The Interplay between RNA Editing Regulator ADAR1 and Immune Environment in Colorectal Cancer

Abstract

An abnormality in the regulation of adenosine deaminase acting on RNA (ADAR) enzymes, which catalyzed adenosine-to-inosine (A-to-I) RNA editing, was closely associated with the highly aggressive biologic behavior and poor prognosis in many malignancies. In the present study, we aimed to investigate the relationship among transcript factors-microRNAs regulatory network, immune environment, and ADAR gene in colorectal carcinoma (CRC). The association among the expression levels of ADAR mRNA and copy number variation, methylation, and mutation status were comprehensively analyzed using cBioPortal, Wanderer, and UALCAN databases in CRC datasets. ADAR-transcript factors (TFs) and ADAR-miRNA regulation networks were constructed by Cistrome Cancer and miRWalk2.0, respectively. The full network and subnetworks for ADAR coexpression genes were constructed using the STRING database and visualized by the MCODE module of the Cytoscape app. The relationship between ADAR mRNA expression and the abundance of infiltrating immune cells in CRC patients was explored by the Tumor Immune Estimation Resource, CIBERSORT, and single-gene gene set enrichment analysis (GSEA). ADAR mRNA was elevated and was a cancer essential gene in CRC. ADAR mRNA and transcripts P110 were significantly elevated in CRC compared to normal controls. Low-level methylation in the promoter region and high copy number amplification of ADAR were responsible for high levels of ADAR mRNA expression. ADAR coexpression genes were mainly involved in immunoregulation, especially T-lymphocyte activation. Hub genes, including CD2, CD274, and FASLG, were also significantly upregulated in the ADAR-high group compared to the control group. Besides, M1 macrophages were enriched in the ADAR-high group compared to the control group. This study demonstrated that ADAR, a new essential gene, was involved in the immune regulator and was a novel immune treatment target in CRC.

Branched-chain keto acids promote an immune-suppressive and neurodegenerative microenvironment in leptomeningeal disease

“…On the other hand, the most significant functional term for ligand-receptor interactions unique to patients with long survival was integrin signaling, which included numerous interactions among integrins and collagens ( Supplemental Figure 5 ). Integrin engagement plays a major role in effective immune activation by promoting immune cell aggregation and TCR signaling 41,42 .…”

Functional Proteomic Profiling Analysis in Four Major Types of Gastrointestinal Cancers

“…Elevated SMAD1 expression was detected in GC tissue and cells; studies demonstrated that SMAD1 can interact with Yes1-associated transcriptional regulator ( YAP1 ) to enhance the cisplatin resistance of GC cells [ 35 ]. The adenosine deaminase acting on RNA ( ADAR ) enzymes was associated with the highly aggressive biologic behaviour and poor prognosis in many cancers [ 36 ]. Studies indicated that ADAR mRNA was elevated and involved in the immune regulator, thus was a novel immune treatment target in CRC [ 36 ].…”

“…The adenosine deaminase acting on RNA ( ADAR ) enzymes was associated with the highly aggressive biologic behaviour and poor prognosis in many cancers [ 36 ]. Studies indicated that ADAR mRNA was elevated and involved in the immune regulator, thus was a novel immune treatment target in CRC [ 36 ]. The protein of progesterone receptor ( PR ) is encoded by the progesterone receptor gene ( PGR ), which can modulate the immune response in different cancers [ 37 ].…”

Harnessing ADAR-Mediated Site-Specific RNA Editing in Immune-Related Disease: Prediction and Therapeutic Implications

“…In human cancers, RNA editing abnormalities are strongly associated with high aggressiveness and poor prognosis in many malignant tumors. ADAR was considered to affect the immune microenvironment, such as by stimulating T lymphocytes and promoting the presence of more abundant M1 macrophages [ 142 ]. Many specific sites have been identified to play roles at different stages of cancer, such as tumor-promoting RES on the intronic region of the CCDC15, which affects the splicing process.…”