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The chemokine receptor CXCR3 is functionally pleiotropic, not only recruiting immune cells to the inflamed liver but also mediating the pathological process of cholestatic liver injury (CLI). However, the mechanism of its involvement in the CLI remains unclear. Both alpha-naphthylisothiocyanate (ANIT) and triptolide are hepatotoxicants that induce CLI by bile acid (BA) dysregulation, inflammation, and endoplasmic reticulum (ER)/oxidative stress. Through molecular docking, CXCR3 is a potential target of ANIT and triptolide. Therefore, this study aimed to investigate the role of CXCR3 in ANIT- and triptolide-induced CLI and to explore the underlying mechanisms. Wild-type mice and CXCR3-deficient mice were administered with ANIT or triptolide to compare CLI, BA profile, hepatic recruitment of IFN-γ/IL-4/IL-17+CD4+T cells, IFN-γ/IL-4/IL-17+iNKT cells and IFN-γ/IL-4+NK cells, and the expression of ER/oxidative stress pathway. The results showed that CXCR3 deficiency ameliorated ANIT- and triptolide-induced CLI. CXCR3 deficiency alleviated ANIT-induced dysregulated BA metabolism, which decreased the recruitment of IFN-γ+NK cells and IL-4+NK cells to the liver and inhibited ER stress. After triptolide administration, CXCR3 deficiency ameliorated dysregulation of BA metabolism, which reduced the migration of IL-4+iNKT cells and IL-17+iNKT cells and reduced oxidative stress through inhibition of Egr1 expression and AKT phosphorylation. Our findings suggest a detrimental role of CXCR3 in ANIT- and triptolide-induced CLI, providing a promising therapeutic target and introducing novel mechanisms for understanding cholestatic liver diseases.
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1-Naftilisotiocianato , Colestasis , Diterpenos , Fenantrenos , Animales , Ratones , 1-Naftilisotiocianato/toxicidad , 1-Naftilisotiocianato/metabolismo , Interleucina-17/toxicidad , Interleucina-17/metabolismo , Interleucina-17/uso terapéutico , Interleucina-4/toxicidad , Interleucina-4/metabolismo , Interleucina-4/uso terapéutico , Simulación del Acoplamiento Molecular , Hígado/metabolismo , Colestasis/inducido químicamente , Ácidos y Sales Biliares , Compuestos EpoxiRESUMEN
Esophageal squamous cell carcinoma is a severe malignancy for its high mortality and poor prognosis. Mainstay chemotherapies cause serious side effects for their ways of inducing cell death. Oridonin is the main bioactive constituent from natural plants that has anticancer ability and weak side effects. The proteomics method is efficient to understand the anticancer mechanism. However, proteins identified by proteomics aimed at understanding oridonin's anticancer mechanism is seldom overlapped by different groups. This study used proteomics based on two-dimensional electrophoresis sodium dodecyl sulfate-polyacrylamide gel electrophoresis (2-DE SDS-PAGE) integrated with mass spectrometry and Gene Set Enrichment Analysis (GSEA) to understand the anticancer mechanism of oridonin on esophageal squamous cell carcinoma (ESCC). The results showed that oridonin induced ESCC cell death via apoptosis by decreasing the protein expression of LASP1 and PDLIM1.
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Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Proteínas con Dominio LIM , Humanos , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Apoptosis , Línea Celular Tumoral , Proliferación Celular , Proteínas del Citoesqueleto/metabolismo , Neoplasias Esofágicas/tratamiento farmacológico , Carcinoma de Células Escamosas de Esófago/tratamiento farmacológico , Proteínas con Dominio LIM/antagonistas & inhibidores , Proteínas con Dominio LIM/metabolismoRESUMEN
The driving roles of fusion genes during tumorigenesis have been recognized for decades, with efficacies demonstrated in clinical diagnosis and targeted therapy. With advances in sequencing technologies and computational biology, a surge in the identification of fusion genes has been witnessed during the past decade. The discovery and presence of splicing based fusions in normal tissues have challenged our canonical conceptions on fusion genes and offered us novel medical opportunities. The specificity of fusion genes to neoplastic tissues and their diverse functionalities during carcinogenesis foster them as promising tools in the battle against cancer. It is time to re-visit and comb through our cutting-edge knowledge on fusion genes to accelerate clinical translation of these internal markers. Urged as such, we are encouraged to categorize fusion events according to mechanisms leading to their generation, oncological consequences and clinical implications, offer insights on fusion occurrence across tumors from the system level, highlight feasible practices in fusion-related pharmaceutical development, and identify understudied yet important niches that may lead future research trend in this field.
