RESUMEN
Nasopharyngeal carcinoma (NPC) is a malignant epithelial tumor with tremendous invasion and metastasis capacities, and it has a high incidence in southeast Asia and southern China. Previous studies identified that far upstream element-binding protein 1 (FBP1), a transcriptional regulator of c-Myc that is one of the most frequently aberrantly expressed oncogenes in various human cancers, including NPC, is an important biomarker for many cancers. Our study aimed to investigate the expression and function of FBP1 in human NPC. Quantitative real-time RT-PCR (qRT-PCR), western blot and immunohistochemical staining (IHC) were performed in NPC cells and biopsies. Furthermore, the effect of FBP1 knockdown on cell proliferation, colony formation, side population tests and tumorigenesis in nude mice were measured by MTT, clonogenicity analysis, flow cytometry and a xenograft model, respectively. The results showed that the mRNA and protein levels of FBP1, which are positively correlated with c-Myc expression, were substantially higher in NPC than that in nasopharyngeal epithelial cells. IHC revealed that the patients with high FBP1 expression had a significantly poorer prognosis compared with the patients with low expression (P=0.020). In univariate analysis, high FBP1 and c-Myc expression predicted poorer overall survival (OS) and poorer progression-free survival. Multivariate analysis indicated that high FBP1 and c-Myc expression were independent prognostic markers. Knockdown of FBP1 reduced cell proliferation, clonogenicity and the ratio of side populations, as well as tumorigenesis in nude mice. These data indicate that FBP1 expression, which is closely correlated with c-Myc expression, is an independent prognostic factor and promotes NPC progression. Our results suggest that FBP1 can not only serve as a useful prognostic biomarker for NPC but also as a potential therapeutic target for NPC patients.
Asunto(s)
Biomarcadores de Tumor/metabolismo , ADN Helicasas/metabolismo , Proteínas de Unión al ADN/metabolismo , Neoplasias Nasofaríngeas/enzimología , Adulto , Anciano , Animales , Antineoplásicos/farmacología , Carcinoma , Línea Celular Tumoral , Proliferación Celular , Progresión de la Enfermedad , Resistencia a Antineoplásicos , Femenino , Técnicas de Silenciamiento del Gen , Humanos , Estimación de Kaplan-Meier , Masculino , Ratones Endogámicos BALB C , Ratones Desnudos , Persona de Mediana Edad , Análisis Multivariante , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/mortalidad , Neoplasias Nasofaríngeas/patología , Trasplante de Neoplasias , Pronóstico , Modelos de Riesgos Proporcionales , Proteínas Proto-Oncogénicas c-myc/metabolismo , Proteínas de Unión al ARN , Tolerancia a Radiación , Células de Población Lateral/metabolismo , Adulto JovenRESUMEN
BACKGROUND: The impact of combining plasma fibrinogen levels with Epstein-Barr Virus DNA (EBV DNA) levels on the prognosis for patients with nasopharyngeal carcinoma (NPC) was evaluated. METHODS: In this observational study, 2563 patients with non-metastatic NPC were evaluated for the effects of circulating plasma fibrinogen and EBV DNA levels on disease-free survival (DFS), distant metastasis-free survival (DMFS), and overall survival (OS). RESULTS: Compared with the bottom biomarker tertiles, TNM stage-adjusted hazard ratios (HR, 95% confidence intervals (CIs)) for predicting DFS in fibrinogen tertiles 2 to 3 were 1.26 (1.00 to 1.60) and 1.81 (1.45 to 2.26), respectively; HR for EBV DNA tertiles 2 to 3 were 1.49 (1.12 to 1.98) and 4.24 (3.27 to 5.49), respectively. After additional adjustment for established risk factors, both biomarkers were still associated (P for trend <0.001) with reduced DFS (HR: 1.79, 95% CI, 1.43 to 2.25 for top fibrinogen tertiles; HR: 4.04, 95% CI: 3.10 to 5.27 for top EBV DNA tertiles compared with the bottom tertiles). For patients with advanced-stage disease, those with high fibrinogen levels (3.34 g l(-1)) presented with worse DFS, regardless of EBV DNA 4000 or <4000 copies ml(-1) subgroup. Similar findings were observed for DMFS and OS. CONCLUSIONS: Circulating fibrinogen and EBV DNA significantly correlate with NPC patients survival. Combined fibrinogen and EBV DNA data lead to improved prognostic prediction in advanced-stage disease.
