ADAR1 and interferon signaling suppression in gastric cancer

Abstract

ADAR (Adenosine Deaminase Acting on RNA) is known to mediate deamination of adenosine to inosine through binding to double-stranded RNA (dsRNA), the phenomenon known as RNA editing. Moreover, another unique property of ADAR1 is its ability to suppress type I interferon (IFN) response. To understand regulation between ADAR1 and type I interferon (IFN) signaling in gastric cancer, we sought to determine the specific target molecule(s) where ADAR1 exerts its activity on IFN signaling, and to determine whether the suppression of IFN response is related to its RNA editing function. We found that protein level of STAT1 and IRF9 was increased upon ADAR1 knockdown even in the absence of type I or type II IFN in AGS cell. Mechanistically, we identified miRNA-302a-3p the level of which decreases upon ADAR1 knockdown, binds to the seed sequence of IRF9. We further found IRF9 UTR reporter level was decreased upon the addition of miRNA 302a-3p, which was ameliorated when the seed-binding sequence in UTR was mutated. In contrast, STAT1 UTR reporter level was not decreased upon the addition of miRNA-302a-5p, suggesting other mechanism of STAT1 over-expression exists. Interestingly, treatment of miRNA-302a-3p mimic to ADAR1 knocked-downed AGS cell reversed IRF9 as well as STAT1 protein level to that of control AGS cells. Altogether, these results suggest that ADAR1 functions in gastric cancer through suppression of STAT1 and IRF9 via miRNA302a-3p, independently from the activation or editing of known IFN production pathway.