DLG4经调控神经胶质细胞-间质转化影响恶性胶质瘤浸润性生长及其分子机制的研究

恶性胶质瘤因侵袭性生长而预后很差，但调节侵袭的分子机制不清。我们初步发现：⑴在恶性胶质瘤中DLG4表达下调并与神经胶质细胞-间质转化(GMT)和侵袭迁移密切相关；⑵DLG4低水平组患者预后较差且PLCβ通路激活；⑶过表达DLG4可抑制恶性胶质瘤细胞的GMT和侵袭迁移；⑷在间质型和预后不良的患者组PLCβ通路显著激活；⑸蛋白质DLG4可与PLCβ结合。由此，我们推测恶性胶质瘤细胞因其DLG4表达下调，使PLCβ通路激活而促进GMT，引起该细胞的侵袭性生长。为此，本课题拟采用多种方法确认DLG4与PLCβ在恶性胶质瘤细胞中的相互作用及其对PLCβ通路的影响，并在细胞、动物和临床标本多个层面研究DLG4的表达及其与PLCβ的相互作用对恶性胶质瘤的GMT、侵袭和化疗敏感性的影响。本研究结果将揭示一种调节恶性胶质瘤细胞GMT、侵袭迁移的新机制，为寻找新型药物作用靶标提供理论依据。

Malignant glioma, the most prevalent primary brain tumor and one of the most deadly of all diseases, is associated with poor prognosis and extensive invasion into surrounding tissues. However, the molecular mechanisms behind the invasion are far from elusive. Our preliminary data showed that: 1) DLG4 was significantly downreguated and significantly associated with glial-mesenchymal transition and invasive growth in malignant glioma tissues; 2) Poorer prognosis and PLCβ signaling activation was associated with patients with lower expression of DLG4; 3) Overexpression DLG4 inhibited glial-mesenchymal transition and invasive growth of malignant glioma cells; 4) PLCβ signaling activation was associated with mesenchymal and poorer prognosis of malignant glioma patients; 5) DLG4 interacted with PLCβ. Therefore, we hypothesize that DLG4 downregulation in malignant glioma cells promotes glial-mesenchymal transition and cellular invasion via activation of PLCβ signaling. Experiments in cellular, animal and clinical levels will be applied to study the effects of DLG4 expression and its interaction with PLCβ in the glial-mesenchymal transition, invasiveness of malignant glioma cells and the sensitivity of malignant glioma cells in response to chemotherapy. Our study will identify a novel mechanism by which DLG4 will regulate proneural-mesenchymal transition and malignant glioma cell invasion, which may help finding potential drug target for malignant glioma.