MicroRNA-1在横纹肌肉瘤中的表观遗传调控机制

MicroRNA plays a crucial role in tumorigenesis、development and prognosis. Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma of childhood. Recent research showed that deregulation of microRNA-1(miR-1) was involved in RMS proliferation and migration by regulating c-Met expression. However the molecular mechanism underlying the deregulation of miR-1 in RMS cells or tissues, especially the epigenetic mechanism was unclear. Our research focus on the mechanism of regulation of miR-1 in RMS cells or tissues, especially the DNA methyltransferase and histone modification enzyme regulation on miR-1. Also our research will pay attention to the their cooperation with miR-1 specific transcriptional factors. Our research will reveal the mechanism of epigenetic regulation of miR-1 involving in RMS proliferation、migration and apotosis. It will provide new insight into regulation of microRNA and clinical target of RMS.

miRNA在肿瘤的生成、发展、预后过程中均发挥重要作用。横纹肌肉瘤(rhabdomyosarcoma)是最常见的儿童软组织肉瘤。研究发现，microRNA-1（miR-1)在横纹肌肉瘤中表达被抑制；miR-1通过调控c-Met蛋白的表达来影响肌肉瘤细胞的增殖和迁移，并最终抑制横纹肌肉瘤的发生。但横纹肌肉瘤细胞和组织中miR-1表达下调的机制特别是表观遗传调控机制却知之甚少。本课题以横纹肌肉瘤细胞和临床组织标本为研究对象，系统的研究了miR-1表达的表观遗传调控机制，重点探讨了DNA甲基转移酶和组蛋白修饰酶对miR-1表达的调控作用，研究了DNA甲基酶、组蛋白修饰酶与转录因子的协同调控作用，以及它们对横纹肌肉瘤细胞的增殖、迁移和凋亡的影响。本研究将microRNA和表观遗传调控结合，为microRNA的表达调控提供了新的思路，同时也为横纹肌肉瘤的防治提供了新的线索和靶点。

miRNA, 20-22bp长的短的非编码RNA, 与靶基因mRNA的3'-UTR区结合调控其稳定性和阻止翻译。估计60%的mRNA都存在miRNA，调控细胞各个功能。本研究发现miR-548c-3p在临床胶质瘤样本中和胶质瘤细胞系中表达增高，miR-548c-3p可通过诱导G1期阻滞抑制胶质瘤细胞的增殖，同时可抑制细胞迁移。利用生物信息学的方法，我们发现c-myc为其潜在的靶基因。抑制c-myc表达后可部分抑制miR-548c-3p的抗肿瘤效果。因此，我们的研究发现miR-548c-3p可通过抑制c-myc实现其抑制胶质瘤的肿瘤形成，为临床治疗提供了新的治疗靶点。