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Biomarcadores de Tumor/genética , Fusión Génica , Neoplasias/genética , Animales , Antineoplásicos/uso terapéutico , Toma de Decisiones Clínicas , Regulación Neoplásica de la Expresión Génica , Predisposición Genética a la Enfermedad , Humanos , Técnicas de Diagnóstico Molecular , Terapia Molecular Dirigida , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Fenotipo , Medicina de Precisión , Valor Predictivo de las PruebasRESUMEN
Hepatocellular carcinoma (HCC) exerts huge effects on the health burden of the world because of its high mortality and poor prognosis. HCC is often clinically detected late in patients. If HCC could be detected and treated earlier, the survival rate of patients will be greatly improved. Therefore, identifying specific biomarkers is urgent and important for HCC. The liver is also recognized as an immune organ. The occurrence of HCC is related to exacerbation of immune tolerance and/or immunosurveillance escape. The host immune system plays an important role in the recognition and targeting of tumor cells in cancer immunotherapy, as can be seen from the clinical success of immune checkpoint inhibitors and chimeric antigen receptor (CAR) T cells. Thus, there is a pressing medical need to discover immunodiagnostic biomarkers specific to HCC for understanding the pathological mechanisms of HCC, especially for immunotherapy targets. We have reviewed the existing literature to summarize the immunodiagnostic markers of HCC, including autoantibodies against tumor-associated antigens (TAAs) and exosomes, to provide new insights into HCC and early detection of this deadly cancer.
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Biomarcadores de Tumor/análisis , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/terapia , Inmunoterapia/métodos , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/terapia , Animales , Carcinoma Hepatocelular/inmunología , Humanos , Neoplasias Hepáticas/inmunología , Microambiente Tumoral/inmunologíaRESUMEN
We evaluated autoantibodies against nine tumor-associated antigens, including p62, p16, Koc, p53, Cyclin B1, Cyclin E, Survivin, HCC1, and RalA as serological markers in lung cancer. Enzyme-linked immunosorbent assay (ELISA) was used to detect autoantibodies in sera from 50 lung cancer patients and 42 normal controls. Then, four tumor-associated antigens of higher values were selected and validated in sera from validation group. Western blot and serum absorption test were used to confirm positive findings from ELISA. When cutoff values were set as mean optical density values plus 3 standard deviation of normal controls, the positive rate of autoantibodies against four tumor-associated antigens (Survivin, Cyclin B1, HCC1, and p53) reached 32%, 20%, 22%, and 18%, with area under the curve values of 0.653, 0.767, 0.622, and 0.623 in sera from 50 lung cancer, respectively (all p < 0.05). Results from the validation group confirmed the results. When lung cancer patients were divided by their clinicopathological characteristics into different subgroups, we have found that serum anti-Cyclin B1 and anti-HCC1 autoantibodies increased in stages 1, 2, and 3 lung cancer; anti-Survivin autoantibodies increased in stages 2 and 3 lung cancer; and anti-p53 autoantibody only increased in stage 1 when compared with their corresponding levels in controls (all p < 0.05). Serum anti-Cyclin B1 and anti-Survivin autoantibodies increased with disease histological grade 2 and 3 (both p < 0.05). And higher serum level of anti-p53 autoantibodies is positively associated with tumor size. Parallel utilization of these four anti-tumor-associated antigens (any positive) can increase sensitivity to 65.0% at 100% specificity with area under the curve of 0.908 ( p < 0.001) in lung cancer detection in validation group. Our results suggest that autoantibodies against these four tumor-associated antigens have higher values in lung cancer detection, and serum anti-Cyclin-B1 has the potential to serve as novel non-invasive biomarkers in early-stage lung cancer.
