转录因子HMGA2介导NR2F2对SHH型髓母细胞瘤的影响的机制研究

Medulloblastomas (MB) are heterogeneous, highly aggressive and the most malignant tumors in central nervous system (CNS). Advances in integrative genomic studies have shown that MB is comprised of at least four subgroups with specific genetic characteristics. In addition, proliferation, invasion and migration are responsible for the refractoriness of MB to treatment. HMGA2 is one of the marker that distinguish MB from other embryonic CNS tumors. NR2F2 is overexpressed and promotes an undifferentiated state in stem cells of SHH MB. Previously, we found that silencing of HMGA2 leads to suppression of proliferation, invasion and migration and down-regulation of NR2F2 in SHH MB cell DAOY. Recovery of NR2F2 expression could significantly reverse these effects. Nevertheless, the significance and molecular mechanism of HMGA2 and NR2F2 in these malignant phenotypes in MB remain unknown. In the present research we aim to comprehensively unveil the role and molecular mechanism of HMGA2 and NR2F2 in proliferation, invasion and migration in SHH MB, and to further reveal the mutual interaction between HMGA2 and NR2F2. Collectively, our project aims to explore the mechanism of tumorigenesis and malignant phenotypes and provide new target for molecular biology therapy in SHH MB.

髓母细胞瘤（MB）是具有异质性和高度侵袭性的恶性程度最高的中枢神经系统（CNS）肿瘤，基因组学的进展将其分为至少4种具有不同分子机制的分子亚型。恶性增殖、侵袭和迁移能力是MB难治性的主要原因。最新研究发现，HMGA2是MB区别于其它胚胎性CNS肿瘤的标记物之一。NR2F2在SHH型MB干细胞中高表达，同时与不良分化相关。我们发现，沉默HMGA2基因可以抑制SHH型细胞系DAOY的增殖、侵袭和迁移功能，并显著下调NR2F2的表达。回复NR2F2表达则可以明显逆转上述变化。但是二者在MB的上述恶性功能中的地位和作用机制尚未见报道。本课题将聚焦于SHH亚型，全方位研究HMGA2和NR2F2在SHH型MB中的增殖、侵袭和迁移能力中的作用和分子机制，并进一步阐明HMGA2和NR2F2之间的精细调控关系。本课题旨在探索SHH型MB的发生发展机制，为靶向生物学治疗提供新的治疗靶点。

髓母细胞瘤（MB）是具有异质性和高度侵袭性的恶性程度最高的中枢神经系统（CNS）肿瘤，基因组学的进展将其分为至少4种具有不同分子机制的分子亚型。恶性增殖、侵袭和迁移能力是MB难治性的主要原因。最新研究发现，HMGA2是MB区别于其它胚胎性CNS肿瘤的标记物之一。NR2F2在SHH型MB干细胞中高表达，同时与不良分化相关。本研究发现，沉默HMGA2基因可以抑制SHH型细胞系DAOY和ONS-76的增殖、侵袭和迁移功能，增强细胞的凋亡，并显著下调NR2F2的表达。回复NR2F2表达则可以明显逆转上述变化。动物水平上利用DAOY构建的裸鼠脑原位和皮下种植瘤模型中，沉默HMGA2表达组皮下种植瘤生长速度明显受到抑制，同时脑原位种植瘤模型小鼠的生存时间明显延长。另外，ChIP-seq实验明确了转录因子HMGA2结合位点在各染色体的分布，以及与启动子相关基因的关系，筛选出了所有HMGA2蛋白可能直接调控的基因。并利用Homer motif软件预测了HMGA2相关的motif的精细结合序列。本课题聚焦于SHH亚型，全方位研究HMGA2和NR2F2在SHH型MB中的增殖、侵袭和迁移能力中的作用和分子机制，并进一步阐明HMGA2和NR2F2之间的精细调控关系。本课题旨在探索SHH型MB的发生发展机制，为靶向生物学治疗提供新的治疗靶点。