Asunto(s)
Biomarcadores de Tumor/sangre , Carcinoma/sangre , ADN Viral/sangre , Fibrinógeno/metabolismo , Herpesvirus Humano 4/genética , Neoplasias Nasofaríngeas/sangre , Recurrencia Local de Neoplasia/sangre , Adulto , Carcinoma/patología , Carcinoma/virología , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Neoplasias Nasofaríngeas/patología , Neoplasias Nasofaríngeas/virología , Recurrencia Local de Neoplasia/virología , Estadificación de Neoplasias , Tasa de SupervivenciaRESUMEN
Aim of the study: To analyze the changes in DNA content, the percentage of apoptosis and the nuclear mitotic frequency of myocytes in transplanted human hearts. Methods: Twenty-three transplanted hearts were obtained from 22 patients. The mean interval between transplantation and death was 649 days (ranging from 13 to 2558 days). Ten control hearts were selected from individuals whose death was not due to primary heart disease. Tissue samples were obtained from the mid section of the lateral wall of left and right ventricles. DNA content was evaluated on isolated myocardial cells using image cytometry. In situ detection of apoptosis was performed by the terminal deoxynucleotidyl transferase-mediated digoxigenin-dUTP nick-end labeling (TUNEL) technique. Mitotic figures were examined by staining the nuclear DNA with YOYO-1 iodide. Myocytes were distinguished from stromal cells by using antibodies reacting with a-sarcomeric actin. Results: Comparing with control hearts, the myocytic changes after cardiac transplantation are characterized by: 1) a decrease in mononucleated myocytes and an increase in binucleated and multinucleated myocytes; 2) a decrease in diploid myocytic nuclei and a distinct augmentation of intermediate ploidies; 3) an increase in myocytic nuclei in DNA ploidies higher than 4c; 4) a marked augmentation of percentage of apoptotic myocytes and 5) an increased frequency of nuclear mitosis of myocytes; this fact appears as a declining phenomenon after six months of cardiac transplantation. Conclusion: After cardiac transplantation the DNA content of myocytes shows two completely different aspects: 1) a distinct increase in subdiploidy and intermediate ploidies related to myocyte injury induced by apoptosis and necrosis; 2) an increase in multinucleation, polyploidization and mitotic proliferation. Both myocyte growth and myocyte injury alter the function of the allograft and contribute to adaptation or failure of the graft. Furthermore, a relevant difference of age between the recipient and the donor may lead to a more marked myocyte damage and a lower myocyte growth. This tendency provides an evidence that age matching could be an important aspect in selecting the donor for the recipient.
RESUMEN
AIM OF THE STUDY: Heart failure is the final clinical presentation of a variety of cardiovascular diseases, such as coronary artery disease, hypertensive, toxic, and inflammatory heart disease. However, the cellular mechanisms responsible for the progressive deterioration of myocardial function observed in heart failure remain unclear and may result from cell death (programmed or not) and from an increase in number of nuclei and in the degree of their ploidy. METHODS: We examined thirty-eight explanted hearts obtained during transplantation for DNA content in the myocytic population. All thirty-eight patients had severe chronic heart failure: 23 had idiopathic dilated cardiomyopathy, and 15 had ischemic cardiomyopathy. Ten hearts of people whose death was not due to primary heart disease or as a consequence of major risk factors of coronary artery disease, including hypertension, diabetes, obesity, or severe atherosclerosis, were used as controls. DNA content in the myocytic population was evaluated using Image Cytometry. RESULTS: The DNA content per nucleus and per myocyte in cardiomyopathic hearts are characterized by: a) a decrease of the diploid DNA content of myocytic nuclei; b) an increase of DNA ploidies higher than 4c; c) a decrease in mononucleated myocytes; d) an increase in binucleated and multinucleated myocytes. The changes are more prominent in dilated cardiomyopathy. e) The total ploidy index, used to calculate the total DNA content, is related to heart weight and ventricular weight. CONCLUSIONS: Ischemic and dilated cardiomyopathies result in reduction of ventricular mass-to-chamber volume ratio and in discrete foci of myocyte cell death, leading to an elevation in systolic and diastolic stress on the remaining viable cells. Therefore mechanical stimuli generated by global and local loading abnormalities associated with end-stage failure may contribute to activate genes implicated in cell proliferation. Observations in this investigation are consistent with recent results documenting that in the presence of overload conditions the myocytes may retain their capacity to proliferate throughout life and this growth reserve mechanism may become operative in response to severe myocardial dysfuntion and overt failure. Polyploidization and multinucleation are prominent phenomena in the end-stage of ischemic and dilated cardiomyopathy in humans.