GSE163025
Splicing factor SRSF1 promotes breast cancer progression via regulating alternative splicing
Purpose:Intensive evidence have highlighted the effect of aberrant alternative splicing (AS) events triggered by dysregulation of SR protein family on cancer progression. 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. Methods:We conducted comprehensive analysis for the expression and the clinical correlation of SRSF1 in BRCA based on TCGA, Metabric database, clinical tissue samples and BRCA cell lines. Functional analysis of SRSF1 in BRCA was conducted in vitro and in vivo. SRSF1-mediated AS events and its binding motif 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. Finally, the expression and their clinical significance were validated in clinical samples and TCGA database. Results:SRSF1 was upregulated in BRCA samples, associated positively with tumor grade and Ki-67 index, and correlated with poor prognosis in hormone receptor positive (HR+) cohort, which facilitated tumor progression in vitro and in vivo. We identified SRSF1-mediated AS events and discovered the SRSF1 binding motif in the regulation of PTPMT1. Furthermore, PTPMT1 splice switching regulated by SRSF1 partially mediated the oncogenic role of SRSF1 via the AKT/C-MYC axis. Additionally, PTPMT1 splice switching was validated in tissue samples of BRCA patients. Conclusions:Collectively, SRSF1 exerts the oncogenic roles in BRCA partially through regulating AS of PTPMT1, which could be a candidate prognostic factor and therapeutic target in HR+ BRCA cohort. Overall design: mRNA alternative splicing profiles of MCF7 NC and MCF7 sh SRSF1 cells