Abstract
ADAR (adenosine deaminase acting on RNA) catalyzes the deamination of adenosine to generate inosine, through its binding to double-stranded RNA (dsRNA), a phenomenon known as RNA editing. One of the functions of ADAR1 is suppressing the type I interferon (IFN) response, but its mechanism in gastric cancer is not clearly understood. We analyzed changes in RNA editing and IFN signaling in ADAR1-depleted gastric cancer cells, to clarify how ADAR1 regulates IFN signaling. Interestingly, we observed a dramatic increase in the protein level of signal transducer and activator of transcription 1 (STAT1) and interferon regulatory factor 9 (IRF9) upon ADAR1 knockdown, in the absence of type I or type II IFN treatment. However, there were no changes in protein expression or localization of the mitochondrial antiviral signaling protein (MAVS) and interferon alpha and beta-receptor subunit 2 (IFNAR2), the two known mediators of IFN production. Instead, we found that miR-302a-3p binds to the untranslated region (UTR) of IRF9 and regulate its expression. The treatment of ADAR1-depleted AGS cells with an miR-302a mimic successfully restored IRF9 as well as STAT1 protein level. Hence, our results suggest that ADAR1 regulates IFN signaling in gastric cancer through the suppression of STAT1 and IRF9 via miR-302a, which is independent from the RNA editing of known IFN production pathway.
Highlights
A-to-I RNA editing is one of the major RNA modifications that occurs co-transcriptionally in the nucleus [1,2]
An immunofluorescence analysis revealed that most of the ADAR1 was abundant in the nucleus of AGS cells at homeostasis, especially enriched in the nucleoli, which was clearly decreased upon knockdown (Figure 1c, bottom left panel)
interferon regulatory factor 9 (IRF9) is a well-known component of the interferon-stimulated gene factor 3 (ISGF3) complex, along with phosphorylated signal transducer and activator of transcription 1 (STAT1) and STAT2, which moves into the nucleus upon stimulation by IFN and binds to Interferon-sensitive response element (ISRE) to promote the transcription of more than 100 Interferon-Stimulated Gene (ISG) [23]
Summary
A-to-I RNA editing is one of the major RNA modifications that occurs co-transcriptionally in the nucleus [1,2]. Since two pioneering reports introduced the impact of ADAR1 in gastric cancer progression [14,15], others have reported targets including Antizyme Inhibitor 1 (AZIN1) [16], mTOR/p70S6K pathway [17], and Phosphatase And Actin Regulator 4 (PHACTR4) [18]. All these studies consistently demonstrated the oncogenic role of ADAR1 in gastric cancer progression. We sought to determine the specific target(s) where ADAR1 exerts its anti-IFN activity and to determine whether the IFN suppressive function of ADAR1 is controlled by its RNA-editing activity
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