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Updated: Feb 2, 2026
Detection of Alternative Splicing During Epithelial-Mesenchymal Transition
Published on: October 9, 2014
SRSF1 modulates PTPMT1 alternative splicing to regulate lung cancer cell radioresistance
Junxiu Sheng1, Qingzhi Zhao2, Jinyao Zhao2
1Department of Radiation Oncology, First Affiliated Hospital, Dalian Medical University, Dalian 116044, China.
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.
Insights
The splicing factor SRSF1 promotes radioresistance in lung cancer by altering PTPMT1 splicing. Reducing SRSF1 sensitizes cancer cells to radiation, offering a potential therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Radioresistance is a primary reason for cancer treatment failure.
- Splicing dysregulation is implicated in tumorigenesis, but its role in radioresistance is unclear.
- This study investigates the role of splicing factor SRSF1 in lung cancer radioresistance.
Purpose of the Study:
- To investigate the role of SRSF1 in radioresistance in lung cancer.
- To elucidate the molecular mechanisms by which SRSF1 influences radioresistance.
- To identify SRSF1 as a potential therapeutic target for enhancing radiotherapy efficacy.
Main Methods:
- Utilized lung cancer cell lines, xenograft mouse models, and RNA-sequencing to study SRSF1 mechanisms.
- Analyzed clinical tumor tissues and TCGA dataset for SRSF1-regulated splicing isoform expression.
- Employed KM-plotter to correlate splicing isoform levels with patient survival.
Main Results:
- SRSF1 levels increase upon irradiation in lung cancer cells; SRSF1 knockdown sensitizes cells to radiation.
- SRSF1 regulates splicing of PTPMT1, a mitochondrial phosphatase.
- Reduced SRSF1 promotes a short PTPMT1 isoform, enhancing DNA double-strand breaks via AMPK phosphorylation, sensitizing cells to radiation.
- Decreased short PTPMT1 isoform levels correlate with poorer patient survival.
Conclusions:
- SRSF1 plays a key role in radioresistance in lung cancer through aberrant splicing.
- SRSF1 is a potential therapeutic target for sensitizing lung cancer patients to radiotherapy.
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