miR-224/FOXD3/miR-199a在胶质瘤形成和发展中的作用及其机制

Glioma is the most common malignagnt tumor in brain and the incidence is increasing year by year. The initation and development of glioma have bearing on angiogenesis. MicroRNAs play an important role in oncogenesis, invasion, metastasis and tumor recurrence through network cascade, feedback and synergy effect. Our prelimonary data showed the following results: ⑴ compared to the normal brain tissues, the expression levels of miR-224 were up-regulated and the expression levels of miR-199a were down-regulated in glioma tissues; ⑵ inhibition of miR-224 or overexpression of miR-199a prominently reduced glioma cells proliferation and tube formation; ⑶ inhibition of miR-224 induced the expression of miR-199a throuth FOXD3, but the mechanisms are unclear and await illustration. From the above, we hypothsize that miR-224 regulate miR-199a expression and its downstream signal pathway via FOXD3, and thus mediating glioma cells proliferation and angiogenesis. In this study, we will establish glioma cells stable over/down-expressing miR-224 or FOXD3 or miR-199a as cell models, further analyze the relationship between miR-224 and miR-199a in glioma tissues and cells, and elaborate their mechanisms in glioma growth and angiopoiesis. The aim of this study is revealing miRNA-miRNA regulation, elaborating the role and mechanisms of miR-224/FOXD3/miR-199a signal pathway in glioma oncogenesis and devolpment, and establishing miRNA based clinical therapy for glioma.

胶质瘤是颅内最常见的恶性肿瘤，发病率逐年上升。胶质瘤的发生发展与肿瘤新的血管生成密不可分。近年来研究表明，miRNAs在胶质瘤的发生、转移、侵袭和复发中发挥着重要的作用。我们前期研究表明与正常脑组织相比，miR-224在胶质瘤组织中高表达，miR-199a在胶质瘤组织中低表达；下调miRNA-224或上调miR-199a可明显抑制胶质瘤细胞的增殖；两者可能通过FOXD3发挥调控作用。因此我们提出假说：miR-224通过FOXD3调控miR-199a及其下游信号通路，进而影响胶质瘤发生发展。本课题拟建立miR-224/FOXD3/miR-199a稳定细胞株模型，探讨miR-224与miR-199a之间的调控关系及其作用机制，揭示“miRNA-miRNA调控”的新机制，阐述miR-224/FOXD3/miR-199a在胶质瘤发生发展中的作用及其机制，为建立微小RNA靶向治疗技术提供依据和思路。

胶质瘤是颅内最常见的恶性肿瘤，发病率逐年上升。胶质瘤的发生发展与肿瘤新的血管生成密不可分。近年来研究表明，miRNAs在胶质瘤的发生、转移、侵袭和复发中发挥着重要的作用。我们研究表明与正常脑组织相比，miR-199a在胶质瘤组织中低表达，并与KRAS的表达成负相关。miR-199a抑制胶质瘤细胞增殖及侵袭。 KRAS是 miR-199a的直接靶基因，通过靶向 KRAS，miR-199a抑制对胶质瘤细胞生长及肿瘤新生血管形成的作用，并且提高了胶质瘤细胞对化疗药物替莫唑胺的敏感性。. 延续以往工作基础，我们发现延续以往工作基础，我们发现在低氧环境中，miR-26a通过降低DNA损伤和保护线粒体功能，可以改善胶质瘤细胞对替莫唑胺（ TMZ）耐药性。 低氧环境诱导线粒体通过 HIF-1a上调 miR-26a在胶质瘤细胞系中的表达水平，这与胶质瘤对替莫唑胺的耐药性相关。 我们还证实了Bad和 Bax是 miR-26a的直接靶基因，HIF-1α/miR-26a/Bax/Bad信号通路为 GBM使用替莫唑胺化疗提供一个新的合适治疗方法 。