The MBNL3 splicing factor promotes hepatocellular carcinoma by increasing PXN expression through the alternative splicing of lncRNA-PXN-AS1
The MBNL3 splicing factor promotes hepatocellular carcinoma by increasing PXN expression through the alternative splicing of lncRNA-PXN-AS1
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MBNL3剪接因子通过lncRNA-PXN-AS1的选择性剪接增加PXN的表达来促进肝细胞癌的发生
DOI：
10.1038/ncb3538
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发表时间：
2017-07-01
影响因子：
21.3
通讯作者：
Sun, Shu-han
中科院分区：
文献类型：
--
作者：
Yuan, Ji-Hang;Liu, Xiao-ning;Sun, Shu-han
了解剪接因子和剪接事件在肿瘤发生过程中的作用将为靶向治疗开辟新的途径。在这里，我们确定了一个癌胚剪接因子，MBNL 3，它促进肿瘤的发生，并表明肝细胞癌患者预后不良。MBNL 3敲低几乎完全消除肝细胞癌肿瘤发生。转录组学分析显示MBNL 3诱导lncRNA-PXN-AS 1外显子4包含。缺少外显子4的转录物与PXN mRNA的编码序列结合，导致翻译延伸因子从PXN mRNA解离，从而抑制PXN mRNA翻译。相反，含有外显子4的转录物优先与PXN mRNA的3′非翻译区结合，保护PXN mRNA免受microRNA-24-AGO 2复合物诱导的降解，从而增加PXN表达。通过诱导外显子4包含，MBNL 3上调PXN，其介导MBNL 3的促肿瘤发生作用。总的来说，这些数据证明了癌胚剪接因子，剪接事件和肿瘤发生之间的详细机制联系，并建立剪接因子和剪接事件作为潜在的治疗靶点。
Understanding the roles of splicing factors and splicing events during tumorigenesis would open new avenues for targeted therapies. Here we identify an oncofetal splicing factor, MBNL3, which promotes tumorigenesis and indicates poor prognosis of hepatocellular carcinoma patients. MBNL3 knockdown almost completely abolishes hepatocellular carcinoma tumorigenesis. Transcriptomic analysis revealed that MBNL3 induces lncRNA-PXN-AS1 exon 4 inclusion. The transcript lacking exon 4 binds to coding sequences of PXN mRNA, causes dissociation of translation elongation factors from PXN mRNA, and thereby inhibits PXN mRNA translation. In contrast, the transcript containing exon 4 preferentially binds to the 3′ untranslated region of PXN mRNA, protects PXN mRNA from microRNA-24–AGO2 complex-induced degradation, and thereby increases PXN expression. Through inducing exon 4 inclusion, MBNL3 upregulates PXN, which mediates the pro-tumorigenic roles of MBNL3. Collectively, these data demonstrate detailed mechanistic links between an oncofetal splicing factor, a splicing event and tumorigenesis, and establish splicing factors and splicing events as potential therapeutic targets.