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Antígenos de Neoplasias/sangre , Autoanticuerpos/sangre , Biomarcadores de Tumor/sangre , Neoplasias Pulmonares/sangre , Anciano , Anciano de 80 o más Años , Antígenos de Neoplasias/inmunología , Autoanticuerpos/inmunología , Biomarcadores de Tumor/inmunología , Ciclina B1/sangre , Ciclina B1/inmunología , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Proteínas Inhibidoras de la Apoptosis/sangre , Proteínas Inhibidoras de la Apoptosis/inmunología , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Proteínas Nucleares/sangre , Proteínas Nucleares/inmunología , Survivin , Proteína p53 Supresora de Tumor/sangre , Proteína p53 Supresora de Tumor/inmunologíaRESUMEN
In this study, enzyme-linked immunosorbent assay has been used to examine the frequencies of serum autoantibodies against two candidate tumor-associated antigens intensively selected from the Human Protein Atlas database, in combination with 13 tumor-associated antigens available from our lab in sera from 44 OC patients and 50 normal healthy controls. Conventional evaluation (mean + 3SD as the cutoff value to determine a positive reactivity), receiver operating characteristic curve analyses, and classification tree analysis were further used to evaluate the diagnostic performance of autoantibodies against these tumor-associated antigens (anti-tumor-associated antigens) in ovarian cancer. For single anti-tumor-associated antigen, when the cutoff values were set as mean + 3SD of normal healthy controls, NPM1, MDM2, PLAT, p53, and c-Myc could achieve sensitivity higher than 20% at 98% specificity. Combinational utilization of autoantibodies against MDM2, PLAT, NPM1, 14-3-3 Zeta, p53, and RalA achieved the optimal diagnostic performance with 72.7% sensitivity at 96% specificity. Receiver operating characteristic curve analysis showed that the area under the receiver operating characteristic curves of autoantibodies against c-Myc, NPM1, MDM2, p16, p53, and 14-3-3 Zeta were greater than 0.80. This indicated that these tumor-associated antigens held high potential to serve as diagnostic biomarkers in ovarian cancer detection. Decision tree analysis indicated that anti-c-Myc held high potential in the detection of ovarian cancer. Further studies are warranted to validate the diagnostic performance of these anti-tumor-associated antigens with high area under the receiver operating characteristic curve, including autoantibodies against c-Myc, MDM2, PLAT, NPM1, 14-3-3 Zeta, p53, and RalA.
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Antígenos de Neoplasias/sangre , Autoanticuerpos/sangre , Biomarcadores de Tumor/sangre , Neoplasias Ováricas/sangre , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Proteínas de Neoplasias/sangre , Nucleofosmina , Neoplasias Ováricas/patologíaRESUMEN
BACKGROUND: The prostate-specific antigen (PSA) testing has been widely implemented for the early detection and management of prostate cancer (PCa). However, the lack of specificity has led to overdiagnosis, resulting in many possibly unnecessary biopsies and overtreatment. Therefore, novel serological biomarkers with high sensitivity and specificity are of vital importance needed to complement PSA testing in the early diagnosis and effective management of PCa. This is particularly critical in the context of PCa health disparities, where early detection and management could help reduce the disproportionately high PCa mortality observed in African-American men. Previous studies have demonstrated that sera from patients with PCa contain autoantibodies that react with tumor-associated antigens (TAAs). METHODS: The serological proteome analysis (SERPA) approach was used to identify tumor-associated antigens (TAAs) of PCa. In evaluation study, the level of anti-NPM1 antibody was examined in sera from test cohort, validation cohort, as well as European-American (EA) and African-American (AA) men with PCa by using immunoassay. RESULTS: Nucleophosmin 1 (NPM1) as a 33 kDa TAA in PCa was identified and characterized by SERPA approach. Anti-NPM1 antibody level in PCa was higher than in benign prostatic hyperplasia (BPH) patients and healthy individuals. Receiver operating characteristic (ROC) curve analysis showed similar high diagnostic value for PCa in the test cohort (area under the curve (AUC):0.860) and validation cohort (AUC: 0.822) to differentiate from normal individuals and BPH. Interestingly, AUC values were significantly higher for AA PCa patients. When considering concurrent serum measurements of anti-NPM1 antibody and PSA, 97.1% PCa patients at early stage were identified correctly, while 69.2% BPH patients who had elevated PSA levels were found to be anti-NPM1 negative. Additionally, anti-NPM1 antibody levels in PCa patients at early stage significantly increased after surgery treatment. CONCLUSION: This intriguing data suggested that NPM1 can elicit autoantibody response in PCa and might be a potential biomarker for the immunodiagnosis and prognosis of PCa, and for supplementing PSA testing in distinguishing PCa from BPH. Prostate 76:1375-1386, 2016. © 2016 Wiley Periodicals, Inc.
