RESUMEN
PURPOSE: To identify Heptocellular carcinoma (HCC) associated antigens by proteomics, and validate whether autoantibodies against tumor-associated antigens (TAAs) could be used for diagnosis and conditional monitoring. RESULTS: The 78 kDa glucose regulated protein (GRP78) was selected as a candidate TAA. The titers of autoantibodies against 78 kDa glucose regulated protein (GRP78) from patients with HCC, liver cirrhosis (LC), and chronic hepatitis (CH) were significantly higher than that from normal controls (P<0.05, P<0.001, and P<0.01, respectively). The expression of autoantibodies against GRP78 was associated with clinical stage (P<0.01), portal vein invasion (P<0.05), and metastasis (P<0.05). The expression of anti-GRP78 antibodies was significantly higher 1 month after surgery in recurrent patients who had accepted hepatic resection 1 month after surgery compared to patients who had surgery before surgery or within 1 week after surgery (P<0.01 and P<0.001). Immunohistochemistry (IHC) showed higher expression of GRP78 in HCC compared to the non-HCC liver tissues (P <0.05). MATERIALS AND METHODS: HCC serum with high titer of autoantibodies against TAAs were screened and used for a proteome-based approach to identify HCC associated antigens. Indirect enzyme-linked immunoassay (ELISA) was used to detect the corresponding autoantibodies against TAAs. CONCLUSION: GRP78 is an autoantigen that could stimulate autoimmune responses and serve as a potential marker for recurrent and metastatic progression in HCC.
Asunto(s)
Autoanticuerpos/sangre , Autoanticuerpos/inmunología , Carcinoma Hepatocelular/inmunología , Proteínas de Choque Térmico/inmunología , Neoplasias Hepáticas/inmunología , Biomarcadores de Tumor/sangre , Biomarcadores de Tumor/inmunología , Carcinoma Hepatocelular/sangre , Carcinoma Hepatocelular/patología , Estudios de Casos y Controles , Línea Celular Tumoral , Chaperón BiP del Retículo Endoplásmico , Ensayo de Inmunoadsorción Enzimática , Técnica del Anticuerpo Fluorescente Indirecta , Células HCT116 , Células HeLa , Proteínas de Choque Térmico/biosíntesis , Células Hep G2 , Humanos , Neoplasias Hepáticas/sangre , Neoplasias Hepáticas/patología , Células MCF-7 , Metástasis de la NeoplasiaRESUMEN
PURPOSE: To identify whether Dickkopf-1 (DKK1) could be a potential biomarker for early detection and prognosis in patients with pancreatic cancer (PC). METHODS: Serum was collected from 140 patients with pancreatic adenocarcinoma and 92 control patients without pancreatic adenocarcinoma. Serological levels of DKK1 were examined by enzyme-linked immunosorbent assay (ELISA). The sensitivity and specificity was compared with carbohydrate antigen 19-9 (CA19-9). A 2-year follow-up was monitored to evaluate the correlation between DKK1 serum levels and overall survival. The expression of DKK1 in PC tumor tissues was also evaluated using immunohistochemistry staining. RESULTS: Serum levels of DKK1 and CA19-9 were elevated in PC patients in the early-stage cases. These levels increased with the advancement of clinical stage. There was significant difference in DKK1 serum levels between early and advanced PC stages. Receiver operating characteristic curve (ROCC) analysis showed that DKK1 was significantly better than CA19-9 in differentiating patients with PC from the controls (area under the curve (AUC) 0.919 versus 0.853, respectively), especially in distinguishing early-stage cancer from chronic pancreatitis (CP). The expression of DKK1 in PC tissues correlated with its expression in serum samples. The overall survival rate was 24.4% in the group with higher DKK1 levels and was found to be significantly different from the group with lower DKK1 levels (33.3%). CONCLUSION: DKK1 may be a novel diagnostic/prognostic biomarker for PC.
