RBM47调控的可变剪接在鼻咽癌发生发展中的调控作用

Nasopharyngeal carcinoma (NPC) is a cancer type of head and neck cancer, which has a particularly high prevalence in South China. The pathogenic factors and related mechanisms still remain mainly obscure now. Alternative splicing of pre-mRNA is very important for protein diversity and aberrant RNA splicing is now recognized to contribute to cancer pathogenesis. RBM47 is a RNA binding protein and has been proved to control alternative splicing recently. In our previous study, we found that RBM47 was frequently upregulated in NPC. Experiment results showed that RBM47 could increase proliferation and tumorigenic potential of NPC, and it was also involved in DNA damage and apoptosis pathways. Moreover, analyses of RNA-seq data revealed RBM47 could regulate some cancer-related splicing events. However, the mechanism is still unclear. Here, we prepare to look for the efficient targets of RBM47 by biochemical, molecular biological and bioinformatics technology, and illustrate the mechanism of its regulating alternative splicing. Our study will provide more precise data for the mechanism study of NPC, and may give further evidences for the NPC diagnoses and treatment.

鼻咽癌是华南地区最常见的头颈部恶性肿瘤，是我国高发的恶性肿瘤之一，目前其致病因素和相关机制尚未明确。mRNA前体的可变剪接是控制基因表达和产生蛋白多样性的重要机制，而可变剪接的异常与肿瘤的发生密切相关。我们前期结果发现，RNA结合蛋白RBM47在鼻咽癌组织中异常高表达，实验结果表明RBM47促进鼻咽癌细胞的增殖，抑制细胞凋亡；RBM47的缺失可以导致细胞DNA损伤增加，体内成瘤能力显著降低；而过表达RBM47则可以促进鼻咽癌细胞的生长。初步RNA-seq的分析结果显示，RBM47参与调控很多细胞生长相关基因的可变剪接，然而其下游具体的靶点及调控机制仍不清楚。本研究拟利用生物化学、分子生物学和生物信息学等技术手段，寻找RBM47的调控作用靶点，并阐明RBM47在鼻咽癌中的剪接调控机制。本研究可以为了解鼻咽癌的发病机制提供更多的理论依据，为将来的诊断和治疗提供新的靶点和思路。

鼻咽癌是一种起源于鼻咽上皮的恶性肿瘤，好发于鼻咽顶部和咽隐窝，在中国南方尤其是广东省发病率极高，其发生发展与遗传基因的改变、EB病毒感染、环境因素及饮食习惯等均有一定关系。RBM47是RNA结合蛋白中的一员，在RNA编辑、可变剪接、转录稳定性和mRNA翻译等方面都发挥着重要作用，而目前RBM47在鼻咽癌中的作用尚无相关报道。本研究通过RNA-seq数据分析发现，在29个RBM家族蛋白中，RBM47在鼻咽癌中的表达明显高于正常组织，且其高表达与预后呈显著负相关。体内体外功能学实验表明RBM47在鼻咽癌细胞中发挥促癌作用。机制研究首次发现RBM47 能够作为转录因子结合在BCAT1的promoter区域，调控BCAT1的表达水平。同时，本研究还发现RBM47作为剪接蛋白可以与另一RNA结合蛋白hnRNPM相互作用，共同调控肿瘤相关基因的可变剪接。我们的研究揭示了RBM47通过多层面调控促进鼻咽癌的发生发展，其可能为潜在的鼻咽癌分子标志物，对鼻咽癌的诊断、预后发挥重要作用。