GATA-4与肌相关microRNAs及环状RNA调控级联在成肌细胞分化及横纹肌肉瘤发生中的作用机制

成肌细胞的分化异常是横纹肌肉瘤发生的主要原因，并且伴随着肌相关microRNAs表达的紊乱。我们的前期结果表明，转录因子GATA-4和肌相关miR-29a都能诱导成肌细胞分化并抑制横纹肌肉瘤的发生, 同时，GATA-4还调控其表达，而miR-29a又可导致环状RNA表达的改变。因此，我们提出了“GATA-4与肌相关microRNAs及环状RNA形成调控级联并在成肌细胞分化及横纹肌肉瘤发生中发挥作用”这一科学假说, 并拟进行下列研究：首先，在正常的成肌细胞分化及异常分化的横纹肌肉瘤细胞中，分析GATA-4与四种肌相关microRNAs及环状RNA的调控级联；其次，通过裸鼠成瘤模型，分析上述调控级联对横纹肌肉瘤增殖和分化的影响；最后，建立成肌细胞分化异常导致小鼠横纹肌肉瘤模型，分析此调控级联对横纹肌肉瘤发生的影响。上述研究将进一步阐明横纹肌肉瘤发生的分子机理，为寻找新的防治靶点提供理论依据。

Rhabdomyosarcoma, the most common pediatric soft tissue sarcoma, mainly results from an aberrant differentiation of myoblasts during the skeletal myogenesis program, and muscle-related microRNAs act as key players and to be dysregulated in Rhabdomyosarcoma. Therefore, it is important to explore the mechanism of the disturbed differentiation of myoblasts for us to understand the genesis of rhabdomyosarcoma. Our previous results showed that both the transcription factor GATA-4 and miR-29a can induce the differentiation of myoblasts and inhibit the genesis of rhabdomyosarcoma. On the other hand, GATA-4 can regulate the expression of miR-29a, which in turn induces the changes of the expression profiles of circRNAs, so we propose the hypothesis that “there is a GATA-4/muscle-related microRNAs/circular RNA regulatory cascade which plays essential roles in myoblasts differentiation and rhabdomyosarcoma development”. To address the hypothesis, we will first analyze the GATA-4/muscle-related microRNAs/circular RNA regulatory cascade in the normal myoblast differentiation and abnormal differentiation such as the rhabdomyosarcoma cells. Next, we will analyze the role of above regulatory cascade in the regulation of the proliferation and differentiation of rhabdomyosarcoma by using the models of nude mice. Finally, we will analyze the role of above regulatory cascade in the genesis of rhabdomyosarcoma by using the models of mouse rhabdomyosarcoma, which was established through the aberrant differentiation of DMD cells. These complementary lines of investigation will provide not only a great potential to further elucidate the molecular mechanism of rhabdomyosarcoma genesis, but also a strong foundation for finding new targets for the prevention and treatment of rhabdomyosarcoma.