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Antígenos de Neoplasias/inmunología , Negro o Afroamericano , Proteínas Nucleares/inmunología , Hiperplasia Prostática/inmunología , Neoplasias de la Próstata/inmunología , Población Blanca , Antígenos de Neoplasias/sangre , Autoanticuerpos/sangre , Autoanticuerpos/inmunología , Biomarcadores de Tumor/sangre , Biomarcadores de Tumor/inmunología , Línea Celular Tumoral , Humanos , Masculino , Proteínas Nucleares/sangre , Nucleofosmina , Hiperplasia Prostática/sangre , Neoplasias de la Próstata/sangre , Neoplasias de la Próstata/etnología , ProteomaRESUMEN
A single-nucleotide polymorphism (rs2274223: A5780G:His1927Arg) in the phospholipase C epsilon gene (PLCϵ) was recently identified as a susceptibility locus for esophageal cancer in Chinese subjects. To determine the underlying mechanisms of PLCϵ and this SNP in esophageal carcinogenesis, we analyzed PLCϵ genotypes, expression, and their correlation in esophageal cancer cell lines, non-transformed esophageal cells, 58 esophageal squamous cell carcinomas and 10,614 non-cancer subjects from China. We found that the G allele (AG or GG) was associated with increased PLCϵ mRNA and protein expression in esophageal cancer tissues and in esophageal cancer cell lines. G allele was also associated with higher enzyme activity, which might be associated with increased protein expression. Quantitative analysis of the C2 domain sequences revealed that A:G allelic imbalance was strongly linked to esophageal malignancy. Moreover, the analysis of 10,614 non-cancer subjects demonstrated that the G allele was strongly associated with moderate to severe esophagitis in the subjects from the high-incidence areas of China (OR 6.03, 95% CI 1.59-22.9 in high-incidence area vs. OR 0.74, 95% CI 0.33-1.64 in low-incidence area; P = 0.008). In conclusion, the PLCϵ gene, particularly the 5780G allele, might play a pivotal role in esophageal carcinogenesis via upregulating PLCϵ mRNA, protein, and enzyme activity, and augmenting inflammatory process in esophageal epithelium. Thus, 5780G allele may constitute a promising biomarker for esophageal squamous cell carcinoma risk stratification, early detection, and progression prediction.
