RESUMEN
BACKGROUND: Ependymoma is the third most common pediatric brain tumor and occurs most frequently in the posterior fossa. However, the lack of immortalized cell lines, xenografts, or animal models has significantly hindered the study of pediatric posterior fossa ependymoma (P-PF-EPN) pathogenesis. This prompted us to use clinical big data to study this rare disease. METHODS: Application of the robust rank aggregation method revealed CD44 as a reliable biomarker in P-PF-EPN. 120 P-PF-EPN samples after surgical resection were selected for Kaplan-Merier and Cox proportion hazard regression survival analysis. Immunohistochemical analysis was performed to assess CD44 expression in the tumor samples. The miRNA profile was determined using a whole-genome miRNA microarray. The expression patterns of related mRNAs, miRNAs and proteins were validated by qRT-PCR or Western blotting. RESULTS: CD44 was found to be an independent predictor of prognosis in survival analysis. It improved the accuracy of using LAMA2/NELL2 for classifying P-PF-EPN molecular subgroups. Fourteen miRNAs were underexpressed, and one miRNA was overexpressed in CD44-positive P-PF-EPNs. miR-543, miR-495-3p, miR-299-3p, miR-139-5p and miR-128-3p were identified to have CD44 positively co-regulated potential target oncogenes. Two PI3K-Akt signaling pathway related potential target oncogenes (VEGFA, CSF1) for miR-299-3p and miR-495-3p were validated overexpression in CD44 positive P-PF-EPNs. Abnormal activation of the PI3K-Akt pathway was confirmed in CD44-positive cases. CONCLUSIONS: CD44 is of great clinical significance as a prognostic biomarker. The survival difference between CD44 positive and negative P-PF-EPN is determined by a complex functional miRNA-mRNA-signaling pathway regulatory network.
Asunto(s)
Ependimoma/diagnóstico , Ependimoma/genética , Receptores de Hialuranos/genética , Neoplasias Infratentoriales/diagnóstico , Neoplasias Infratentoriales/genética , MicroARNs/genética , Adolescente , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Niño , Preescolar , Ependimoma/mortalidad , Ependimoma/patología , Femenino , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Receptores de Hialuranos/metabolismo , Neoplasias Infratentoriales/mortalidad , Neoplasias Infratentoriales/patología , Masculino , Análisis por Micromatrices , Pronóstico , Análisis de SupervivenciaRESUMEN
Keshan disease (KSD), a potentially fatal cardiomyopathy, has very high incidence in some selenium-poor regions of China. KSD may be accompanied with a variety of arrhythmia, which is associated with mutations in the gene coding for cardiac voltage-gated sodium channel (SCN5A). The molecular mechanism of KSD is still largely obscure. We aimed to determine the association between the H558R polymorphism of SCN5A and KSD. We recruited 71 patients with KSD and 80 geographical region-matched control subjects in our study. Vital sign and electrocardiographic (ECG) measurements were performed for heart rate, systolic pressure, diastolic pressure, PR interval, QT interval, QRS duration, ST-T changes and complete right bundle branch block (CRBBB), and H558R polymorphism was genotyped using the polymerase chain reaction single-strand conformation polymorphism (PCR-SSCP) method and sequencing. A significant association was found between the H558R polymorphism of exon 12 and KSD. Allele C carriers had a decreased risk for KSD with an odds ratio of 0.332 [95% confidence interval (CI), 0.160-0.692] as well as for QRS prolongation in KSD patients with an odds ratio of 0.089 (95%CI, 0.022-0.361). Our results provide support to the association between H558R polymorphism and the decreased risk for KSD. H558R polymorphism might increase susceptibility to KSD, and SCN5A containing the polymorphism might be a predisposing gene for QRS prolongation.