HPPCn参与调控胶质瘤对替莫唑胺敏感性及其机制

Temozolomide（TMZ）is the most common adjuvant chemotherapy for glioma. Drug-resistance is very frequently in glioma to lead to poor prognosis. Our previous study showed that a novel growth factor HPPCn( hepatopoietin Cn ) has a close relationship with clinical classification of glioma. Both extracellular and intracellular treatment of HPPCn could increase the sensitivity of U251 cell lines to the cytotoxicity of TMZ. The expression and location from nucleus to cytoplasm of RNA binding protein HuR were promoted by HPPCn. The expression and distribution of HuR is accordant to which of HPPCn in glioma tissues. It were reported that HuR contributed to drug-resistance in many tumors. It implied that HPPCn may regulate TMZ resistance by the way of effect on the HuR. In this study, we will investigate the function of HPPCn on the progression and drug-resistance of glioma in tumor tissues and primary cultured glioma cells. Target mRNAs of HuR which regulated by HPPCn in TMZ resistance and molecular interaction network would also be studied. The sensitization of TMZ regulated by HPPCn/HuR pathway would be observed in mouse intracalvarium glioma model. To investigate the mechanism of glioma drug-resistance is significant for better clinical treatment on glioma.

替莫唑胺（TMZ）是脑胶质瘤辅助性化疗的一线药物，但胶质瘤耐药往往导致化疗失败。HPPCn是我们发现和鉴定的新型细胞因子，前期研究显示HPPCn与胶质瘤恶性分级密切相关，其细胞外刺激或细胞内过表达均可显著提高TMZ敏感性，并逆转TMZ诱导的U251细胞耐药,同时引起RNA结合蛋白HuR的表达及细胞定位改变，而胶质瘤组织中HuR的表达分布与HPPCn一致。已有报道表明HuR与多种肿瘤耐药调控相关，提示HPPCn可能通过调节HuR影响胶质瘤对TMZ敏感性。本研究旨在以HuR调控为线索，通过临床样本和原代细胞培养分析进一步明确HPPCn对胶质瘤进展及耐药通路的影响；揭示HPPCn调节HuR生物活性及其TMZ耐药相关靶基因，并绘制相互作用调控网络图；小鼠颅内胶质瘤模型等方法观察针对HPPCn/HuR调控通路改善TMZ化疗的体内效果。深入揭示胶质瘤耐药新机制，为胶质瘤治疗提供更多靶点和选择。

胶质瘤是颅内最常见且预后最差的的恶性肿瘤，手术、放疗和辅以替莫唑胺化疗是目前新诊断的神经胶质瘤患者首选治疗方案，然而胶质瘤通常会再次复发，胶质瘤耐药是导致化疗失败的主要原因之一。本研究通过细胞学实验、斑马鱼体内实验和临床病例分析均表明，HPPCn/ANP32A可促进胶质瘤进展，HPPCn/ANP32A高表达是患者预后不良的独立预测指标；HPPCn/ANP32A可影响胶质瘤细胞U251对替莫唑胺、过氧化氢、四氯化碳和乙醇等化学药物的敏感性，并增强胶质瘤细胞的缺氧耐受性；表达谱基因芯片分析等结果提示，ANP32A/HPPCn可能通过RNA结合蛋白HuR介导，激活AKT- NF-kb信号通路，影响蛋白剪切、RNA转运及囊泡运输等通路基因表达和功能，调控胶质瘤细胞对替莫唑胺的耐药。.本研究提示HPPCn/ANP32A可作为胶质瘤标志物用于分子诊断、预后评价，并作为胶质瘤耐药的新靶标，为胶质瘤诊断和治疗提供新的思路。