Abstract
ADAR1, one of adenosine deaminases acting on RNA, modulates RNA transcripts through converting adenosine (A) to inosine (I) by deamination. Emerging evidence has implicated that ADAR1 plays an important role in a few of human cancers, however, its expression and physiological significance in gastric cancer remain undefined. In the present study, we demonstrated that ADAR1 was frequently overexpressed in gastric cancer samples by quantitative real-time PCR analysis. In a gastric cancer tissue microarray, ADAR1 staining was closely correlated with tumor stage (P < 0.001) and N classification (P < 0.001). Functional analysis indicated that ADAR1 overexpression promoted cell proliferation and migration in vitro, whereas ADAR1 knockdown resulted in an opposite phenotypes. Furthermore, ADAR1 knockdown also inhibited tumorigenicity and lung metastasis potential of gastric cancer cells in nude mice models. Mechanistically, ADAR1 expression had a significant effect on phosphorylation level of mTOR, p70S kinase, and S6 ribosomal protein, implying its involvement in the regulation of mTOR signaling pathway. We conclude that ADAR1 contributes to gastric cancer development and progression via activating mTOR/p70S6K/S6 ribosomal protein signaling axis. Our findings suggest that ADAR1 may be a valuable biomarker for GC diagnosis and prognosis and may represent a new novel therapeutic opportunities.
Highlights
There are many hypotheses about the formation of malignancies, the exact pathogenesis of tumor still remains unknown
The results showed that ADAR1 was highly expressed in AGS, BGC823 and HGC27 cells relative to the MGC803 cell line and two cases of adjacent non-cancerous tissues (Figure 1E), supporting the notion that ADAR1 was frequently overexpressed in Gastric cancer (GC)
Previous reports have shown that ADAR1 is involved in the regulation of tumorigenesis, little is known about its roles in gastric cancer
Summary
There are many hypotheses about the formation of malignancies, the exact pathogenesis of tumor still remains unknown. The most prevalent type of RNA editing in higher eukaryotes is adenosine (A) to inosine (I) editing which can be highly selective [8,9,10,11] or occur at multiple sites [12, 13]. A-to-I editing could alter several biological processes because I is recognized as G instead of A. These processes include mRNA translation, splicing site recognition and RNA structure-dependent activities. A-to-I editing is catalyzed by the adenosine deaminases acting on RNA (ADARs) class of enzymes and it usually occurs in regions of doublestranded RNA (dsRNA). ADAR1 and ADAR2 were shown to be active for RNA editing. There are two isoforms of ADAR1, an IFN-inducible ~150kDa form (p150) found in both the cytoplasm and nucleus and a constitutively expressed ~110kDa form (p110), found predominantly if not exclusively in the nucleus [16, 17]
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