EGFR/GRβ/Shf调控环路在胶质瘤中的作用机制研究

糖皮质激素受体β（GRβ）是胶质瘤的一个新促癌基因，它与Wnt信号通路在细胞核中的相互作用维持了TCF/LEF复合体的高活性，但何种因素导致GRβ在细胞核中高表达尚未明确。我们近期研究发现正常胶质细胞和胶质瘤中GRβ核浆分布可能受表皮生长因子受体(EGFR)活性调控，而胶质瘤中EGFR高活性与SH2衔接蛋白Shf的低表达有关，通过基因芯片、转录因子结合位点预测和报告基因分析提示GRβ可能在转录水平抑制Shf。基于上述研究背景，我们提出EGFR-GRβ-Shf调控环路假说：胶质瘤中异常活化的EGFR及下游信号通路促进GRβ在细胞核中高表达，GRβ在转录水平抑制Shf间接促进非配体依赖的EGFR活化从而促进胶质瘤的发生发展。本项目将通过体内外实验验证该假说，以期解释胶质瘤中EGFR异常活化及GRβ细胞核优势表达这两个关键问题，为胶质瘤的防治提供新靶点和新思路。

Previous studies have documented that GRβ serves as a co-activator for Wnt signaling potentiating glioma progression by interacting to TCF-4. While, what factors leading to GRβ nuclear localization remains unclear. Our recent data showed that the nucleus-cytoplasm trafficking of GRβ in normal glial cells and glioma cells is regulated by the activity of EGFR; the abnormal activation of receptor tyrosine kinase (RTK) activity of EGFR is associated with low expression of Shf (SH2 domain-containing adapter protein F) in gliomas; moreover, the results from cDNA array, transcription factor binding sites prediction and reporter gene assay suggested that Shf is a direct transcriptional target of GRβ. Accordingly, this project proposed a hypothesis of EGFR-GRβ-Shf regulation loop in gliomas: abnormal activation of EGFR and its downstream pathway induces nuclear translocation of GRβ which suppresses Shf expression at transcriptional level; as a result, the low level of Shf indirectly contributes EGFR autophosphorylation and its downstream pathway activation. We expect to expand the understanding the mechanism of EGFR abnormal activation and GRβ nuclear-superiority distribution in gliomas and further uncover a key EGFR associated pathway in regulating glioma progression.