Asunto(s)
Biomarcadores de Tumor/sangre , Carcinoma Ductal Pancreático/sangre , Péptidos y Proteínas de Señalización Intercelular/sangre , Neoplasias Pancreáticas/sangre , Adulto , Anciano , Anciano de 80 o más Años , Área Bajo la Curva , Biomarcadores de Tumor/análisis , Antígeno CA-19-9/sangre , Carcinoma Ductal Pancreático/química , Carcinoma Ductal Pancreático/mortalidad , Carcinoma Ductal Pancreático/patología , Carcinoma Ductal Pancreático/terapia , Estudios de Casos y Controles , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Inmunohistoquímica , Péptidos y Proteínas de Señalización Intercelular/análisis , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias Pancreáticas/química , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/terapia , Valor Predictivo de las Pruebas , Curva ROC , Factores de Riesgo , Resultado del TratamientoRESUMEN
Intrahepatic cholangiocarcinoma (ICC) constitutes the second-most common primary hepatic malignancy. MicroRNAs (miRNAs) play important roles in the pathogenesis of ICC. However, the clinical significance of miR-21 levels in ICC remains unclear. Here, we investigated the role of miR-21 in ICC and found that its expression was significantly upregulated in serum of ICC patients. Serum miR-21 levels robustly distinguished ICC patients from control subjects. Further experiments showed that inhibition of miR-21 suppressed ICC cell proliferation in vitro and tumor growth in vivo. Specifically, inhibition of miR-21 induced cell cycle arrest and apoptosis. Moreover, PTPN14 and PTEN were identified as direct and functional targets of miR-21. Finally, we showed high expression levels of miR-21 were closely related to adverse clinical features, diminished survival, and poor prognosis in ICC patients. This study revealed functional and mechanistic links between miR-21 and tumor suppressor genes, PTPN14 and PTEN, in the pathogenesis of ICC. MiR-21 not only plays important roles in the regulation of cell proliferation and tumor growth in ICC, but is also a diagnostic and prognostic marker, and a potential therapeutic target for ICC.
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Neoplasias de los Conductos Biliares/genética , Colangiocarcinoma/genética , MicroARNs/genética , Fosfohidrolasa PTEN/genética , Proteínas Tirosina Fosfatasas no Receptoras/genética , Animales , Neoplasias de los Conductos Biliares/sangre , Neoplasias de los Conductos Biliares/metabolismo , Neoplasias de los Conductos Biliares/patología , Línea Celular Tumoral , Proliferación Celular/fisiología , Colangiocarcinoma/sangre , Colangiocarcinoma/metabolismo , Colangiocarcinoma/patología , Femenino , Xenoinjertos , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , MicroARNs/antagonistas & inhibidores , MicroARNs/metabolismo , Persona de Mediana Edad , Fosfohidrolasa PTEN/biosíntesis , Fosfohidrolasa PTEN/metabolismo , Proteínas Tirosina Fosfatasas no Receptoras/biosíntesis , Proteínas Tirosina Fosfatasas no Receptoras/metabolismo , TransfecciónRESUMEN
Osteopontin (OPN) is a secreted phosphorylated and glycosylated protein, which plays an important role in carcinogenesis and metastasis. In hepatocellular carcinoma (HCC), OPN is being investigated either as a therapeutic target gene or as a biomarker for diagnosis. Yet, the role of the anti-OPN autoantibody in HCC remains unclear. In the present study, the level of serum anti-OPN autoantibody in HCC was analyzed by enzyme-linked immunosorbent assay. Immunohistochemistry (IHC) was also performed to analyze protein expression profiles and the prognostic significance of OPN in HCC. In this study, the prevalence and titer of anti-OPN autoantibodies in HCC were significantly higher than these values in normal human serum (NHS) (P=0.001, P=0.000, respectively). When both α-fetoprotein and the autoantibody against OPN were used simultaneously as diagnostic biomarkers, the sensitivity was up to 65%. In IHC, 59 of the 83 (65.6%) HCC specimens expressed OPN with cytoplasmic positive staining. The overall survival (OS) of HCC patients with OPN-positive tumors was 28.81 months compared to 39.37 months for HCC patients with OPN-negative tumors (P<0.01). Furthermore, multivariate analysis showed that OPN overexpression was the strongest independent adverse prognostic factor for OS (P=0.02). Taken together, our data indicate that the anti-OPN autoantibody may be a supplementary serological biomarker for HCC, and is correlated with poor prognosis in HCC patients.