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Carcinoma de Células Escamosas/genética , Neoplasias Esofágicas/genética , Esofagitis/genética , Fosfoinositido Fosfolipasa C/genética , Polimorfismo de Nucleótido Simple/genética , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Carcinoma de Células Escamosas/enzimología , Carcinoma de Células Escamosas/patología , Estudios de Casos y Controles , Neoplasias Esofágicas/enzimología , Neoplasias Esofágicas/patología , Esofagitis/enzimología , Esofagitis/patología , Genotipo , Humanos , Immunoblotting , Técnicas para Inmunoenzimas , Estadificación de Neoplasias , Fosfoinositido Fosfolipasa C/metabolismo , Reacción en Cadena de la Polimerasa , Pronóstico , Reacción en Cadena en Tiempo Real de la Polimerasa , Células Tumorales CultivadasRESUMEN
Displacement measurement is of great significance to monitor the crack variation and ensure the health of building structures. Aiming at the problems of low sensitivity and high temperature error of fiber Bragg grating (FBG) displacement sensors in displacement monitoring, this paper presents an adjustable cantilever beam displacement sensor with the FBGs as the sensing element. The sensor adds double FBGs on the relative surfaces of the equal-strength cantilever beam, which increases the bending deformation on the FBG of the beam surface to improve the sensitivity and realize the temperature compensation of the sensor. By adding an adjustable external rod structure between a flexible spring and a fixed foot stand, the sensor can regulate the range of initial crack width for different occasions. A theoretical analysis of the displacement sensor is performed, and the simulation analysis and optimization design for the structural parameters of the cantilever beam elastic sensitive element are implemented by adopting SolidWorks and ANSYS software. Finally, a displacement testing platform is constructed to test its performance. Experimental results show that this design has a high sensitivity coefficient of 39.47 pm/mm and a temperature coefficient of 1.04 pm/°C in the range of initial crack width from 0 to 110 mm or from 0 to 130 mm depending on different monitoring situations. Furthermore, good linearity, hysteresis delay, repeatability, and temperature compensation performance have also been demonstrated.
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Purpose: This study was based on hepatocellular carcinoma (HCC) patients of early-stage to explore the diagnostic capability and possible production causes of anti-GNAS autoantibody. Methods: We evaluated the frequency of anti-GNAS autoantibody in sera from patients with early-stage HCC by enzyme-linked immunosorbent assay (ELISA) and the expression of GNAS protein in early-stage HCC tissues by immunohistochemistry. Western blotting (WB) and real-time polymerase chain reaction (RT-PCR) were utilized to examine the expressions of GNAS protein and mRNA in cell lines. GEO and International Cancer Genome Consortium (ICGC) databases were inquired to explore mRNA expression and mutation of GNAS in HCC tissues. Results: The positive rates of anti-GNAS autoantibody in HCC patients at clinical stage I (78.1 %) and clinical stage II (57.1 %) were all significantly higher than that in healthy control (20 %). There was also a significant difference in GNAS protein expression between HCC and its adjacent normal liver tissues. The results from WB and RT-PCR showed a significant difference at the mRNA level but no statistical difference at the protein level between HCC and normal liver cell lines. The difference in mRNA level between HCC and adjacent normal liver tissues was verified to be significant. Furthermore, the ICGC database demonstrated a 10.6 % mutation frequency for GNAS in HCC patients. Conclusion: The coordination of elevated anti-GNAS autoantibody, high expression of GNAS in the mRNA and protein levels in HCC, and high frequency of GNAS mutation indicates that anti-GNAS autoantibody may be used as an early indicator of HCC.
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BACKGROUND: As the main component of oral contraceptives (OCs), ethinylestradiol (EE) has been widely applied as a model drug to induce murine intrahepatic cholestasis. The clinical counterpart of EE-induced cholestasis includes women who are taking OCs, sex hormone replacement therapy, and susceptible pregnant women. Taking intrahepatic cholestasis of pregnancy (ICP) as an example, ICP consumes the medical system due to its high-risk fetal burden and the impotency of ursodeoxycholic acid in reducing adverse perinatal outcomes. AIM: To explore the mechanisms and therapeutic strategies of EE-induced cholestasis based on the liver immune microenvironment. METHODS: Male C57BL/6J mice or invariant natural killer T (iNKT) cell deficiency (Jα18-/- mice) were administered with EE (10 mg/kg, subcutaneous) for 14 d. RESULTS: Both Th1 and Th2 cytokines produced by NKT cells increased in the liver skewing toward a Th1 bias. The expression of the chemokine/chemokine receptor Cxcr6/Cxcl16, toll-like receptors, Ras/Rad, and PI3K/Bad signaling was upregulated after EE administration. EE also influenced bile acid synthase Cyp7a1, Cyp8b1, and tight junctions ZO-1 and Occludin, which might be associated with EE-induced cholestasis. iNKT cell deficiency (Jα18-/- mice) robustly alleviated cholestatic liver damage and lowered the expression of the abovementioned signaling pathways. CONCLUSION: Hepatic NKT cells play a pathogenic role in EE-induced intrahepatic cholestasis. Our research improves the understanding of intrahepatic cholestasis by revealing the hepatic immune microenvironment and also provides a potential clinical treatment by regulating iNKT cells.
