化疗诱导的细胞衰老在神经母细胞瘤复发中的作用及分子机制

项目名称： 化疗诱导的细胞衰老在神经母细胞瘤复发中的作用及分子机制

项目编号： No.81472706

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 刘爱国

作者单位： 华中科技大学

项目金额： 72万元

中文摘要： MYCN扩增的神经母细胞瘤预后不良，化疗仅暂缓肿瘤生长。除凋亡外，化疗也诱导细胞衰老，而衰老相关分泌表型（senescence-associated secretory phenotype）中IL-6/STAT3信号激活，可能促进衰老逆转。前期发现，低浓度阿霉素可诱导神经母细胞瘤衰老，伴有N-Myc蛋白水平下降，而IL-6可使衰老现象减弱。本项目将以细胞衰老和IL-6/STAT3信号通路为研究靶点，利用细胞系和动物模型及临床标本，采用RNA干扰、慢病毒感染等方法，阐明化疗诱导神经母细胞瘤发生细胞衰老的分子机制；揭示衰老细胞IL-6/STAT3/c-Myc信号激活与衰老逆转和肿瘤复发的关系及机制；探索中和性抗体和小分子抑制剂阻断衰老细胞的IL-6/STAT3信号途径，抑制衰老逆转。研究结果将为神经母细胞瘤阐明新的复发机制，为探索细胞衰老及相关信号作为新的治疗靶点提供重要实验理论基础。

中文关键词： C25_其它肿瘤；神经母细胞瘤；细胞衰老；信号传导与转录激活因子；白介素6

英文摘要： Amplification of MYCN is associated with rapid tumor progression and poor prognosis in neuroblastomas. Chemtherapy can only delay the tumor growth. In addition to apoptosis, chemtherapy also induces cellular senescence. The activation of interleukin-6 (IL-6) and signal transducer and activator of transcription factor-3 (STAT3) pathway, which is a very important component of the senescence-associated secretory phenotype, may promote the progression and tumor recurrence. Our preliminary data demonstrated that low concentration of doxorubicin could induce cellular senescence in neuroblastoma, accompanied by significant decrease of N-Myc protein. In addition, we also found IL-6 could weaken the cellular senescence induced by chemotherapy. This project intends to focus on cellular senescence and IL-6/STAT3 signaling pathway, using primary cells, cell lines and mouse model of transplanted tumor with siRNA and lentiviral infection to further clarify the molecular mechanism of chemotherapy-induced cellular senescence in neuroblastoma; to reveal the relation and mechanism between IL-6/STAT3/c-Myc signal activation of senescent cells and senecence reversion/tumor recurrence; to explore whether blocking IL-6/STAT3 signaling pathway in senescent cells with IL-6 neutralizing antibody or small-molecule inhibitors can suppress senecence reversion and prevent tumor recurrence. The results will provide important experimental and theoretical basis for elucidating a new relapse mechanism of neuroblastoma and exploring novel therapeutic targets on cellular senescence and IL-6/STAT3 signaling.

英文关键词： ;neuroblastoma;cellular senescence;STAT3;interleukin 6