ZEB1调节神经胶质瘤上皮-间质转化及肿瘤干细胞干性维持的分子机制

Gliomablstoma is the most malignant tumor in central neuron system, and epithelial-mesenchymal transition (EMT) is one of key ways to mediate gliomagenesis. However, the mechanisms of EMT-regulated gliomagenesis are still elusive. Previous we and others found that PDGFR alpha is a main driver of glioma proliferation and invasion. We also found that ZEB1 and PDGFRA co-expression in clinical specimens by Meta-data analysis, and PDGF-A stimulation promoted ZEB1 transcription and phosphorylation. Morevoer, knockdown of ZEB1 inhibited PDGFR alpha-driven glioma proliferation and EMT. Most interestingly, compared gene expression differentiation between in various glioma stem cells and in various glioma cells, it was shown that ZEB1, a member of EMT-related protein family, was highly and specifically expressed in glioma stem cells. Depletion of ZEB1 significantly decreased the colony formation of glioma stem cells. Our project will deeply explore the mechanisms of ZEB1-regulated glioma EMT and glioma stem cell stemness. Binding with clinical specimen analysis, we will also address the roles of ZEB1 in clinical treatment and tumor radioresistance. This will help not only to understand the molecular mechanisms of ZEB1-mediated gliomagenesis, but also to provide potential research basis for clinical diagnosis and therapy.

胶质瘤是最主要的恶性神经系统肿瘤，上皮-间质转化（EMT）是调节胶质瘤生物学的主要调控方式之一，但缺乏EMT调节胶质瘤发生的分子机制研究。我们前期发现血小板衍生因子受体（PDGFR alpha）是调节胶质瘤增殖与侵袭的关键驱动因子；对临床大数据分析表明ZEB1和PDGFRA共表达；PDGF-A刺激，促进ZEB1转录上调和磷酸化；敲除ZEB1抑制了PDGFR alpha驱动的胶质瘤的EMT。并且，比较多个胶质瘤干细胞和肿瘤细胞，结果表明EMT家族中的ZEB1特异的在肿瘤干细胞中高表达；敲除ZEB1降低肿瘤干细胞的克隆形成。本项目将深入揭示ZEB1及其磷酸化参与调节胶质瘤EMT和干细胞干性的分子机制，同时，结合临床样本，分析ZEB1的临床应用价值，探讨干扰ZEB1敏化放疗的方法。该研究的顺利完成，不仅有助于揭示ZEB1调节胶质瘤发生的分子机制，而且将为临床疾病预测和治疗提供坚实的理论基础。

胶质瘤是成人最主要最恶性的颅内肿瘤，而上皮-间质转化（EMT）和组蛋白的表观遗传学修饰是其恶性增殖和侵袭的关键分子调控机制，深入揭示这些分子调控机制对临床治疗显得极为重要和迫切。通过本项目的研究，取得如下成果：1）发现SHP-2调控胶质瘤EMT和肿瘤干细胞干性维持的新的信号通路-miR-200-ZEB1（Oncogene 2016)；2）阐明组蛋白乙酰转移酶KAT6A乙酰化的组蛋白H3K23招募TRIM24与染色质结合,而TRIM24作为转录因子共激活子，稳定并激活STAT3转录活性，增强STAT3下游通路的活化，导致胶质瘤的恶性增殖（Nat Commun 2017；Cancer Res 2017）；3）揭示了EGFR/CDK5调控的TRIM59通过泛素化降解异型组蛋白macroH2A1，核TRIM59并与TC45竞争性结合，从而双重激活STAT3参与调控胶质发展的新机制（Nat Commun 2019；Cancer Res 2018）； 4）发现TGF-beta-特异上调的长链非编码RNA-LINC00115作为一个“miRNA海绵”结合miRNA-200，调控胶质瘤干细胞的干性维持和成瘤性（EMBO Reports 2019）；5）阐明SHP2磷酸酶抑制剂SHP099特异抑制胶质瘤干细胞的体外增殖和颅内成瘤性，具有易口服、低毒性、能通过血脑屏障的特点(Neuro-Oncology 2019)。总之，该项目的研究水平处于国际同行的前列，不仅阐明了新的胶质瘤恶性增殖和肿瘤干细胞干性维持的分子机制，并且发现多个新的分子标记物及一个新的靶向胶质瘤干细胞的潜在临床治疗的小分子药物。这将有利于制定新的临床胶质瘤预测和治疗策略。