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Colestasis Intrahepática , Colestasis , Células T Asesinas Naturales , Animales , Colestasis/patología , Colestasis Intrahepática/inducido químicamente , Etinilestradiol/efectos adversos , Etinilestradiol/metabolismo , Femenino , Humanos , Hígado/patología , Masculino , Ratones , Ratones Endogámicos C57BL , EmbarazoRESUMEN
Acute myeloid leukemia (AML) is a hematological malignancy derived from immature myeloid cells, which have the characteristics of abnormal proliferation and differentiation. Glycolysis has been a popular topic of research in recent years, with increasing uptake and consumption of glucose. The present study aimed to investigate the glycolysis of tumor cells in patients with AML; in particular, how programmed cell death 1 ligand 1 (PDL1) regulates tumor cells glycolysis using real time PCR (RTPCR), western blotting and flow cytometry. PDL1 high expression predicted poor outcome in patients with AML in the public database Gene Expression Profiling Interactive Analysis. PDL1 expression was decreased in the samples from patients with AML with complete remission compared to that in patients with relapsed or refractory AML. In AML cell lines, glycolysisassociated genes ALDOA, PGK1, LDHA and HK2 were highly expressed in a PDL1 highexpressed cell line. Overexpressed PDL1 enhanced glucose consumption and the extracellular acidification rate, accompanied by decreased apoptosis and accumulation of cells in the S phase. In contrast, the apoptosis rate of tumor cells and the percentage of cells in the S phase were significantly increased following PDL1 knockdown in the THP1 cell line. HK2 and LDHA expression decreased after AML tumor cells were treated with Akt inhibitor or rapamycin. In addition, the PDL1overexpressed cell line (PDL1OV) MOLM13 exhibited rapid tumor progression. Glycolysisassociated genes were highly expressed in tumor tissues of PDL1OV MOLM13, with increased Ki67. Based on these findings, PDL1 may be considered as a suitable marker for prognosis and treatment in the clinical setting.
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Antígeno B7-H1/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Leucemia Mieloide Aguda/genética , Serina-Treonina Quinasas TOR/genética , Apoptosis/genética , Línea Celular Tumoral , Fructosa-Bifosfato Aldolasa/genética , Regulación Neoplásica de la Expresión Génica/genética , Glucólisis/genética , Hexoquinasa/genética , Humanos , L-Lactato Deshidrogenasa/genética , Leucemia Mieloide Aguda/patología , Proteína Oncogénica v-akt/genética , Fosfoglicerato Quinasa/genética , Transducción de Señal/genéticaRESUMEN
p62/IMP2 is an oncofetal protein that was first reported as a tumor-associated antigen in hepatocellular carcinoma (HCC). In our previous studies, we demonstrated a high frequency of p62/IMP2 autoantibodies appearing in various types of cancer. Therefore, we hypothesize that p62/IMP2 plays an important role in the progression of HCC, although the mechanism remains to be explored. In this study, we evaluated the expression of p62/IMP2 protein both in human tissues and liver cancer cell lines by immunohistochemistry and western blotting analysis and found that p62/IMP2 protein is overexpressed in human HCC tissue in comparison to normal human liver tissue. To explore the role that p62/IMP2 plays in HCC, p62/IMP2 was knocked out in two p62/IMP2-positive liver cancer cell lines (SNU449 and HepG2). Due to the low expression level of p62/IMP2 in SNU449, we overexpressed p62/IMP2 in this cell line. We subsequently demonstrated that high expression of p62/IMP2 in both cell lines can promote cell migration and invasion abilities in vitro by activating the Wnt/ß-catenin pathway. We also used the Wnt/ß-catenin pathway inhibitor, XAV 939, and a phosphoproteome assay to confirm our findings. Conclusion: Our results suggest that p62/IMP2 is an essential regulator of Wnt signaling pathways and plays an important role in HCC progression and metastasis.
