组蛋白甲基化酶SMYD-3在胶质瘤发生发展、增殖转移及其肿瘤干细胞中的作用及分子机制

Glioma is the most common primary tumor affecting adult central nervous system, and the current average survival of glioblastoma patients is only 12-15 months. Histone methyltransferase SMYD3 are attacting growing concerns of researchers, but SMYD3 researches in gliomas has not been reported at home and abroad. Previous studies found that histone methyltransferase SMYD3 was overexpressed in glioma tissues, while there was almost no SMYD3 expression in normal brain tissue. We interfered SMYD3 at the cellular level and found that cell proliferation was inhibited, the cell cycle was arrested in G2 / M phase, and apoptosis was induced. In addition, the ability of glioma stem cells into balls dropped. In vivo experiments showed that the growth rate of SMYD3-interfered glioma cells subcutaneous model was significantly reduced. Based on the preliminary experimental results, the project plans to explore and analyse the correlation between SMYD3 expression and glioma through clinical glioma samples and glioma tissue microarray, and furtherly employing a variety of technical methods (gene chip, etc.) and animal models in vivo and vitro deeply study the roles and molecular mechanism of Histone methyltransferase SMYD-3 in glioma progression, proliferation and metastasis and cancer stem cells, which will provide the theoretical basis for further studying whether SMYD3 is a potential therapeutic target.

胶质瘤是影响成人中枢神经系统最常见的原发性肿瘤，目前胶质母细胞瘤患者的平均生存期仅为12-15个月。组蛋白甲基化酶SMYD3的研究日益受到关注，但SMYD3在胶质瘤中的研究国内外至今未见报道。前期研究发现组蛋白甲基化酶SMYD3在胶质瘤组织中异常高表达，而正常脑组织几乎不表达，我们在细胞水平干扰SMYD3，发现细胞增殖被抑制，细胞周期被阻滞到G2/M期，并且引起细胞凋亡，此外胶质瘤干细胞的成球能力明显下降。在体内实验发现，SMYD3干扰的胶质瘤细胞，在小鼠皮下模型中的生长速度明显降低。本项目拟在前期研究基础之上，通过临床胶质瘤样本及胶质瘤组织芯片技术研究分析SMYD3的表达与胶质瘤的相关性；并进一步利用多种技术方法（基因芯片技术等）和动物模型，在体内外深入研究SMYD3在胶质瘤发生发展、侵袭与转移以及肿瘤干细胞中的作用及其分子机制,为进一步探讨SMYD3是否具有潜在治疗靶点提供理论依据。

胶质瘤是影响成人中枢神经系统最常见的原发性肿瘤，胶质瘤患者通常采用手术、化疗和放疗及其联合治疗，虽然这些治疗方式在一定程度上改善了胶质瘤患者的生存质量，但是由于肿瘤和正常组织的分界不是很清晰，致使手术切除很难清理干净，最终导致肿瘤的复发，而放化疗也容易使肿瘤产生耐受，因此胶质母细胞瘤患者的平均生存期仅仅为 12-15 个月。组蛋白甲基化酶SMYD3的研究日益受到关注，但SMYD3在胶质瘤中的研究国内外至今未见报道。我们通过体内外实验发现：1. 组蛋白甲基化酶SMYD3在胶质瘤组织中异常高表达，而正常脑组织几乎不表达，并且随着肿瘤的恶性程度升高，SMYD3的表达量逐渐升高；2. 在细胞层面，干扰SMYD3蛋白分子后，胶质瘤细胞的增殖被抑制，细胞周期被阻滞到G2/M期，细胞发生了凋亡；3.体内动物发现，通过siRNA敲除SMYD3，在胶质瘤的皮下瘤模型中，经过SMYD3的敲除可以有效抑制胶质瘤的生长；4. 根据SMYD3设计小分子抑制剂可以在体内外有效抑制胶质瘤的生长，诱导胶质瘤细胞凋亡。基于以上研究结果发现，SMYD3可以调控胶质瘤的增殖、凋亡等生命过程，为SMYD3作为治疗胶质瘤的靶点提供了理论依据。