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Cellular and Molecular Biology

Spliceosomal GTPase EFTUD2 mediates DDX41 intron retention to promote the malignant progression of ovarian cancer

British Journal of Cancer (2025)Cite this article

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Abstract

Background

Dysregulation of alternative splicing (AS) has been identified as a promising target for cancer therapy. Nevertheless, the precise molecular mechanisms by which AS influences ovarian cancer (OC) progression have not yet been fully elucidated.

Methods

A comprehensive bioinformatics analysis was conducted to identify and screen core splicing factors in OC. The splicing factor EFTUD2 was found to be significantly overexpressed in clinical OC samples. Subsequent in vitro and in vivo assays elucidated the oncogenic role of EFTUD2 in OC. RNA-seq and AS events analysis were employed to determine the key downstream target regulated by EFTUD2. ASOs targeting EFTUD2 were developed for efficacy validation.

Results

EFTUD2 was identified as a critical splicing factor in the pathogenesis of OC, and EFTUD2 knockdown impeded OC tumorigenesis and progression. The EFTUD2-ASO significantly inhibited tumor growth in vivo. Mechanistically, EFTUD2 was shown to promote the malignant biological behavior of OC by facilitating the efficient splicing of DDX41 and maintaining the oncogenic expression of its functional proteins. Knockdown of DDX41 partially mitigated the EFTUD2-induced malignant progression of OC cells.

Conclusions

Our findings suggest that the EFTUD2/DDX41 axis is a viable target for OC. ASO-mediated silencing of EFTUD2 presents promising new therapeutic options for OC patients.

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Fig. 1: EFTUD2 expression is upregulated in OC.
Fig. 2: Silencing EFTUD2 reduces proliferation, migration, and invasion of OC cells both in vitro and in vivo.
Fig. 3: ASO-mediated EFTUD2 knockdown inhibits the malignant behaviors of OC cells in vitro and in vivo.
Fig. 4: DDX41 is a critical downstream target of EFTUD2 based on RNA-seq analysis.
Fig. 5: EFTUD2 maintains efficient splicing of DDX41 intron 6 in OC cells.
Fig. 6: DDX41 inhibition suppresses the growth and decreases the metastatic potential of OC cells in vitro.
Fig. 7: DDX41 knockdown attenuates the malignant phenotype of EFTUD2- overexpressing OC cells.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

This work was supported by the Tai-Shan Scholar Program of Shandong Province, China (tstp20231248); and the Natural Science Foundation of Shandong Province (ZR2023MH183). We thank American Journal Experts (AJE) for English language editing. The authors also thank the Laboratory Animal Center of Shandong University for mouse housing and care.

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Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Shandong Key Laboratory of Reproductive Health and Birth Defects Prevention and Control, Ji’nan, Shandong Province, China

    Yanling Liu, Zhongshao Chen, Zixian Shao, Yuliang Chen, Ning Yang, Huimin Xiao, Yingwei Li & Kun Song

  2. Department of Obstetrics and Gynecology, Shengli Oilfield Central Hospital, Dongying, Shandong Province, China

    Yanling Liu & Yan Duan

  3. Medical Integration and Practice Center, Cheeloo College of Medicine, Shandong University, Ji’nan, Shandong Province, China

    Yingwei Li

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Contributions

KS and YWL conceived and designed the study. YLL, ZSC, ZXS, YLC, and NY collected and assembled the data. YLL, ZSC, and HMX analyzed and interpreted the data. KS, YWL, YD, and NY provided administrative, technical, or material support. KS and YWL supervised the study. YLL and YWL wrote, reviewed, and revised the manuscript. All authors reviewed the results and approved the final version of the manuscript.

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Correspondence to Yingwei Li or Kun Song.

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The authors declare no competing interests.

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Ethical approval was obtained from the Ethics Committee of Qilu Hospital, Shandong University (KYLL-202410-045). The animal experiment received approval from the Animal Care and Use Committee of Cheeloo College of Medicine, Shandong University (24044). All experiments were performed in compliance with relevant guidelines and regulations.

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Liu, Y., Chen, Z., Duan, Y. et al. Spliceosomal GTPase EFTUD2 mediates DDX41 intron retention to promote the malignant progression of ovarian cancer. Br J Cancer (2025). https://doi.org/10.1038/s41416-025-03079-1

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  • DOI: https://doi.org/10.1038/s41416-025-03079-1

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