Endogenous retrovirus expression activates type-I interferon signaling in an experimental mouse model of mesothelioma development

Sun, Suna; Frontini, Francesca; Qi, Weihong; Hariharan, Ananya; Ronner, Manuel; Wipplinger, Martin; Blanquart, Christophe; Rehrauer, Hubert; Fonteneau, Jean-François; Felley‐Bosco, Emanuela

doi:10.1016/j.canlet.2021.03.004

Cited by 23 publications

(54 citation statements)

References 63 publications

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“…Indeed, ADAR-dependent editing increases upon mesothelioma development [ 14 , 15 ], and in this study, we demonstrate that it participates in translational control in mesothelioma. To our knowledge, this is the first time that RBM8A 3′UTR editing has been functionally characterized.…”

Section: Discussionsupporting

confidence: 59%

“…In our previous studies [ 14 , 15 ] investigating mesothelioma development in mice exposed to crocidolite (blue asbestos), we observed increased RNA editing, and one of the genes that were significantly more edited in asbestos-exposed mice was Rbm8a ( Figure 2 A), suggesting that one possible post-transcriptional process controlling Rbm8a expression is RNA editing. Indeed, A-to-I editing can affect RNA stability, miRNA- or RNA-binding protein binding ability, and translational activity (recently reviewed in [ 16 ]).…”

Section: Resultsmentioning

confidence: 66%

“…In our previous study on mesothelioma development in asbestos-exposed mice, we observed an increase in RNA editing [ 14 , 15 ] upon mesothelioma development. One of the coding genes where we observed increased editing levels upon exposure to asbestos is Rbm8a.…”

Section: Introductionmentioning

confidence: 99%

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Double-Stranded RNA Structural Elements Holding the Key to Translational Regulation in Cancer: The Case of Editing in RNA-Binding Motif Protein 8A

Abukar

Wipplinger

Hariharan

et al. 2021

Cells

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Mesothelioma is an aggressive cancer associated with asbestos exposure. RNA-binding motif protein 8a (RBM8A) mRNA editing increases in mouse tissues upon asbestos exposure. The aim of this study was to further characterize the role of RBM8A in mesothelioma and the consequences of its mRNA editing. RBM8A protein expression was higher in mesothelioma compared to mesothelial cells. Silencing RBM8A changed splicing patterns in mesothelial and mesothelioma cells but drastically reduced viability only in mesothelioma cells. In the tissues of asbestos-exposed mice, editing of Rbm8a mRNA was associated with increased protein immunoreactivity, with no change in mRNA levels. Increased adenosine deaminase acting on dsRNA (ADAR)-dependent editing of Alu elements in the RBM8A 3′UTR was observed in mesothelioma cells compared to mesothelial cells. Editing stabilized protein expression. The unedited RBM8A 3′UTR had a stronger interaction with Musashi (MSI) compared to the edited form. The silencing of MSI2 in mesothelioma or overexpression of Adar2 in mesothelial cells resulted in increased RBM8A protein levels. Therefore, ADAR-dependent editing contributes to maintaining elevated RBM8A protein levels in mesothelioma by counteracting MSI2-driven downregulation. A wider implication of this mechanism for the translational control of protein expression is suggested by the editing of similarly structured Alu elements in several other transcripts.

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Section: Discussionsupporting

confidence: 59%

Section: Resultsmentioning

confidence: 66%

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Double-Stranded RNA Structural Elements Holding the Key to Translational Regulation in Cancer: The Case of Editing in RNA-Binding Motif Protein 8A

Abukar

Wipplinger

Hariharan

et al. 2021

Cells

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“…Presence of mitochondrial or nuclear DNA in the cytoplasm of tumor cells can induce the secretion of IFN I via the STING pathway ( 31 – 39 ). Expression of endogenous retrovirus (ERV) under the form of dsRNA due to epigenetic deregulation in tumor cells can also trigger the expression of IFN I via the MAVS pathway ( 35 , 40 – 44 ). Non-malignant cells from the tumor microenvironment, such as phagocytic cells notably dendritic cells (DC), can also produce IFN I via activation of the STING pathway after engulfment of dead tumor cells.…”

Section: The Type I Interferon Response In Thoracic Cancersmentioning

confidence: 99%

“…These studies highlight the important role on the antitumor immune response of triggering the IFN I response via the STING pathway in tumor cells. However, IFN I response in tumor cells can also be induced by the sensing of endogenous dsRNA via the MAVS pathway and that also plays a role in the stimulation of the antitumor immune response ( 35 , 40 – 44 ). Best evidences come from the study of an ISG, the adenosine deaminase acting on RNA (ADAR) that acts on the MAVS pathway like Trex1 does on the STING pathway ( 35 , 40 ).…”

Section: Potential Consequences Of Ifn I Genes Hd For Thoracic Cancers Therapymentioning

confidence: 99%

Homozygous Co-Deletion of Type I Interferons and CDKN2A Genes in Thoracic Cancers: Potential Consequences for Therapy

et al. 2021

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Homozygous deletion (HD) of the tumor suppressor gene CDKN2A is the most frequent genetic alteration in malignant pleural mesothelioma and is also frequent in non-small cell lung cancers. This HD is often accompanied by the HD of the type I interferons (IFN I) genes that are located closed to the CDKN2A gene on the p21.3 region of chromosome 9. IFN I genes encode sixteen cytokines (IFN-α, IFN-β…) that are implicated in cellular antiviral and antitumor defense and in the induction of the immune response. In this review, we discuss the potential influence of IFN I genes HD on thoracic cancers therapy and speak in favor of better taking these HD into account in patients monitoring.

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Heterogeneous RNA editing and influence of ADAR2 on mesothelioma chemoresistance and the tumor microenvironment

Hariharan

Rehrauer

et al. 2022

Molecular Oncology

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We previously observed increased levels of adenosine-deaminase-acting-on-dsRNA (Adar)-dependent RNA editing during mesothelioma development in mice exposed to asbestos. The aim of this study was to characterize and assess the role of ADAR-dependent RNA editing in mesothelioma. We found that tumors and mesothelioma primary cultures have higher ADAR-mediated RNA editing compared to mesothelial cells. Unsupervised clustering of editing in different genomic regions revealed heterogeneity between tumor samples as well as mesothelioma primary cultures. ADAR2 expression levels are higher in BRCA1-associated protein 1 wild-type tumors, with corresponding changes in RNA editing in transcripts and 3'UTR. ADAR2 knockdown and rescue models indicated a role in cell proliferation, altered cell cycle, increased sensitivity to antifolate treatment, and type-1 interferon signaling upregulation, leading to changes in the microenvironment in vivo. Our data indicate that RNA editing contributes to mesothelioma heterogeneity and highlights an important role of ADAR2 not only in growth regulation in mesothelioma but also in chemotherapy response, in addition to regulating inflammatory response downstream of sensing nucleic acid structures.

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Endogenous retrovirus expression activates type-I interferon signaling in an experimental mouse model of mesothelioma development

Cited by 23 publications

References 63 publications

Double-Stranded RNA Structural Elements Holding the Key to Translational Regulation in Cancer: The Case of Editing in RNA-Binding Motif Protein 8A

Double-Stranded RNA Structural Elements Holding the Key to Translational Regulation in Cancer: The Case of Editing in RNA-Binding Motif Protein 8A

Homozygous Co-Deletion of Type I Interferons and CDKN2A Genes in Thoracic Cancers: Potential Consequences for Therapy

Heterogeneous RNA editing and influence of ADAR2 on mesothelioma chemoresistance and the tumor microenvironment

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