基于转录组学的复杂炎症网络与脑胶质瘤恶性转化的研究

Up to now, nonresolving inflammation has been reported to play an important role in malignant transformation of human epithelial cancers including glioma, However, the mechanism of nonresolving inflammation network involved in carcinogenesis has not been extensively studied. Our mRNA and miRNA array data showed that the invasive malignant phenotype and the resistance to chemotherapy in glioma were associated with inflammation network. According to the development of transcriptomics and high throughput sequencing technology, our aim is to explore the relationship between inflammation network based on transcriptomics and glioma malignant transformation. In the study, we will choose glioma tissues with different grades as models，and RNA, miRNA and lncRNA sequencing and bioinformatics analysis as major methods, construct glioma inflammation network based on mRNA, miRNA and lncRNA. Further, we construct transcript factors mediated- glioma inflammation network to evaluate its regulation pattern. Finally, we analyze the role and mechanism of the key notes in glioma malignant transformation and targeting therapy. In conclusion, our finding will reveal the role and mechanism of the complex inflammation network based on transcriptomics and glioma malignant transformation, and provides more potential approaches for glioma treatment.

非可控性炎症是上皮系统肿瘤(包括脑胶质瘤)恶性转化的关键因素，但其相关网络调控机制有待阐明。本课题组前期mRNA与miRNA表达谱芯片研究提示，胶质瘤跨脑叶侵袭恶性表型和化疗耐药现象与炎症信号网络密切相关。基于转录组学研究和高通量测序技术的融合发展，本研究拟以胶质瘤恶性转化过程为轴线，以不同级别肿瘤组织为模型，进行全基因组RNA、miRNA和lncRNA测序，采用生物信息学手段，构建基于mRNA、miRNA与lncRNA三个水平的胶质瘤炎症网络；进一步选择转录因子作为纽带来解析转录因子介导的mRNA、miRNA和lncRNA相互作用的胶质瘤复杂炎症网络，确立其精细调控模式；最终行体内外试验研究胶质瘤炎症调控网络关键节点的功能、机制与靶向治疗策略。本研究将建立基于转录组学的胶质瘤复杂炎症网络，阐释其内在功能机制与作用模式，为寻找胶质瘤新的治疗靶点奠定基础，也为肿瘤炎症研究提供积极的借鉴。

脑胶质瘤是最常见的颅内原发肿瘤，由于发病部位特殊，脑胶质瘤手术致残率高，癫痫发生率高，其中恶性程度最高（WHO IV级）的胶质母细胞瘤（Glioblastoma Multiforme，GBM）约占颅内原发恶性肿瘤的80%。即使经手术、术后放化疗等标准治疗，其中位生存期仍仅为14.6个月，5年生存率不足10%，是全球难治性脑疾病，给家庭、经济、社会造成了沉重负担。较低级别脑胶质瘤近乎100%会进展为继发性GBM，其具体机制多年来均未明确。.本项目围绕“非可控炎症对脑胶质瘤恶性转化的作用机制”这一科学问题开展系列性研究，发现了以微小RNA(miRNA)、长链非编码RNA(lncRNA)和融合基因(fusion)为关键节点的脑胶质瘤复杂炎症调控网络，研究了其下游的EGFR/JAK2/STAT3相关炎症信号通路、HOTAIR/NLK/wnt相关炎症信号通路、MET/STAT3相关炎症信号通路等脑胶质瘤非可控炎症恶性转化过程中的关键信号通路，为其中关键节点作为脑胶质瘤的诊断标记物和治疗靶点奠定基础。