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Autoanticuerpos/inmunología , Biomarcadores de Tumor/inmunología , Carcinoma Hepatocelular/inmunología , Neoplasias Hepáticas/inmunología , Osteopontina/inmunología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/metabolismo , Ensayo de Inmunoadsorción Enzimática , Femenino , Hepatitis B Crónica/inmunología , Hepatitis B Crónica/metabolismo , Hepatitis C Crónica/inmunología , Hepatitis C Crónica/metabolismo , Humanos , Cirrosis Hepática/inmunología , Cirrosis Hepática/metabolismo , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/metabolismo , Masculino , Persona de Mediana Edad , Pronóstico , Sensibilidad y Especificidad , Adulto Joven , alfa-Fetoproteínas/metabolismoRESUMEN
Radiation therapy is one of the standard therapeutic modalities for esophageal cancer, achieving its main antitumor efficacy through DNA damage. However, accumulating evidence shows that radiotherapy can substantially alter the tumor microenvironment, particularly with respect to its effects on immune cells. We hypothesized that the immune response elicited by radiotherapy may be as important as the radiation itself for successful treatment. More specifically, immunomodulatory cytokines may enhance the effectiveness of radiotherapy. To investigate this hypothesis, we measured changes in the serum interferon-gamma (IFN- γ ) and interleukin-2 (IL-2) concentrations during radiotherapy and compared these modifications with outcomes. We found that serum concentrations of IL-2 and IFN- γ were positively associated with local response to radiotherapy in esophageal cancer. More generally, the intensity of the radiotherapy-elicited immune response was positively associated with local response to radiotherapy in esophageal cancer. Changes in serum IL-2 and IFN- γ concentrations were further associated with increased risks of acute hematologic toxicity and acute organ toxicity of the esophagus, lung, and skin. These results suggest that deciphering the mechanisms of radiotherapy-elicited immune response may help in the development of therapeutic interventions that would enhance the efficacy of radiotherapy and convert some ineffective responses to effective responses.
Asunto(s)
Neoplasias Esofágicas/inmunología , Neoplasias Esofágicas/radioterapia , Rayos gamma/uso terapéutico , Microambiente Tumoral/efectos de la radiación , Adulto , Anciano , Anciano de 80 o más Años , Relación Dosis-Respuesta en la Radiación , Neoplasias Esofágicas/sangre , Neoplasias Esofágicas/patología , Femenino , Humanos , Interferón gamma/sangre , Interleucina-2/sangre , Masculino , Persona de Mediana Edad , Estadificación de NeoplasiasRESUMEN
PURPOSE: Yes-associated protein (YAP) and PDZ-binding motif (TAZ) are two important effectors of Hippo pathway controlling the balance of organ size and carcinogenesis. Amphiregulin (AREG) is a member of the epidermal growth factor family, a direct target gene of YAP and TAZ. The role of these proteins in hepatocellular carcinoma (HCC) is unclear. METHODS: The expression of YAP, TAZ, and AREG in HCC was analyzed by immunohistochemical staining. The level of secreted serum AREG was also assayed by enzyme-linked immunosorbent (ELISA) assay. RESULTS: YAP, TAZ, and AREG were expressed in 69.2% (27/39), 66.7% (26/39), and 61.5% (24/39) of HCC patients. The expression of YAP was significantly correlated with Edmondson stage (P>0.05), serum AFP level (P>0.05), and HCC prognosis (P>0.05). AREG expression was also significantly correlated with Edmondson stage (P>0.05) and serum AFP level (P>0.05). In addition, the expression of serum AREG was higher than serum AFP in HCC patients. Further multivariate analysis showed that YAP expression was an independent prognostic factor that significantly affected the overall survival of HCC patients. CONCLUSIONS: YAP maybe an independent prognostic indicator for HCC patients and serum AREG may be a serological biomarker of HCC.
