Research Paper Volume 15, Issue 13 pp 6302—6330
Clinical significance, tumor immune landscape and immunotherapy responses of ADAR in pan-cancer and its association with proliferation and metastasis of bladder cancer
- 1 Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, PR China
- 2 Institute of Urology and Andrology, Nanjing Medical University, Nanjing 210029, PR China
Received: April 21, 2023 Accepted: June 19, 2023 Published: July 6, 2023
https://doi.org/10.18632/aging.204853How to Cite
Copyright: © 2023 Yu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
Background: ADAR is an enzyme involved in adenosine-inosine RNA editing. However, the role of ADAR in tumorigenesis, progression, and immunotherapy has not been fully elucidated.
Methods: The TCGA, GTEx and GEO databases were extensively utilized to explore the expression level of ADAR across cancers. Combined with the clinical information of patients, the risk profile of ADAR in various cancers was delineated. We identified pathways enriched in ADAR and their related genes and explored the association between ADAR expression and the cancer immune microenvironment score and response to immunotherapy. Finally, we specifically explored the potential value of ADAR in the treatment of the bladder cancer immune response and verified the critical role of ADAR in the development and progression of bladder cancer through experiments.
Results: ADAR is highly expressed in most cancers at both the RNA and protein level. ADAR is associated with the aggressiveness of some cancers, especially bladder cancer. In addition, ADAR is associated with immune-related genes, especially immune checkpoint genes, in the tumor immune microenvironment. Moreover, ADAR expression is positively correlated with tumor mutation burden and microsatellite instability in a variety of cancers, indicating that ADAR could be used as a biomarker of immunotherapy. Finally, we demonstrated that ADAR is a key pathogenic factor in bladder cancer. ADAR promoted proliferation and metastasis of bladder cancer cells.
Conclusion: ADAR regulates the tumor immune microenvironment and can be used as a biomarker of the tumor immunotherapy response, providing a novel strategy for the treatment of tumors, especially bladder cancer.
Abbreviations
ADAR: adenosine deaminase acting on RNA; dsRNA: double-stranded RNA; TME: tumor microenvironment; TMB/MSI: tumor mutation burden/microsatellite instability; IPS: immunophenoscore; MHC: MHC molecules; CP: immunomodulators; EC: effector cells; SC: suppressor cells; BLCA: bladder cancer; TCGA: the cancer genome atlas; ICB: immune checkpoint blockade; OS: overall survival; PFS: progression-free survival; DSS: disease-specific survival; RFS: relapse-free survival; HRs: hazard ratios; GO: gene ontology; KEGG: Kyoto encyclopedia of genes and genomes; GSEA: gene set enrichment analysis; GTEx: the genotype-tissue expression; T: tumour size or extension, or both; N: regional lymph node involvement; M: distant metastasis; ROC: receiver operator characteristic curve; AUC: area under the curve; PD-1: programmed cell death protein-1; CTLA-4: cytotoxic T lymphocyte antigen 4; CCL: C-C motif chemokine ligand; CXCL: C-X-C motif chemokine ligand.