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

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.

SUBMITTER: Santos M

PROVIDER: S-EPMC9108184 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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

Santos Mafalda M Fidalgo Ana A Varanda Ana Sofia AS Soares Ana Raquel AR Almeida Gabriela M GM Martins Diana D Mendes Nuno N Oliveira Carla C Santos Manuel A S MAS

Frontiers in molecular biosciences 20220502

Serine tRNAs (tRNA<sup>Ser</sup>) 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<sup>Ser</sup> 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 ...[more]

PMID: 35586191

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Project description:BackgroundThe recent development of dendritic cell (DC)-based immunotherapy has resulted in advances in glioblastoma multiforme (GBM) treatment. However, the cell fate of DCs in the GBM microenvironment, especially in microenvironments in which glioma stem cell (GSCs)-mediated remodeling has resulted in highly immunosuppressive conditions, has not yet been fully investigated.MethodsObserved the interaction between GSCs and primary cultured DCs in a dual-color tracing model, monoclonal and continuously passaged highly proliferative DCs, and named transformed DCs (t-DCs). The expression of DC-specific surface markers was analyzed using RT-PCR, chromosome karyotype, and flow cytometry. The expression of long pentraxin 3 (PTX3) and its transcription factor zinc finger protein 148 (ZNF148) in t-DCs was detected using qRT-PCR and western blot. CCK8 and transwell assays were conducted to assess the effect of ZNF148 and PTX3 on the proliferation, migration, and invasion of t-DCs. Bioinformatics analysis, dual-luciferase reporter assay, and chromatin immunoprecipitation (ChIP)-qPCR assay were used to explore the relation between ZNF148 and PTX3.ResultsTransformed DCs (t-DCs) still expressed DC-specific surface markers, namely, CD80 and CD11c, and immune-related costimulatory molecules, namely, CD80, CD86, CD40, and ICAM-1. However, the expression levels of these molecules in t-DCs decreased moderately compared to those in naive DCs. Stable overexpression of PTX3 further promoted the proliferation and migration of t-DCs in vitro, decreased the expression of costimulatory molecules, and increased the tumorigenicity of t-DCs in vivo. The transcription factor zinc finger protein 148 (ZNF148) was directly bound to the PTX3 promoter region and enhanced PTX3 expression. Downregulation of ZNF148 significantly decreased PTX3 expression and reduced the proliferation and migration of t-DCs. Overexpression of ZNF148 significantly increased PTX3 expression and promoted the proliferation and migration of t-DCs, achieving the same biological effects as PTX3 overexpression in t-DCs. Simultaneously, the downregulation of ZNF148 partially reversed the effect of PTX3 overexpression in t-DCs.ConclusionThe ZNF148/PTX3 axis played an important role in regulating the malignant transformation of DCs after cross-talk with GSCs, and this axis may serve as a new target for sensitizing GBM to DC-based immunotherapy.

Dataset Information

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

Publications

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

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