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tRNA-derived small RNA 3′U-tRFValCAC promotes tumour migration and early progression in ovarian cancer

  • Konstantina Panoutsopoulou
    Affiliations
    Department of Biochemistry and Molecular Biology, Faculty of Biology, National and Kapodistrian University of Athens, Athens, Greece
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  • Paraskevi Magkou
    Affiliations
    Department of Biochemistry and Molecular Biology, Faculty of Biology, National and Kapodistrian University of Athens, Athens, Greece
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  • Tobias Dreyer
    Affiliations
    Clinical Research Unit, Department of Obstetrics and Gynecology, School of Medicine, Technical University of Munich, Munich, Germany
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  • Julia Dorn
    Affiliations
    Clinical Research Unit, Department of Obstetrics and Gynecology, School of Medicine, Technical University of Munich, Munich, Germany
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  • Eva Obermayr
    Affiliations
    Molecular Oncology Group, Department of Obstetrics and Gynecology, Comprehensive Cancer Center-Gynecologic Cancer Unit, Medical University of Vienna, Vienna, Austria
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  • Author Footnotes
    1 Current address: Department of Obstetrics and Gynecology, University Hospital, Ludwig-Maximilians-University Munich, Munich, Germany.
    Sven Mahner
    Footnotes
    1 Current address: Department of Obstetrics and Gynecology, University Hospital, Ludwig-Maximilians-University Munich, Munich, Germany.
    Affiliations
    Department of Gynecology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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  • Toon van Gorp
    Affiliations
    Department of Obstetrics and Gynaecology, Division of Gynecologic Oncology, University Hospital Leuven, Leuven Cancer Institute, Leuven, Belgium
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  • Ioana Braicu
    Affiliations
    Department of Gynecology, Charité University Medicine, Campus Virchow, Berlin, Germany
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  • Viktor Magdolen
    Affiliations
    Clinical Research Unit, Department of Obstetrics and Gynecology, School of Medicine, Technical University of Munich, Munich, Germany
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  • Robert Zeillinger
    Affiliations
    Molecular Oncology Group, Department of Obstetrics and Gynecology, Comprehensive Cancer Center-Gynecologic Cancer Unit, Medical University of Vienna, Vienna, Austria
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  • Author Footnotes
    2 Equal contribution as last authors.
    Margaritis Avgeris
    Correspondence
    Corresponding author: Laboratory of Clinical Biochemistry – Molecular Diagnostics, Second Department of Pediatrics, “P. & A. Kyriakou” Children's Hospital, School of Medicine, National and Kapodistrian University of Athens, 24 Mesogeion Ave, 11527 Athens, Greece.
    Footnotes
    2 Equal contribution as last authors.
    Affiliations
    Department of Biochemistry and Molecular Biology, Faculty of Biology, National and Kapodistrian University of Athens, Athens, Greece

    Laboratory of Clinical Biochemistry – Molecular Diagnostics, Second Department of Pediatrics, School of Medicine, National and Kapodistrian University of Athens, “P. & A. Kyriakou” Children's Hospital, Athens, Greece
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  • Author Footnotes
    2 Equal contribution as last authors.
    Andreas Scorilas
    Correspondence
    Corresponding author: Department of Biochemistry and Molecular Biology, Faculty of Biology, National and Kapodistrian University of Athens, Panepistimiopolis, 15771 Athens, Greece.
    Footnotes
    2 Equal contribution as last authors.
    Affiliations
    Department of Biochemistry and Molecular Biology, Faculty of Biology, National and Kapodistrian University of Athens, Athens, Greece
    Search for articles by this author
  • Author Footnotes
    1 Current address: Department of Obstetrics and Gynecology, University Hospital, Ludwig-Maximilians-University Munich, Munich, Germany.
    2 Equal contribution as last authors.
Published:January 02, 2023DOI:https://doi.org/10.1016/j.ejca.2022.11.033

      Highlights

      • 3′U-tRFValCAC enhances cell growth and migration of ovarian cancer cells.
      • Patients with elevated 3′U-tRFValCAC are at higher risk for early progression.
      • 3′U-tRFValCAC is significantly associated with poor overall survival in ovarian cancer.
      • 3′U-tRFValCAC-fitted multivariate models improved risk stratification and prognosis.

      Abstract

      Introduction

      Despite recent advances in epithelial ovarian cancer (EOC) management, the highly heterogenous histological/molecular tumour background and patients' treatment response obstructs personalised prognosis and therapeutics. Herein, we have studied the role and clinical utility of the novel subclass of tRNA-derived small RNA fragments emerging via 3′-trailer processing of pre-tRNAs (3′U-tRFs) in EOC.

      Methods

      SK-OV-3 and OVCAR-3 cells were used for in vitro study. Following transfection, cell growth and migration were assessed by CCK8 and wound healing assays, respectively. 3′U-tRFs levels were assessed by reverse transcription quantitative PCR (RT-qPCR), following 3′-end RNA polyadenylation. A screening (OVCAD, n = 100) and institutionally independent validation (TU Munich, n = 103) cohorts were employed for survival analysis using disease progression and patients' death as clinical end-points. Bootstrap analysis was performed for internal validation, and decision curve analysis was used to evaluate clinical benefit on disease prognosis.

      Results

      Following primary clinical assessment, target prediction and gene ontology analyses, the 3′U-tRFValCAC (derived from pre-tRNAValCAC) was highlighted to regulate cell proliferation and adhesion, and to correlate with inferior patients' outcome. 3′U-tRFValCAC transfection of SK-OV-3 and OVCAR-3 cells resulted in significantly increased cell growth and migration, in a dose-dependent manner. Elevated tumour 3′U-tRFValCAC levels were associated with significantly higher risk for early progression and worse survival following first-line platinum-based chemotherapy, independently of patients' clinicopathological data, chemotherapy response, and residual tumour. Interestingly, 3′U-tRFValCAC-fitted multivariate models improved risk stratification and provided superior clinical net benefit in prediction of treatment outcome compared to disease established markers.

      Conclusions

      3′U-tRFValCAC promotes tumour cell growth and migration and supports modern risk stratification and prognosis in EOC.

      Keywords

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