Activación Enzimática/efectos de los fármacos , Técnicas de Silenciamiento del Gen , Hepatocitos/inmunología , Hepatocitos/metabolismo , Hepatocitos/patología , Peróxido de Hidrógeno/farmacología , Masculino , Ratones , Proteínas Quinasas Activadas por Mitógenos/metabolismo , FN-kappa B/metabolismo , Daño por Reperfusión/inmunología , Daño por Reperfusión/metabolismo , Daño por Reperfusión/patologíaRESUMEN
Interleukin-26 (IL-26) is one of the cytokines secreted by Th17 cells whose role in human tumors remains unknown. Here, we investigated the expression and potential role of IL-26 in human gastric cancer (GC). The expression of IL-26 and related molecules such as IL-20R1, STAT1 and STAT3 was examined by real-time PCR and immunohistochemisty. The effects of IL-26 on cell proliferation and cisplatin-induced apoptosis were analyzed by BrdU cooperation assay and PI-Annexin V co-staining, respectively. Lentiviral mediated siRNA was used to explore its mechanism of action, and IL-26 related signaling was analyzed by western blotting. Human GC tissues showed increased levels of IL-26 and its related molecules and activation of STAT3 signaling, whereas STAT1 activation did not differ significantly between GC and normal gastric tissues. Moreover, IL-26 was primarily produced by Th17 and NK cells. IL-26 promoted the proliferation and survival of MKN45 and SGC-7901 gastric cancer cells in a dose-dependent manner. Furthermore, IL-20R2 and IL-10R1, which are two essential receptors for IL-26 signaling, were expressed in both cell lines. IL-26 activated STAT1 and STAT3 signaling; however, the upregulation of the expression of Bcl-2, Bcl-xl and c-myc indicated that the effect of IL-26 is mediated by STAT3 activation. Knockdown of STAT1 and STAT3 expression suggested that the proliferative and anti-apoptotic effects of IL-26 are mediated by the modulation of STAT1/STAT3 activation. In summary, elevated levels of IL-26 in human GC promote proliferation and survival by modulating STAT1/STAT3 signaling.
Asunto(s)
Interleucinas/metabolismo , Factor de Transcripción STAT1/metabolismo , Factor de Transcripción STAT3/metabolismo , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patología , Apoptosis/efectos de los fármacos , Apoptosis/genética , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Interleucinas/genética , Interleucinas/farmacología , Células Asesinas Naturales/efectos de los fármacos , Células Asesinas Naturales/metabolismo , Masculino , Persona de Mediana Edad , Transducción de Señal/efectos de los fármacos , Neoplasias Gástricas/genética , Células Th17/efectos de los fármacos , Células Th17/metabolismoRESUMEN
BACKGROUND: Glycogen synthase kinase (GSK)-3beta/beta-catenin signaling regulates ischemia-reperfusion (I/R)-induced apoptosis and proliferation, and inhibition of GSK-3beta has beneficial effects on I/R injury in the heart and the central nervous system. However, the role of this signaling in hepatic I/R injury remains unclear. The present study aimed to investigate the effects and mechanism of GSK-3beta/beta-catenin signaling in hepatic I/R injury. METHODS: Male C57BL/6 mice (weighing 22-25 g) were pretreated with either SB216763, an inhibitor of GSK-3beta, or vehicle. These mice were subjected to partial hepatic I/R. Blood was collected for test of alanine aminotransferase (ALT), and liver specimen for assays of phosphorylation at the Ser9 residue of GSK-3beta, GSK-3beta activity, axin 2 and the anti-apoptotic factors Bcl-2 and survivin, as well as the proliferative factors cyclin D1 and proliferating cell nuclear antigen, and apoptotic index (TUNEL). Real-time PCR, Western blotting and immunohistochemical staining were used. RESULTS: SB216763 increased phospho-GSK-3beta levels and suppressed GSK-3beta activity (1880+/-229 vs 3280+/-272 cpm, P<0.01). ALT peaked at 6 hours after reperfusion. Compared with control, SB216763 decreased ALT after 6 hours of reperfusion (4451+/-424 vs 7868+/-845 IU/L, P<0.01), and alleviated hepatocyte necrosis and vacuolization. GSK-3beta inhibition led to the accumulation of beta-catenin in the cytosol (0.40+/-0.05 vs 1.31+/-0.11, P<0.05) and nucleus (0.62+/-0.14 vs 1.73+/-0.12, P<0.05), beta-catenin further upregulated the expression of axin 2. Upregulation of GSK-3beta/beta-catenin signaling increased Bcl-2, survivin and cyclin D1. Serological and histological analyses showed that SB216763 alleviated hepatic I/R-induced injury by reducing apoptosis (1.4+/-0.2% vs 3.6+/-0.4%, P<0.05) and enhanced liver proliferation (56+/-8% vs 19+/-4%, P<0.05). CONCLUSION: Inhibition of GSK-3beta ameliorates hepatic I/R injury through the GSK-3beta/beta-catenin signaling pathway.
