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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Article info
Publication history
Published online: January 02, 2023
Accepted:
November 23,
2022
Received:
November 11,
2022
Identification
Copyright
© 2022 Elsevier Ltd. All rights reserved.
