Aberrant overexpression of ADAR1 promotes gastric cancer progression by activating mTOR/p70S6K signaling.
Aberrant overexpression of ADAR1 promotes gastric cancer progression by activating mTOR/p70S6K signaling.
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ADAR1 的异常过度表达通过激活 mTOR/p70S6K 信号传导促进胃癌进展。
DOI：
10.18632/oncotarget.13354
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发表时间：
2016-12-27
期刊：
影响因子：
--
通讯作者：
Gao Y
中科院分区：
文献类型：
--
作者：
Dou N;Yu S;Ye X;Yang D;Li Y;Gao Y
ADAR 1是作用于RNA的腺苷脱氨酶之一，通过脱氨将腺苷（A）转化为肌苷（I）来调节RNA转录。新的证据表明ADAR 1在一些人类癌症中起重要作用，然而其在胃癌中的表达和生理意义尚不清楚。在本研究中，我们通过实时定量PCR分析证实了ADAR 1在胃癌样本中频繁过表达。在胃癌组织芯片中，ADAR 1表达与肿瘤分期（P < 0.001）和N分型（P < 0.001）密切相关。功能分析表明，ADAR 1过表达促进体外细胞增殖和迁移，而ADAR 1敲低导致相反的表型。此外，ADAR 1基因敲低还可抑制胃癌细胞在裸鼠模型中的致瘤性和肺转移潜能。ADAR 1的表达对mTOR、p70 S激酶和S6核糖体蛋白的磷酸化水平有显著影响，提示ADAR 1参与了mTOR信号通路的调节。结论ADAR 1通过激活mTOR/p70 S6 K/S6核糖体蛋白信号转导轴参与胃癌的发生发展。我们的研究结果表明，ADAR 1可能是一个有价值的生物标志物GC的诊断和预后，并可能代表一个新的新的治疗机会。
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.