深海天然产物Grincamycin B诱导胶质瘤干细胞分化作用及机制研究

Malignant glioma is one of the incurable tumors with patient’s survial time no more than 2 years. Cancer stem cells have been proved to play a critical role in tumor invasion, metastasis and recurrence and induction CSCs to differentiate has been proposed to be one of the most effective ways to treat cancer. The biological activity of deep-sea actinomycetes metabolites were screened in our provious study and a new anthraquinone glycoside (Grincamycin B) were identified to own strongest biological activity. We also found Grincamycin B significantly inhibited glioma and induced glioma stem cells to differentiation. Gene chip analysis showed that differentiation-associated genes were over-expressed and some molecules of WNT signaling pathway, including TCF4,JUN and CDK6, were down-regulated in glioma CSCs treated with Grincamycin B. In this project, we will investigate the role of TCF4 in Grincamycin B induced CSCs differentiation by construction TCF4 luciferase reporter and changing TCF4 expression. Our study will provide new insights and lead compound for the development of new anti-cancer drugs targeting CSCs.

（限400字）：恶性胶质瘤预后差、缺乏有效治疗策略。肿瘤干细胞是肿瘤发生、复发、转移及耐药的“根源”，诱导肿瘤干细胞分化被认为是行之有效的肿瘤治疗策略之一。我们前期从深海天然产物中鉴定出新化合物Grincamycin B，并发现其通过诱导胶质瘤干细胞分化显著抑制胶质瘤(已申请发明专利)。基因芯片结果显示，Grincamycin B处理后，胶质瘤干细胞中WNT通路TCF4、 JUN、CDK6等相关基因都显著下调，其中TCF4位于变化基因中最上游，且下调倍数最高，提示TCF4在Grincamycin B诱导胶质瘤干细胞分化过程中发挥关键作用。本项目拟采用构建TCF4荧光素酶报告检测系统及敲除与过表达TCF4等实验技术，阐明TCF4在化合物Grincamycin B诱导胶质瘤干细胞分化中的作用及机制，为进一步研发靶向诱导CSCs分化的新药提供理论和实验依据及先导化合物。

恶性胶质瘤预后差、缺乏有效治疗策略。肿瘤干细胞是肿瘤发生、复发、转移及耐药的“根源”，诱导肿瘤干细胞分化被认为是行之有效的肿瘤治疗策略之一。我们前期从深海天然产物中鉴定出新化合物Grincamycin B，并发现低剂量的Grincamycin B对胶质瘤细胞有选择性毒性作用，诱导胶质瘤细胞凋亡，显著抑制胶质瘤细胞克隆形成能力，抑制胶质瘤细胞干性基因的表达，诱导胶质瘤干细胞GFAP表达向星型胶质细胞分化。 基因芯片分析，Grincamycin B处理胶质瘤干细胞后MAPK信号通路是最重要发生改变之一（P-value 3.73e-7）；进一步生物信息Signal-net分析差异基因，发现RHOA处于最中间；同时利用药物作用靶点软件分析，发现RHOA 得分最高9.3631; 进一步研究受体RHOA结构与配体小分子Grincamycin B相互作用，通过sybyl对接结果显示，配体小分子通过THR-37,GLN -63,ASP-120三个氨基酸残基发生氢键与受体作用。.阐明化合物Grincamycin B诱导胶质瘤干细胞分化中的作用及其分子机制，为进一步研发靶向诱导CSCs分化的新药提供理论和实验依据及先导化合物。