肿瘤侵袭新分子14-3-3β对干细胞介导的胶质瘤侵袭的影响及其分子机制研究

Glioma which is the most common primary brain tumor is easy to invasion and metastasis with higher malignancy, short-term median survival period and poor quality living. According to the reports, the glioma stem cells is a key factor to the glioma invasion and metastasis. Our previous study also showed that high expression of 14-3-3β in glioma stem cells can affect the biological characteristics of the glioma stem cells significantly. But there are still no any reports whether 14-3-3β play a key role in glioma stem cell-mediated glioma invasion and metastasis process. Based on some previous work, the effect of 14-3-3β on the invasion and metastasis characteristics of glioma stem cell by the methods of gene transfection and RNA interference technology. Furthermore, the signaling pathways of above process will be explored using co-immunoprecipitation and gene chips. the relationship among 14-3-3β, miR-128,HIF-1α and VEGF will be evaluated through observing the expression of these protein in glioma tissue via immunohistochemistry method.This study will provide the important evidence to the underlying mechanism of glima invasion and metastasis and improve the survival time of glioma patient.

神经胶质瘤是最常见的原发性脑肿瘤，恶性程度高、易发生侵袭。胶质瘤干细胞是决定胶质瘤侵袭的关键因素。我们的研究发现：胶质瘤干细胞中高表达14-3-3β分子，可能是miR-128潜在的下游靶基因；14-3-3β能够影响胶质瘤干细胞中HIF-1α和VEGF的表达，但胶质瘤干细胞中是否通过miR-128 →14-3-3β→ HIF-1α / VEGF信号通路调控胶质瘤侵袭过程，目前尚未见报道。本课题拟在前期工作基础上，利用基因转染、RNA干扰等技术，评价14-3-3β对干细胞介导的胶质瘤侵袭特性的影响；利用蛋白质研究方法和基因芯片等技术，探讨干细胞中14-3-3β影响胶质瘤侵袭的信号通路；结合临床资料分析，明确 miR-128，14-3-3β，HIF-1α和VEGF分子与胶质瘤侵袭的相关性。本研究对于阐明胶质瘤侵袭的分子机制具有重要的理论意义，对于提高患者生存时间、改善生存质量具有实际的意义。

神经胶质瘤是最常见的原发性脑肿瘤，恶性程度高、易发生侵袭，患者生存质量差、中位生存期短。胶质瘤干细胞是决定胶质瘤侵袭的关键因素，但其具体分子机制和信号调控网络尚不清楚。我们的研究发现：胶质瘤干细胞中，高表达14-3-3β，HIF-1α和VEGF分子；同时，miR-128水平在胶质瘤干细胞中显著降低，miR-128负向调控胶质瘤中14-3-3β分子的表达，过表达miR-128，可显著抑制14-3-3β, HIF-1α和VEGF的表达水平；抑制胶质瘤干细胞中14-3-3β表达或过表达miRNA-128，可显著降低细胞的移行和侵袭进程，抑制胶质瘤干细胞凋亡；我们也发现，过表达miRNA -128的这一效应可被共转染14-3-3β cDNA所逆转，提示miR-128可能通过下游分子14-3-3β发生效应，14-3-3β可能为miR-128潜在的下游靶基因。14-3-3β，HIF-1α和VEGF在胶质瘤中共表达，与临床胶质瘤的病理分型密切相关；干涉14-3-3β表达能够降低胶质瘤干细胞中HIF-1α和VEGF的表达水平。上述结果提示，在胶质瘤干细胞中可能存在miR-128 →14-3-3β→ HIF-1α / VEGF信号通路，调控胶质瘤的侵袭过程。本研究对于阐明胶质瘤侵袭的分子机制具有重要的理论意义，对于探寻针对胶质瘤的有效预防和治疗措施，提高患者中位生存期、改善生存质量，具有重要的临床应用价值。