miR-31在髓母细胞瘤发生过程中的作用以及机制研究

Medulloblastoma (MB) is closely related with the activation of Sonic Hedgehog (Shh) pathway. Deficiency of Shh receptor Patched (Ptch) in human and mouse leads to highly activated Shh signaling, resulting in the elevated occurrence of MB. Recently, more and more studies on miRNAs suggest that some miRNAs are also involved in MB, but specific miRNAs in Shh-MB are barely investigated. In order to find the role of miRNAs in the MB caused by Ptch deficiency, we compared the profile of miRNAs in the MB from Ptch+/- mice with that in the normal cerebellum by deep sequencing. Our results showed that miR-31 was dramatically decreased in the MB, and miR-31 gene was deleted in a human MB cell line DAOY. Additionally，over expression of miR-31 in DAOY cells reduced their ability to form tumors. So we are going to further examine the role of miR-31 in Shh-MB and the molecular mechanism involved. This study will help to understand the role of miRNAs in Shh-MB, and provide new possible therapies for this type of MB.

髓母细胞瘤（Medulloblastoma, MB）的发生与Sonic Hedgehog （Shh）通路激活密切相关。在Shh受体Patched (Ptch) 缺陷的人和小鼠中， Shh通路异常激活，导致MB高发。近年关于小RNA（miRNA）的研究表明，一些miRNAs也与MB有重要关系。但MB中Shh通路相关miRNAs的研究尚非常有限。本课题组通过深度测序筛选Ptch单倍体缺失小鼠MB中差异表达的miRNAs，以阐明该MB中miRNAs的作用。结果显示，miR-31在该MB中显著低表达，并在人MB细胞系DAOY中有基因水平缺失，而且过表达miR-31抑制DAOY成瘤性。本研究将深入探讨miR-31抑制该MB的分子机制，为该MB的临床诊断及治疗提供新的思路。本研究包含两方面：1.寻找miR-31的靶基因。2. 阐明miR-31对该MB的作用机理。

microRNAs的调控异常与肿瘤发生关系密切。髓母细胞瘤是一种儿童脑部恶性肿瘤，但具体的分子发病机制尚不完全清楚。在Shh 受体Ptch基因变异的人和小鼠，存在Shh通路的异常激活，导致MB高发。通过对Ptch单倍体缺失小鼠髓母细胞瘤标本的深度测序发现，miR-31在该类型髓母细胞瘤中显著低表达，并在人髓母细胞瘤 细胞系DAOY 中有基因组水平的缺失。回补miR-31抑制DAOY成瘤性，主要通过miR-31的靶基因MCM2。在髓母细胞瘤发生过程中，由于遗传或表观遗传学的原因导致miR-31低表达，导致其下游靶基因MCM2高表达。结合到染色体上的MCM2增多加速了DNA的复制和肿瘤的恶性转化。横纹肌肉瘤是另一种儿童恶性肿瘤，我们研究发现miR-214经N-ras抑制横纹肌肉瘤细胞生长。胃癌是消化道常见肿瘤，miR-206是抑制胃癌细胞生长和转移的新的miRNA。本研究为肿瘤的靶向治疗提供了新的思路，也将上述miRNAs作为今后作为肿瘤的早期诊断及预后的特异性生物标记物提供了科学依据。