Identification of regulatory molecules related to the differentiation of glioma stem-like cells by an integrated protoemics.

在本研究中，为了阐明GSC分化的分子机制，我们建立了具有向胶质母细胞瘤分化潜能的GSC克隆，并进行了基于DNA微阵列和iTRAQ的整合蛋白质组学研究。我们利用序列数据挖掘软件将从整合蛋白质组学中获得的所有数据结合在一起。GO分析显示，在血清诱导GSC分化过程中，细胞黏附分子(包括整合素AV)和细胞外基质(ECM)如纤维连接蛋白1的表达显著上调。整合素抑制剂和抗癌药物替莫唑胺(TMZ)的联合治疗显著抑制了GSC分化和胶质瘤进展的早期事件，并延长了小鼠GSC异种移植模型的存活时间。这些结果表明，GSCs诱导/分泌ECM在血清因素的作用下形成微环境，即进一步刺激GSC分化和增殖的分化生态位。

In this study, to clarify the molecular mechanism of GSC differentiation, we established GSC clones having the potential to differentiate into glioblastoma, and subjected to DNA microarray and iTRAQ based integrated proteomics. We combined all of the data obtained from the integrated proteomics by utilizing sequential data mining software. GO analysis revealed that the expression of cell adhesion molecules, including integrin aV, and extracellular matrices (ECMs), such as fibronectin 1, was significantly upregulated during serum-induced GSC differentiation. Combinational treatments with integrin inhibitors and anti-cancer drug temozolomide (TMZ) significantly suppressed early events in GSC differentiation, glioma progression and lead the longer survival of mouse GSC xenograft models. These results indicate that GSCs induce/secrete ECMs to develop microenvironments with serum factors, namely differentiation niches that further stimulate GSC differentiation and proliferation.