miR-138与EZH2信号环路的相互作用及对神经胶质瘤增殖与侵袭的影响

Glioma is the most common brain tumor with deadly poor clinical prognosis and its pathogenesis remains unclear. Our preliminary results showed that oncogene EZH2 was abundantly expressed in Glioma, down-regulating of which was responsible for inhibition of glioma cell proliferation and lower expression of CDK4 and E2F1. Herein, EZH2 exerts a vital regulation on cell cycle and proliferation of Glioma. MicroRNAs are important post-transcriptional regulators, which negatively modulate gene expression. Our previous study displayed that miR-138 could effectively suppress Glioma cell proliferation and arrest cell cycle. Moreover, miR-138 was potent to inhibit EZH2 and EGFR, which implicated a potential value for Glioma treatment. Taken together, we hypothesize that there exists a negative crosstalk between miR-138 and EZH2; EZH2 promotes Glioma progression by mediating two signal curcuit pathways: EZH2 - CDK4/6-pRB-E2F1 and EZH2 - EGFR-E2F1; through suppressing the two pathways by directly inhibiting EZH2, miR-138 plays a great role in cell cycle, proliferation and invading process of Glioma. Our research will be available to further unravel mechanisms of Glioma tumorigenesis and new targets for glioma clinical treatment.

胶质瘤是发病率最高的颅内肿瘤，临床预后极差。发病机制尚不清楚。我们前期研究发现，癌基因EZH2在胶质瘤中高表达，其降低则能抑制胶质瘤增殖，且能下调CDK4和E2F1表达，提示EZH2对胶质瘤细胞周期与增殖发挥关键调控作用。miRNAs是重要的转录后调控分子，负向调控靶基因表达。我们前期研究提示：miR-138能有效抑制胶质瘤细胞增殖和阻遏细胞周期；而且发现miR-138抑制EZH2效力最佳，并能下调EGFR基因表达。因此，miR-138具有胶质瘤治疗的潜在价值。我们假设：miR-138与EZH2存在交互抑制作用；EZH2介导两条信号环路即：EZH2 - CDK4/6-pRB-E2F1与EZH2 - EGFR-E2F1促进胶质瘤演进；miR-138通过直接靶向抑制EZH2阻遏该信号环路，发挥抑制胶质瘤细胞增殖和侵袭的调控作用。因此，本研究将进一步揭示胶质瘤发生机制并为临床治疗提供新的治疗靶标

胶质母细胞瘤（Glioblastoma multiforme，GBM)是最常见的恶性程度最高的成人颅内肿瘤，临床预后极差。目前人们对胶质瘤的发生发展的生物学机制仍不清楚，而且其诊断和预后缺乏特异性的生物标记物。大量研究表明EZH2对胶质瘤细胞周期与增殖发挥关键调控作用。我们通过临床胶质瘤样品标本及TCGA数据库，验证了miR-138在GBM中显著下调且与患者的生存率正相关，并通过不同胶质瘤细胞系和裸鼠胶质瘤模型，证明了miR-138可抑制GBM细胞增殖并使其细胞周期进入静息期，而且我们明确了EZH2及CDK6是miR-138在GBM中的直接靶基因。进一步我们通过基因干扰，验证了EZH2-CDK4/6-pRb-E2F1信号通路在胶质瘤细胞周期与增殖中的重要作用，以及miR-138对该通路的抑制作用。我们的研究结果究对于明晰miR-138在GBM细胞周期与增殖过程的作用及完善EZH2-CDK4/6-pRb-E2F1信号通路分子机制具有重要意义，表明miR-138可以作为GBM诊断和未来治疗的靶点。