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    顾宏

    • 教授     博士生导师   硕士生导师
    • 性别:男
    • 毕业院校:浙江大学
    • 学位:博士
    • 所在单位:控制科学与工程学院
    • 学科:模式识别与智能系统
    • 办公地点:创新园大厦B0715
    • 电子邮箱:guhong@dlut.edu.cn

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    SRSF1 modulates PTPMT1 alternative splicing to regulate lung cancer cell radioresistance

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    论文类型:期刊论文

    发表时间:2018-12-01

    发表刊物:EBIOMEDICINE

    收录刊物:SCIE、PubMed、Scopus

    卷号:38

    页面范围:113-126

    ISSN号:2352-3964

    关键字:Alternative splicing; SRSF1; PTPMT1; AMPK; Radio-resistance

    摘要:Background: Radioresistance is the major cause of cancer treatment failure. Additionally, splicing dysregulation plays critical roles in tumorigenesis. However, the involvement of alternative splicing in resistance of cancer cells to radiotherapy remains elusive. We sought to investigate the key role of the splicing factor SRSF1 in the radioresistance in lung cancer.
       Methods: Lung cancer cell lines, xenograft mice models, and RNA-seq were employed to study the detailed mechanisms of SRSF1 in lung cancer radioresistance. Clinical tumor tissues and TCGA dataset were utilized to determine the expression levels of distinct SRSF1-regulated splicing isoforms. KM-plotter was applied to analyze the survival of cancer patients with various levels of SRSF1-regulated splicing isoforms.
       Findings: Splicing factors were screened to identify their roles in radioresistance, and SRSF1 was found to be involved in radioresistance in cancer cells. The level of SRSF1 is elevated in irradiation treated lung cancer cells, whereas knockdown of SRSF1 sensitizes cancer cells to irradiation. Mechanistically, SRSF1 modulates various cancer-related splicing events, particularly the splicing of PTPMT1, a PTEN-like mitochondrial phosphatase. Reduced SRSF1 favors the production of short isoforms of PTPMT1 upon irradiation, which in turn promotes phosphorylation of AMPK, thereby inducing DNA double-strand break to sensitize cancer cells to irradiation. Additionally, the level of the short isoform of PTPMT1 is decreased in cancer samples, which is correlated to cancer patients' survival.
       Conclusions: Our study provides mechanistic analyses of aberrant splicing in radioresistance in lung cancer cells, and establishes SRSF1 as a potential therapeutic target for sensitization of patients to radiotherapy. (c) 2018 The Authors. Published by Elsevier B.V.