학술논문
Heterogeneous RNA editing and influence of ADAR2 on mesothelioma chemoresistance and the tumor microenvironment
Document Type
Academic Journal
Author
Hariharan, Ananya; Qi, Weihong; Rehrauer, Hubert; Wu, Licun; Ronner, Manuel; Wipplinger, Martin; Kresoja‐Rakic, Jelena; Sun, Suna; Oton‐Gonzalez, Lucia; Sculco, Marika; Serre‐Beinier, Véronique; Meiller, Clément; Blanquart, Christophe; Fonteneau, Jean‐François; Vrugt, Bart; Rüschoff, Jan Hendrik; Opitz, Isabelle; Jean, Didier; Perrot, Marc; Felley‐Bosco, Emanuela
Source
Molecular Oncology. December 2022, Vol. 16 Issue 22, p3949, 3974 p.
Subject
Language
English
ISSN
1574-7891
Abstract
Abbreviations Introduction Pleural mesothelioma (PM) is the most frequent cancer arising from the mesothelial cell layer [1]. It is a rapidly fatal [2] tumor primarily associated with previous exposure to [...]
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.
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.