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

Konstantina Panoutsopoulou; Paraskevi Magkou; Tobias Dreyer; Julia Dorn; Eva Obermayr; Sven Mahner; Toon van Gorp; Ioana Braicu; Viktor Magdolen; Robert Zeillinger; Margaritis Avgeris; Andreas Scorilas

doi:10.1016/j.ejca.2022.11.033

tRNA-derived small RNA 3'U-tRF^ValCAC promotes tumour migration and early progression in ovarian cancer

Eur J Cancer. 2023 Feb:180:134-145. doi: 10.1016/j.ejca.2022.11.033. Epub 2022 Dec 10.

Authors

Affiliations

¹ Department of Biochemistry and Molecular Biology, Faculty of Biology, National and Kapodistrian University of Athens, Athens, Greece.
² Clinical Research Unit, Department of Obstetrics and Gynecology, School of Medicine, Technical University of Munich, Munich, Germany.
³ Molecular Oncology Group, Department of Obstetrics and Gynecology, Comprehensive Cancer Center-Gynecologic Cancer Unit, Medical University of Vienna, Vienna, Austria.
⁴ Department of Gynecology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
⁵ Department of Obstetrics and Gynaecology, Division of Gynecologic Oncology, University Hospital Leuven, Leuven Cancer Institute, Leuven, Belgium.
⁶ Department of Gynecology, Charité University Medicine, Campus Virchow, Berlin, Germany.
⁷ 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. Electronic address: margaritis.avgeris@gmail.com.
⁸ Department of Biochemistry and Molecular Biology, Faculty of Biology, National and Kapodistrian University of Athens, Athens, Greece. Electronic address: ascorilas@biol.uoa.gr.

PMID: 36599181
DOI: 10.1016/j.ejca.2022.11.033

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-tRF^ValCAC (derived from pre-tRNA^ValCAC) was highlighted to regulate cell proliferation and adhesion, and to correlate with inferior patients' outcome. 3'U-tRF^ValCAC 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-tRF^ValCAC 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-tRF^ValCAC-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-tRF^ValCAC promotes tumour cell growth and migration and supports modern risk stratification and prognosis in EOC.

Keywords: 3′U-tRF; Molecular diagnostics; Non-coding RNAs; Prognosis; ncRNAs; tRF-1; tRFs; tRNA-derived fragments; tsRNAs.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Apoptosis
Cell Line, Tumor
Female
Humans
Ovarian Neoplasms* / genetics
RNA*
RNA, Transfer / genetics
RNA, Transfer / metabolism

Substances

RNA
RNA, Transfer