Cancer Res：剪接蛋白SRSF2在肝癌发生发展中的调控作用

1月12日，国际学术期刊Cancer Research在线发表了中国科学院上海健康研究院（暂名）冯英组的最新研究进展“SRSF2 regulates alternative splicing to drive hepatocellular carcinoma development”。该研究揭示剪接蛋白SRSF2通过调控与肿瘤相关基因的选择性剪接，从而促进肝癌的发生发展。

SRSF2是一个经典的SR蛋白家族成员，不仅可以调控基因的选择性剪接，同时还在转录过程中发挥激活功能。冯英组之前的研究发现，肝脏中特异性敲除SRSF2基因，导致小鼠生长迟滞，肝脏功能严重损害，并伴有肝细胞气球样变性和严重的肝细胞纤维化等（Mol Cell Biol, 2016），说明SRSF2蛋白在维持肝脏稳态过程中发挥重要的调控功能。但是SRSF2在人类肝癌中的表达以及调控机制目前尚不清楚。

在冯英研究员的指导下，博士生罗春玲等通过对90对肝癌患者样品的组织芯片研究发现，SRSF2蛋白在肝癌病人样品中呈现高表达的趋势，并且蛋白的表达水平与肝癌的病理分级以及病人的预后之间存在着显著的相关性。研究发现，SRSF2对肝癌细胞的生长有明显的促进作用，并且其功能的发挥大部分依赖于其对下游多个基因的剪接调控。SRSF2调控靶基因GCH1和STK39等的选择性剪接，导致促进肝癌细胞生长的剪接异构体表达增加，后者与肝癌的恶性程度相关联。剪接机制方面，SRSF2可以增强外显子接入和抑制外显子接入的双重功能；另一通讯作者吴文武博士（现就职于浙江农业大学）通过对剪接底物结合序列的分析发现，外显子的接入与否与SRSF2的结合位点在调控外显子上的分布密切相关。

该研究表明：剪接蛋白SRSF2通过调控基因如GCH1，STK39等的选择性剪接，从而在肝癌的发生发展中发挥重要功能，这一工作不仅有助于深入了解肝癌的发病机制，并且也为将来的诊断和治疗提供了新的靶点和思路。

原文摘要：

SRSF2 regulates alternative splicing to drive hepatocellular carcinoma development

Aberrant RNA splicing is recognized to contribute to cancer pathogenesis but the underlying mechanisms remain mainly obscure. Here we report that the splicing factor SRSF2 is upregulated frequently in human hepatocellular carcinoma (HCC) where this event is associated with poor prognosis in patients. RNA-seq and other molecular analyses were used to identify SRSF2-regulated alternative splicing events. SRSF2 binding within an alternative exon was associated with its inclusion in the RNA, whereas SRSF2 binding in a flanking constitutive exon was associated with exclusion of the alternative exon. Notably, cancer-associated splice variants upregulated by SRSF2 in clinical specimens of HCC were found to be crucial for pathogenesis and progression in hepatoma cells, where SRSF2 expression increased cell proliferation and tumorigenic potential by controlling expression of these variants. Our findings identify SRSF2 as a key regulator of RNA splicing dysregulation in cancer, with possible clinical implications as a candidate prognostic factor in HCC patients.