Hedgehog信号通路通过细胞自噬调控神经胶质细胞瘤生长的分子机制

Hedgehog-GLI（Hh）信号通路在神经胶质瘤中异常活化，但导致其异常活化以及异常活化诱导细胞增殖、凋亡抵抗的机制尚不明确。我们最近发现神经胶质瘤中转录因子GLI2启动子区甲基化程度明显低于癌旁组织；阻断Hh通路抑制神经胶质瘤细胞增殖并导致细胞自噬增高。此外基因芯片发现：抑制Hh通路后神经胶质瘤细胞中IκBα表达增加，NFκB表达减少，同时BNIP3表达增加。据此推测：GLI2启动子区低甲基化导致Hh通路异常活化；Hh通路通过"GLI2-IκBα/NFκB-BNIP3"信号轴调控细胞自噬，影响肿瘤细胞存活。本项目以神经胶质瘤为研究对象，研究导致GLI2异常活化的表观遗传学机制；发掘受GLI2调控的新靶基因；从分子、细胞及整体层面采用多种手段阐明Hh通路通过"GLI2-IκBα/NFκB-BNIP3"信号轴调控细胞自噬影响肿瘤细胞存活的分子机制。该项研究将为神经胶质瘤治疗提供理论依据。

The etiology of glioma is tightly linked to aberrant Hedgehog (Hh)/GLI activity. However, the activation mechanism of Hh/GLI pathway, as well as subsequent induction of proliferation and apoptosis resistance have not been completely elucidated. In our preliminary studies, level of GLI2 DNA methylation at promoter region was found to be much lower in glioma tissues than adjacent normal tissues. Furthermore, blockade of Hh signaling pathway resulted in inhibited proliferation and increased antophagy. Gene microarray technique allowed us to discover elevated expression of IκBα and BNIP3 and diminished NFκB in glioma cells. Therefore, we speculate that GLI2 DNA methylation at promoter region may contribute to aberrant activation of Hh/Gli signaling pathway. Hh signaling pathway may regulate autophagy through "GLI2-IκBα/NFκB-BNIP3" signaling axis. This project aims to study the effect and epigenetic mechanisms of aberrant activation of Hh/Gli signaling pathway in proliferation and survival of glioma cells, find new target genes regulated by GLI2, and investigate roles of "GLI2-IκBα/NFκB-BNIP3" signaling axis in autophagy. These findings will provide new insights into molecular mechanisms of cancer progression and identify potential targets for therapeutic intervention.