缺氧微环境中长链非编码RNA HOTTIP通过激活ZEB1表达促进胶质瘤EMT的分子机制和临床意义

Being an important microenvironment, hypoxia usually initiates epithelial-mesenchymal transition (EMT) to promote the invasive growth of glioma. We find that long noncoding RNAs (lncRNAs) are key molecules for biological behaviors of gliomas. The production of lncRNAs, is dramatically influenced by hypoxia, however, the effect and mechanism of lncRNA on EMT in gliomas under hypoxic conditions has not been investigated. HOTTIP, one of lncRNAs selected based on our RNA-seq data, is found to be highly expressed in glioma cells induced by hypoxia, and probably to be positively regulated by HIF1α. Moreover, our work shows that knockdown of this lncRNA significantly inhibits the invasion and migration of the cells. These observations suggest that HOTTIP may be activated by HIF1α and promotes EMT. It is known that HIF1α-ZEB1 signaling axis plays an important role in promoting hypoxia induced EMT in glioma. So we will investigate whether HOTTIP mediates the regulation of HIF1α on ZEB1. And then we will explore further whether HOTTIP upregulates the expression of ZEB1 through the WNT/β-catenin and miR-200 family, respectively. Finally, we will evaluate the clinical significance of HOTTIP expression patterns in tissue samples in hypoxia. This project aims to provide new targets and novel strategies for the precise prevention and treatment of malignant glioma.

缺氧是诱发胶质瘤上皮-间质转变(EMT)从而促进其侵袭性生长的重要微环境。我们发现lncRNAs是影响胶质瘤生物学行为的关键作用分子(Oncotarget, 2016)，缺氧则能显著改变lncRNAs的产生(Tumor Biology, 2015)。但缺氧微环境中lncRNAs对胶质瘤EMT的影响，尚无报道。我们通过测序筛选出的lncRNA HOTTIP在缺氧诱导的胶质瘤细胞中高表达，它可能受HIF1α的正调控，敲低后则可显著抑制细胞侵袭和迁移，提示其可能在HIF1α的激活下促进EMT。缺氧时HIF1α-ZEB1轴对胶质瘤EMT有重要影响，我们将明确HOTTIP是否介导了HIF1α对ZEB1的促进作用，并进一步探索其是否通过WNT/β-catenin和miR-200途径上调ZEB1的表达，再对HOTTIP的临床意义做出评估。本项目的成功开展将有可能为恶性胶质瘤的精准防治提供新靶点和新策略。

缺氧微环境是诱发胶质瘤上皮-间质转变(EMT)从而促进恶性进展的重要条件。我们发现lncRNAs是影响胶质瘤生物学行为的关键作用分子，缺氧则能显著改变lncRNAs的产生。但缺氧微环境中lncRNAs对胶质瘤EMT的影响，尚无报道。我们通过测序筛选出的lncRNA HOTTIP在缺氧诱导的胶质瘤细胞中高表达，它可能受HIF1α的正调控，敲低后则可显著抑制细胞侵袭和迁移，提示其可能在HIF1α的激活下促进EMT。缺氧时HIF1α-ZEB1轴对胶质瘤EMT有重要影响，我们将明确HOTTIP是否介导了HIF1α对ZEB1的促进作用，并进一步探索其是否通过WNT/β-catenin和miR-200途径上调ZEB1的表达，再对HOTTIP的临床意义做出评估。本项目的成功开展将有可能为恶性胶质瘤的精准防治提供新靶点和新策略。