Splicing factor SRSF1 promotes breast cancer progression via oncogenic splice switching of PTPMT1.
Splicing factor SRSF1 promotes breast cancer progression via oncogenic splice switching of PTPMT1.
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剪接因子 SRSF1 通过 PTPMT1 的致癌剪接转换促进乳腺癌进展
DOI：
10.1186/s13046-021-01978-8
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发表时间：
2021-05-15
期刊：
影响因子：
--
通讯作者：
Zhu W
中科院分区：
文献类型：
--
作者：
Du JX;Luo YH;Zhang SJ;Wang B;Chen C;Zhu GQ;Zhu P;Cai CZ;Wan JL;Cai JL;Chen SP;Dai Z;Zhu W
大量的证据已经强调了当由SR蛋白家族的失调触发时，异常选择性剪接（AS）事件对癌症进展的影响。尽管如此，乳腺癌（BRCA）的潜在机制仍然难以捉摸。在此，我们试图探索SRSF 1的分子功能，并确定BRCA中SRSF 1调控的关键AS事件。我们基于TCGA数据集、Metabric数据库和临床组织样本，对SRSF 1在BRCA中的表达和临床相关性进行了综合分析。在体外和体内进行BRCA中SRSF 1的功能分析。SRSF 1介导的AS事件及其结合基序通过RNA-seq、RNA免疫沉淀-PCR（RIP-PCR）和体内交联随后免疫沉淀（CLIP）鉴定，其通过小基因报告基因测定进一步验证。PTPMT 1外显子3（E3）AS被鉴定为通过P-AKT/C-MYC轴部分介导SRSF 1的致癌作用。最后，这些AS事件的表达和临床意义进行了验证，在临床样本和使用TCGA数据库。在BRCA样本中SRSF 1表达持续上调，与肿瘤分级和Ki-67指数呈正相关，并与激素受体阳性（HR+）队列中的不良预后相关，这促进了体外和体内的增殖，细胞迁移和抑制凋亡。我们确定了SRSF 1介导的AS事件，并发现了SRSF 1结合基序在PTPMT 1剪接转换的调节。此外，PTPMT 1剪接转换由SRSF 1通过直接结合其在E3中的基序来调节，E3通过AKT/C-MYC轴部分介导SRSF 1的致癌作用。此外，PTPMT 1剪接转换在BRCA患者的组织样本中进行了验证，并使用TCGA数据库。在I/II期TCGA BRCA队列中，通过PTPMT 1的AS和SRSF 1的表达确定的高危组具有较差的预后。SRSF 1通过调节PTPMT 1的AS在BRCA中发挥致癌作用，可能成为BRCA治疗的候选靶点和HR+ BRCA患者的预后因子。在线版本包含补充材料，可通过10.1186/s13046-021-01978-8获得。
Intensive evidence has highlighted the effect of aberrant alternative splicing (AS) events on cancer progression when triggered by dysregulation of the SR protein family. Nonetheless, the underlying mechanism in breast cancer (BRCA) remains elusive. Here we sought to explore the molecular function of SRSF1 and identify the key AS events regulated by SRSF1 in BRCA. We conducted a comprehensive analysis of the expression and clinical correlation of SRSF1 in BRCA based on the TCGA dataset, Metabric database and clinical tissue samples. Functional analysis of SRSF1 in BRCA was conducted in vitro and in vivo. SRSF1-mediated AS events and their binding motifs were identified by RNA-seq, RNA immunoprecipitation-PCR (RIP-PCR) and in vivo crosslinking followed by immunoprecipitation (CLIP), which was further validated by the minigene reporter assay. PTPMT1 exon 3 (E3) AS was identified to partially mediate the oncogenic role of SRSF1 by the P-AKT/C-MYC axis. Finally, the expression and clinical significance of these AS events were validated in clinical samples and using the TCGA database. SRSF1 expression was consistently upregulated in BRCA samples, positively associated with tumor grade and the Ki-67 index, and correlated with poor prognosis in a hormone receptor-positive (HR+) cohort, which facilitated proliferation, cell migration and inhibited apoptosis in vitro and in vivo. We identified SRSF1-mediated AS events and discovered the SRSF1 binding motif in the regulation of splice switching of PTPMT1. Furthermore, PTPMT1 splice switching was regulated by SRSF1 by binding directly to its motif in E3 which partially mediated the oncogenic role of SRSF1 by the AKT/C-MYC axis. Additionally, PTPMT1 splice switching was validated in tissue samples of BRCA patients and using the TCGA database. The high-risk group, identified by AS of PTPMT1 and expression of SRSF1, possessed poorer prognosis in the stage I/II TCGA BRCA cohort. SRSF1 exerts oncogenic roles in BRCA partially by regulating the AS of PTPMT1, which could be a therapeutic target candidate in BRCA and a prognostic factor in HR+ BRCA patient. The online version contains supplementary material available at 10.1186/s13046-021-01978-8.
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