SRSF1 modulates PTPMT1 alternative splicing to regulate lung cancer cell radioresistance
SRSF1 modulates PTPMT1 alternative splicing to regulate lung cancer cell radioresistance
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SRSF1调节PTPMT1选择性剪接调节肺癌细胞放射抗性
DOI：
10.1016/j.ebiom.2018.11.007
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发表时间：
2018-12-01
期刊：
影响因子：
11.1
通讯作者：
Wang，Yang
中科院分区：
文献类型：
--
作者：
Sheng，Junxiu;Zhao，Qingzhi;Wang，Yang
背景放射抵抗是导致癌症治疗失败的主要原因。此外，剪接失调在肿瘤发生中起关键作用。然而，选择性剪接参与癌细胞对放射治疗的抗性仍然是难以捉摸的。我们试图探讨剪接因子SRSF 1在肺癌放射抵抗中的关键作用。方法采用肺癌细胞系、异种移植小鼠模型和RNA-seq研究SRSF 1在肺癌放射抵抗中的详细机制。利用临床肿瘤组织和TCGA数据集来确定不同SRSF 1调节的剪接异构体的表达水平。应用KM-RT-PCR分析了SRSF 1调控剪接异构体水平不同的癌症患者的生存率，筛选剪接因子以确定其在放射抗性中的作用，发现SRSF 1参与了癌细胞的放射抗性。SRSF 1的水平在辐射处理的肺癌细胞中升高，而SRSF 1的敲低使癌细胞对辐射敏感。从机制上讲，SRSF 1调节各种癌症相关的剪接事件，特别是PTPMT 1（一种PTEN样线粒体磷酸酶）的剪接。SRSF 1的减少有利于照射后PTPMT 1的短同种型的产生，这反过来又促进AMPK的磷酸化，从而诱导DNA双链断裂以使癌细胞对照射敏感。此外，PTPMT 1的短亚型的水平降低，在癌症样品中，这是相关的癌症患者的survival.ConclusionsOur研究提供了异常剪接在肺癌细胞中的放射抗性的机制分析，并建立SRSF 1作为一个潜在的治疗靶点，为敏感的患者放疗。
BackgroundRadioresistance 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.MethodsLung 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.FindingsSplicing 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.ConclusionsOur 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.