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Autoantibodies against intracellular tumor-associated antigens (TAAs) are commonly found in human cancers. In this study, we characterized the serum autoantibody response to the RalA, Ras-like GTPase, in patients with prostate cancer (PCa). The autoantibodies were detected by immunofluorescence assay in PCa cell lines, ELISA, and immunoblotting in 339 serum samples from patients with PCa and benign prostatic hyperplasia (BPH), and in normal human sera (NHS). The expression of RalA in prostate tumor tissues was evaluated by immunohistochemistry (IHC) in tumor microarrays. The autoantibody level to RalA (median) in NHS was significantly lower than in PCa (0.053 vs 0.138; P < 0.001) and BPH (0.053 vs 0.132; P < 0.005) groups. The circulating anti-RalA autoantibody could distinguish PCa patients from normal individuals with the area under the receiver operating characteristic (ROC) curve (AUC) performing at 0.861, with sensitivity of 52.9% and specificity of 91.0%. Elevation in serum immunoreactivity was observed in PCa patients after radical prostatectomy. The combined use of both anti-RalA autoantibody and PSA showed a significantly higher discriminatory ability compared with either of those markers alone. RalA protein expression was detected by IHC in 85.3% of tumor tissues from PCa patients, but without significant difference compared to BPH or normal control tissues. Together, our study shows the additional benefits of anti-RalA autoantibody as a potential serological biomarker for PCa, particularly in patients with normal PSA, and further demonstrate the utility of biomarker combinations in the immunodiagnosis of PCa.
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Antígenos de Neoplasias/inmunología , Autoanticuerpos/sangre , Neoplasias de la Próstata/sangre , Neoplasias de la Próstata/inmunología , Proteínas de Unión al GTP ral/inmunología , Anciano , Área Bajo la Curva , Autoantígenos/inmunología , Autoantígenos/metabolismo , Biomarcadores de Tumor/sangre , Western Blotting , Ensayo de Inmunoadsorción Enzimática , Humanos , Inmunohistoquímica , Masculino , Microscopía Fluorescente , Persona de Mediana Edad , Clasificación del Tumor , Estadificación de Neoplasias , Próstata/patología , Antígeno Prostático Específico/sangre , Hiperplasia Prostática/sangre , Hiperplasia Prostática/inmunología , Neoplasias de la Próstata/patología , Curva ROC , Proteínas Recombinantes/inmunología , Estudios Retrospectivos , Análisis de Matrices Tisulares , Proteínas de Unión al GTP ral/metabolismoRESUMEN
Selenium is an essential trace element and has shown chemopreventive or therapeutic activities on human solid cancers; however, whether it has anticancer effects on leukemia has not yet been elucidated. The present study was designed to determine the role of selenium on HL-60 human promyelocytic leukemia cells. We found that 100 nM of sodium selenite (Se) had no significant effects on cell proliferation, apoptosis and the cell cycle; however, a higher concentration of 250 nM of Se significantly inhibited cell proliferation, promoted apoptosis and induced cell cycle arrest at the S phase after 48 h of treatment (P<0.05), thus demonstrating the anticancer activities of selenium in leukemia. However, the decrease in c-Jun NH2-terminal kinase 1 (JNK1) expression by targeting JNK1 using small interfering RNA attenuated the inhibitory effects of Se on cell proliferation and the induction of apoptosis. Mechanistic studies showed that the anticancer activities of Se were associated with the enhanced phosphorylation of JNK1 and the increased expression of the cell cycle regulators, p21 and p27, as well as the downregulation of cyclin D1. Our data provide further evidence that the appropriate concentration of selenium has therapeutic potential in leukemia.
