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Splicing factor SRSF1 promotes breast cancer progression via oncogenic splice switching of PTPMT1.
Du, Jun-Xian; Luo, Yi-Hong; Zhang, Si-Jia; Wang, Biao; Chen, Cong; Zhu, Gui-Qi; Zhu, Ping; Cai, Cheng-Zhe; Wan, Jing-Lei; Cai, Jia-Liang; Chen, Shi-Ping; Dai, Zhi; Zhu, Wei.
Afiliação
  • Du JX; Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
  • Luo YH; Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
  • Zhang SJ; Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
  • Wang B; Liver Cancer Institute, Zhongshan Hospital, Fudan University & State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, 200032, China.
  • Chen C; Key Laboratory of Carcinogenesis and Cancer Invasion, Fudan University, Ministry of Education, Shanghai, 200032, China.
  • Zhu GQ; Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
  • Zhu P; Liver Cancer Institute, Zhongshan Hospital, Fudan University & State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, 200032, China.
  • Cai CZ; Key Laboratory of Carcinogenesis and Cancer Invasion, Fudan University, Ministry of Education, Shanghai, 200032, China.
  • Wan JL; Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, No. 130 Dongan Road, Shanghai, 200032, China.
  • Cai JL; Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
  • Chen SP; Liver Cancer Institute, Zhongshan Hospital, Fudan University & State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, 200032, China.
  • Dai Z; Key Laboratory of Carcinogenesis and Cancer Invasion, Fudan University, Ministry of Education, Shanghai, 200032, China.
  • Zhu W; Liver Cancer Institute, Zhongshan Hospital, Fudan University & State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, 200032, China.
J Exp Clin Cancer Res ; 40(1): 171, 2021 May 15.
Article em En | MEDLINE | ID: mdl-33992102
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Neoplasias da Mama / PTEN Fosfo-Hidrolase / Fatores de Processamento de Serina-Arginina Tipo de estudo: Prognostic_studies Limite: Female / Humans Idioma: En Revista: J Exp Clin Cancer Res Ano de publicação: 2021 Tipo de documento: Article País de afiliação: China

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Neoplasias da Mama / PTEN Fosfo-Hidrolase / Fatores de Processamento de Serina-Arginina Tipo de estudo: Prognostic_studies Limite: Female / Humans Idioma: En Revista: J Exp Clin Cancer Res Ano de publicação: 2021 Tipo de documento: Article País de afiliação: China