Asunto(s)
Glucógeno Sintasa Quinasa 3/antagonistas & inhibidores , Indoles/farmacología , Hígado/efectos de los fármacos , Maleimidas/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Daño por Reperfusión/prevención & control , Transducción de Señal/efectos de los fármacos , beta Catenina/metabolismo , Alanina Transaminasa/sangre , Animales , Apoptosis/efectos de los fármacos , Proteína Axina/metabolismo , Western Blotting , Proliferación Celular/efectos de los fármacos , Ciclina D1/metabolismo , Modelos Animales de Enfermedad , Regulación de la Expresión Génica , Glucógeno Sintasa Quinasa 3/metabolismo , Glucógeno Sintasa Quinasa 3 beta , Inmunohistoquímica , Proteínas Inhibidoras de la Apoptosis/metabolismo , Hígado/irrigación sanguínea , Hígado/enzimología , Hígado/patología , Regeneración Hepática/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Fosforilación , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2 , Reacción en Cadena en Tiempo Real de la Polimerasa , Daño por Reperfusión/enzimología , Daño por Reperfusión/genética , Daño por Reperfusión/patología , Proteínas Represoras/metabolismo , Survivin , Factores de TiempoRESUMEN
Omega-3 fatty acid supplemented total parenteral nutrition improves the clinical outcome of patients undergoing certain operations; however, its benefits for patients with hepatitis type B virus (HBV)-associated hepatocellular carcinoma (HCC) who have undergone hepatectomy are still not clear. The aim of this study was to evaluate the effect of omega-3 fatty acid supplemented total parenteral nutrition on the clinical outcome of patients with HBV-associated HCC who underwent hepatectomy at our institution. A total of 63 patients with HBV-associated HCC who underwent hepatectomy were included in this study. These patients were randomly assigned to receive standard total parenteral nutrition (the control group, n = 31) or omega-3 fatty acid supplemented total parenteral nutrition (the omega-3 fatty acid group, n = 32) for at least 5 d. The study endpoints were the occurrence of infection-related complications, recovery of liver function and length of hospital stay. The results showed that the omega-3 fatty acid group had a lower infection rate (omega-3 fatty acid, 19.4% vs control, 43.8%, P < 0.05), a better liver function after hepatectomy: alanine transaminase (omega-3 fatty acid, 48.23±18.48 U/L vs control, 73.34±40.60 U/L, P < 0.01), aspartate transaminase (omega-3 fatty acid, 35.77±14.56 U/L vs control, 50.53±24.62 U/L, P < 0.01), total bilirubin (omega-3 fatty acid, 24.29±7.40 mmol/L vs control, 28. 37±8.06 mmol/L, P < 0.05) and a shorter length of hospital stay (omega-3 fatty acid, 12.71±2.58 d vs control, 15.91±3.23 d, P < 0.01). The serum contents of IL-6 (omega-3 fatty acid, 23.98±5.63 pg/mL vs control, 35.55±7.5 pg/mL, P < 0.01) and TNF-α (omega-3 fatty acid, 4.43±1.22 pg/mL vs control, 5.96±1.58 pg/mL, P < 0.01) after hepatectomy were significantly lower in the omega-3 fatty acid group than those of the control group. In conclusion, administration of omega-3 fatty acid may reduce infection rate and improve liver function recovery in HBV-associated HCC patients after hepatectomy. This improvement is associated with suppressed production of proinflammatory cytokines in these patients.