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Apoptosis/efectos de los fármacos , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/metabolismo , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Selenito de Sodio/farmacología , Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Células HL-60 , Humanos , Modelos Biológicos , Fosforilación/efectos de los fármacosRESUMEN
Triptolide (TP)-induced liver injury can be attributed to the Th17/Treg imbalance with the enhancement of the expansion of Th17 cells and suppression of the production of Tregs, especially the significant increase of interleukin (IL)-17 secreted by helper T (Th) 17 cells. To further investigate the involvement of IL-17-mediated immune response in the TP-induced hepatotoxicity, we examined the plasma transaminase, histopathological changes, hepatic frequencies of Th17 cells, hepatic expression of transcriptional factors and cytokines genes and plasma IL-17 levels after administration of TP (600 µg/kg) by oral gavage to female C57BL/6 mice. Mice treated with TP displayed acute liver injury with significantly increased hepatic frequencies of Th17 cells, mRNA expression of retinoid-related orphan receptor (ROR)-γt and plasma IL-17 level as well as the plasma ALT and AST. Neutralization study using anti-IL-17 antibody ameliorated TP-induced liver injury. In contrast, when challenged by coadministration of recombinant IL-17, hepatotoxicity was exacerbated in the triptolide-administered mice. In summary, this report was demonstrated for the first time that IL-17-mediated immune response is involved in the pathogenesis of TP-induced liver injury in mice, which may shed light on the mechanisms of TP-induced liver injury.
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Diterpenos/toxicidad , Interleucina-17/farmacología , Hígado/efectos de los fármacos , Fenantrenos/toxicidad , Animales , Secuencia de Bases , Quimiocinas/metabolismo , Citocinas/metabolismo , Cartilla de ADN , Ensayo de Inmunoadsorción Enzimática , Compuestos Epoxi/toxicidad , Femenino , Interleucina-17/sangre , Interleucina-17/inmunología , Ratones , Ratones Endogámicos C57BL , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
KU004 is a newly synthesized compound which has been demonstrated possessing potent anti-cancer activities through targeting the highly-expressed protein HER2 on the surface of the cells. In this study, we investigated the potential roles of KU004 in the induced-cell cycle arrest in human breast cancer SK-BR-3 cells. KU004 could not only inhibit the proliferation of SK-BR-3 in a concentration-dependent manner but also induce G1 phase arrest in SK-BR-3 cells. The western blot results showed KU004 decreased the expression of cyclin D, CDK-4, p-Rb708/780, and up-regulated the p21. In order to verify whether KU004 takes the anti-tumor effect thought the regulation of PI3K/Akt pathway, we used western blot to detect the expression of protein Akt, Her2, p-Akt and p-Her2. Our results shown that after KU004 treatment, the amount of p-Akt and p-Her2 decreased but the total amount of Akt and Her2 remained unchanged. In conclusion, these results provide a framework for further exploration of KU004 as a novel chemotherapeutic for human breast tumors by modulating PI3K/Akt pathway.
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Neoplasias de la Mama/enzimología , Neoplasias de la Mama/patología , Óxidos P-Cíclicos/farmacología , Puntos de Control de la Fase G1 del Ciclo Celular/efectos de los fármacos , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Quinazolinas/farmacología , Transducción de Señal/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Femenino , Humanos , Fosforilación/efectos de los fármacos , Receptor ErbB-2/metabolismo , Puntos de Control de la Fase S del Ciclo Celular/efectos de los fármacosRESUMEN
The non-steroidal anti-inflammatory agent, sulindac, has shown strong effects on cancer prevention in colorectal cancers, however, its anticancer activities on prostate cancer remain unclear. In the current study, human prostate cancer cell lines, LNCaP and PC-3, were treated with various concentrations of sulindac and it was found that sulindac significantly inhibits prostate cancer cell proliferation and promotes cell apoptosis in a dose- and time-dependent manner. Further studies revealed that sulindac significantly induces c-Jun NH2-terminal kinase (JNK) 1 phosphorylation and inhibits ß-catenin at the transcriptional and post-transcriptional levels. In conclusion, by targeting the JNK1/ß-catenin signaling pathway, sulindac may present a potential preventive or therapeutic agent for treatment of patients with prostate cancer.