RESUMO
AIMS: Diffuse large B-cell lymphoma (DLBCL) is the most common type of aggressive lymphoma. This study was designed to compare epigenetic alterations observed in Enhancer of Zeste Homolog 2 (EZH2)-target genes between plasma-derived exosomes and primary tumors in DLBCL patients. MAIN METHODS: Exosomes were isolated from plasma of 21 DLBCL patients and 21 controls. We analyzed the methylation status of the target genes using methylation-specific PCR. We also examined whether the exosomes and the tumor samples contained transcripts of the target genes. KEY FINDINGS: We found that CDKN2A and CDKN2B were methylated in both plasma exosomes and primary tumor tissue samples. None of the transcripts were found in the exosomes except CDKN1B which was expressed in 8 (38%) of the exosome samples. SIGNIFICANCE: This study showed that plasma exosomes might preferably package certain target molecules from primary tumors and the exosomes containing dual methylated DNAs of CDKN2A and CDKN2B, or CDKN1B transcript may contribute to DLBCL pathogenesis.
Assuntos
Metilação de DNA , Proteína Potenciadora do Homólogo 2 de Zeste/biossíntese , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Exossomos/genética , Regulação Neoplásica da Expressão Gênica , Linfoma Difuso de Grandes Células B/genética , Humanos , Linfoma Difuso de Grandes Células B/sangueRESUMO
Pediatric myelodysplastic syndrome (MDS) is an uncommon disease and little is known about the molecular alterations of its development and evolution to acute myeloid leukemia (AML). The Enhancer of Zeste Homolog 2 (EZH2) is the catalytic subunit of Polycomb repressive complex 2 (PCR2). It is a histone methyltransferase, that targets lysine 27 of histone 3. This methylated H3-K27 is usually associated with the silencing of genes that are involved in fundamental cellular processes, such as cell proliferation and differentiation. There are only few studies showing the status of EZH2 expression in patients with MDS and they were performed in adult MDS patients. The aim of this study was to analyze the EZH2 expression in pediatric patients with MDS and its association with karyotypes and evolution to acute myeloid leukemia (AML). We conducted the first study of EZH2 expression in pediatric patients with MDS. Considering the EZH2 expression levels in 42 patients and 17 healthy pediatric donors, it was possible to define three groups of expression in patients: low, intermediate, and high. The intermediate level encompassed patients with normal karyotypes, low level included patients with monosomy 7 and del(7q) and high level included patients with trisomy 8 and del(11q) (p < 0.0001). Comparing the leukemic evolution, the low expression group presented disease evolution in 100% (8/8) of the cases, the intermediate expression group showed disease evolution in 4.34% (1/23) and in the high expression group, 63.63% (7/11) patients showed evolution from MDS to AML (p < 0.0001). It is important to note that low and high EZH2 expression are associated with leukemic evolution, however low expression showed a stronger association with evolution from MDS to AML than the high expression. Our results suggest a scale of measure for EZH2 expression in pediatric MDS, where aberrant EZH2 expression may be a potential biomarker of disease evolution.
Assuntos
Biomarcadores Tumorais/biossíntese , Proteína Potenciadora do Homólogo 2 de Zeste/biossíntese , Regulação Leucêmica da Expressão Gênica , Leucemia Mieloide Aguda/metabolismo , Síndromes Mielodisplásicas/metabolismo , Proteínas de Neoplasias/biossíntese , Adolescente , Biomarcadores Tumorais/genética , Criança , Pré-Escolar , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Feminino , Humanos , Lactente , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Masculino , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/patologia , Proteínas de Neoplasias/genéticaRESUMO
We investigated the expression and clinical implications of enhancer of Zeste homolog 2 (EZH2) and p53 protein in cervical squamous cell carcinoma (SCC) and precancerous lesions. EZH2 and p53 expressions in SCC (168), cervical intraepithelial neoplasia (CIN)-I (19), CIN-II (35), and normal tissues (30) were detected by streptavidin-peroxidase-conjugation. The correlation between co-expression of EZH2 and p53 protein and the clinic pathological features and prognosis of SCC were discussed. The positive expression rates of EZH2 and p53 were 6.7, 37.0, and 75.6%, and 3.3, 21.1, and 39.3% in normal cervical tissues, CIN, and SCC, respectively, which were significantly different (P < 0.05). The positive expression rate of EZH2 and p53 protein in SCC patients with and without lymph node metastasis was 82.9 and 70.4% (EZH2) and 45.7 and 34.7% (p53), respectively, which was also a significant difference (P < 0.05). The progression-free survival (PFS) rates in followed-up patients (N = 143) who were EZH2- and p53-negative, EZH2- or p53-positive, and EZH2- and p53-positive were 71.3 ± 1.9, 66.1 ± 2.0, and 51.3 ± 3.8 months, respectively, which was a significant difference (P < 0.001); the overall survival among these groups was 72.9 ± 1.1, 68.6 ± 1.8, and 57.4 ± 3.4 months, respectively (P < 0.001). Multivariate analyses revealed that EZH2 expression, lymph node metastasis, and tumor staging were independent prognostic factors of SCC. EZH2 and p53, which affect lymph node metastasis and prognosis of SCC, may play a key role in the occurrence and development of SCC.