RESUMO
The clinical features of EBV-positive diffuse large B cell lymphoma (DLBCL) indicate a poorer prognosis than EBV-negative DLBCL. Currently, there is no efficacious drug for EBV-positive DLBCL. The cytokine interleukin-21 (IL-21) has been reported to be pro-apoptotic in DLBCL cell lines and is being explored as a new therapeutic strategy for this type of lymphomas. However, our previous studies showed that IL-21 stimulation of EBV-positive DLBCL cell lines leads to increased proliferation. Here, analysis of a rare clinical sample of EBV-positive DLBCL, in combination with a NOD/SCID mouse xenograft model, confirmed the effect of IL-21 on the proliferation of EBV-positive DLBCL cells. Using RNA-sequencing, we identified the pattern of differentially-expressed genes following IL-21 treatment and verified the expression of key genes at the protein level using western blotting. We found that IL-21 upregulates expression of the host MYC and AP-1 (composed of related Jun and Fos family proteins) and STAT3 phosphorylation, as well as expression of the viral LMP-1 protein. These proteins are known to promote the G1/S phase transition to accelerate cell cycle progression. Furthermore, in NOD/SCID mouse xenograft model experiments, we found that IL-21 treatment increases glucose uptake and angiogenesis in EBV-positive DLBCL tumours. Although more samples are needed to validate these observations, our study reconfirms the adverse effects of IL-21 on EBV-positive DLBCL, which has implications for the drug development of DLBCL.
Assuntos
Ciclo Celular , Herpesvirus Humano 4/fisiologia , Interleucinas/farmacologia , Linfoma Difuso de Grandes Células B/patologia , Linfoma Difuso de Grandes Células B/virologia , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Biomarcadores Tumorais/metabolismo , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Ontologia Genética , Redes Reguladoras de Genes , Humanos , Linfoma Difuso de Grandes Células B/genética , Camundongos Endogâmicos NOD , Camundongos SCID , Modelos Biológicos , Neovascularização Patológica/genética , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genética , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Epileptic spasms are a catastrophic form of epilepsy. When epileptic spasms occur under 2-year-old, they may be also called "infantile spasms". Adrenocorticotropic hormone (ACTH) is recommended as first line intervention for the treatment of epileptic spasms without tuberous sclerosis complex. The chief risks of ACTH therapy are immunosuppression and hypertension. We reported rare cases of abnormal high blood pressure in two male epileptic spasms patients during ACTH therapy. Both patients' blood pressure reached a high blood pressure stage 2 on the 9th day and 10th day of ACTH treatment, respectively. The blood pressure returned to normal range after the drug dosage was reduced or stopped. The lower level of neutrophil%, neutrophil count, and a higher level of lymphocyte%, lymphocyte count and prealbumin than normal range were observed in both patients before ACTH therapy. The neutrophil to lymphocyte rate might be a predictor for high blood pressure among patients treated with ACTH. The rates of both patients were under 0.50 (0.42 for Case 1 and 0.17 for Case 2). We reported the documented cases in two Chinese pediatric patients who suffered from epileptic spasms treated with ACTH resulted in abnormal high blood pressure, which could be predicted by using neutrophil to lymphocyte rate. We also mentioned serum prealbumin might be another predictor. More clinical data is required to elucidate the relationship between serum prealbumin level and blood pressure.