Upregulation of tRNA-Ser-AGA-2-1 Promotes Malignant Behavior in Normal Bronchial Cells

Mafalda Santos; Ana Fidalgo; Ana Sofia Varanda; Ana Raquel Soares; Gabriela M Almeida; Diana Martins; Nuno Mendes; Carla Oliveira; Manuel A S Santos

doi:10.3389/fmolb.2022.809985

Upregulation of tRNA-Ser-AGA-2-1 Promotes Malignant Behavior in Normal Bronchial Cells

Front Mol Biosci. 2022 May 2:9:809985. doi: 10.3389/fmolb.2022.809985. eCollection 2022.

Authors

Mafalda Santos^{1

2

3}, Ana Fidalgo³, Ana Sofia Varanda^{1

2

3}, Ana Raquel Soares³, Gabriela M Almeida^{1

2

4}, Diana Martins^{1

2}, Nuno Mendes^{1

2}, Carla Oliveira^{1

2

4}, Manuel A S Santos³

Affiliations

¹ Expression Regulation in Cancer, Instituto de Investigação e Inovação em Saúde, University of Porto, Porto, Portugal.
² Institute of Molecular Pathology and Immunology University of Porto (IPATIMUP), Porto, Portugal.
³ Department of Medical Sciences, Institute of Biomedicine - iBiMED, University of Aveiro, Aveiro, Portugal.
⁴ Department Pathology, Medical Faculty of Porto, Porto, Portugal.

Abstract

Serine tRNAs (tRNA^Ser) are frequently overexpressed in tumors and associated with poor prognosis and increased risk of recurrence in breast cancer. Impairment of tRNA biogenesis and abundance also impacts proteome homeostasis, and activates protein quality control systems. Herein, we aimed at testing whether increasing tRNA^Ser abundance could foster tumor establishment through activation of the UPR. In order to do so, firstly we confirmed that the expression of tRNA-Ser-AGA-2-1 [hereafter tRNA^Ser(AGA)] was upregulated by 1.79-fold in Stage I NSCLC tumors when compared to normal adjacent tissue. To study the impact of tRNA^Ser(AGA) in early stage tumorigenesis, we induced its upregulation in a non-tumoral bronchial cell line, BEAS-2B. Upregulation of this tRNA increased cellular proliferation and protein synthesis rate, driven by eIF2α dephosphorylation and ATF4 activation downstream of PERK signaling. Futhermore, tRNA^Ser(AGA) enhanced transformation potential in vitro, and promoted the establishment of slow growing tumors with aggressive features in nude mice. Our work highlights the importance of studying tRNA deregulation on early stage tumorigenesis, as they may be potential malignancy and aggressiveness biomarkers.

Keywords: UPR; cancer; lung cancer; tRNA deregulation; tumor establishment.