Asunto(s)
Biomarcadores de Tumor/genética , Carcinoma Hepatocelular/genética , Familia de Proteínas EGF/genética , Regulación Neoplásica de la Expresión Génica , Neoplasias Hepáticas/genética , Proteínas Nucleares/genética , Factores de Transcripción/genética , alfa-Fetoproteínas/genética , Aciltransferasas , Adolescente , Adulto , Anciano , Anfirregulina , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/mortalidad , Carcinoma Hepatocelular/patología , Proteínas de Ciclo Celular , Femenino , Humanos , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/patología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Análisis de SupervivenciaRESUMEN
AIM: Sal-like protein 4 (SALL4), is reexpressed in tissues of a subgroup of HCC associated with poor prognosis. Reports of SALL4 serological levels linked to HCC patients are meager and unclear in the prognosis of this malignancy. METHODS: Immunohistochemistry and optical microscopy protocols were used to examine the presence of SALL4 in liver tissues from the following patients: 38 HCC, 11 chronic hepatitis B virus (HBV), 13 liver cirrhosis, and 12 healthy controls. Additionally, enzyme-linked immunosorbent assay (ELISA) was used to measure the SALL4 levels in serum samples isolated from patients as follows: 127 with HCC, 27 with HBV, 24 with liver cirrhosis, and 23 normal controls. RESULTS: Analysis of liver tissues sections from HCC patients (18 out 38; 47.4%) showed positive staining for SALL4 and its expression did no correlate with any of the clinicopathologic characteristics. HCC patients displayed higher levels (50.4%) of SALL4 protein in serum, compared with the three control groups. Moreover, SALL4 concentration reached the maximum level after one week after treatment and dropped quickly after one month. These HCC patients showing high SALL4 serum levels had poor prognosis, evidenced by both tumor recurrence and overall survival rate. CONCLUSIONS: High SALL4 serum levels are a novel biomarker in the prognosis of HCC patients.
Asunto(s)
Biomarcadores de Tumor/genética , Carcinoma Hepatocelular/genética , Regulación Neoplásica de la Expresión Génica , Neoplasias Hepáticas/genética , Recurrencia Local de Neoplasia/genética , Factores de Transcripción/genética , Adulto , Anciano , Biomarcadores de Tumor/sangre , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/mortalidad , Carcinoma Hepatocelular/patología , Femenino , Hepatitis B Crónica/diagnóstico , Hepatitis B Crónica/genética , Hepatitis B Crónica/patología , Humanos , Cirrosis Hepática/diagnóstico , Cirrosis Hepática/genética , Cirrosis Hepática/patología , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/patología , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/diagnóstico , Recurrencia Local de Neoplasia/mortalidad , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias , Pronóstico , Análisis de Supervivencia , Factores de Transcripción/sangreRESUMEN
Receptor-binding cancer antigen expressed on SiSo cells (RCAS1) plays an important role in tumor progression by helping tumor cell to escape from host immunological surveillance or modifying the characteristics of connective tissue around. RCAS1 may appropriately reflect the development and prognosis of tumor. In the study, we sought to identify the clinical significance of RCAS1 in colorectal cancer (CRC) diagnosis and tumor recurrence monitoring. Immunohistochemistry (IHC) with tissue array slides was preformed to analyze RCAS1 protein expression in CRC, colorectal polyps, and normal colon tissues. RCAS1 levels in colorectal cancer were significantly higher than those in colorectal polyps and normal colon tissues (P<0.001). Silencing RCAS1 gene in human colonic adenocarcinoma cells decreased cell proliferation and enhanced apoptosis through the p53 signaling pathway. Further analysis by an enzyme-linked immunosorbent assay (ELISA) showed that serum RCAS1 levels in CRC are significantly higher than in healthy controls and polyps (P<0.05), in which the highest serum RCAS1 level is reported in the recurrence group. The serum RCAS1 levels have a significant correlation with clinical stage and pathologic grading. Furthermore, the positive rate of serum RCAS1 in CRC was 82.1 %, which was higher than carcinoembryonic antigen (CEA). Especially in CEA-negative cases, the sensitivity of RCAS1 was 88.2 %. Finally, CRC patients who were followed up showed a serum RCAS1 level which significantly decreased after surgery (P<0.001) and obviously increased in the recurrence group. Taken together, our data demonstrated that RCAS1 is not only a supplementary serological biomarker for CRC diagnosis but also useful for monitoring tumor recurrence. RCAS1 might be a supplementary serological marker for CRC.