Chen Yuan-Bin, Liao Xiao-Yu, Zhang Jiang-Bo, Wang Fang, Qin Hai-De, Zhang Lanjun, Shugart Yin Yao, Zeng Yi-Xin, Jia Wei-Hua
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, P.R. China.
Unit on Statistical Genomics, Division of Intramural Research Programs, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, USA.
Int J Oncol. 2017 Feb;50(2):622-630. doi: 10.3892/ijo.2016.3823. Epub 2016 Dec 29.
Esophageal squamous cell carcinoma (ESCC), one of the most aggressive cancers, is characterized by heterogeneous genetic and epigenetic changes. Recently, A-to-I RNA editing, catalyzed by adenosine deaminases acting on RNA (ADARs), was found to be aberrantly regulated during tumorigenesis. We previously reported that ADAR2 was downregulated in ESCC but its role was unclear. Thus, we report here that overexpression of ADAR2 can induce apoptosis in ESCC cell lines and inhibit tumor growth in vitro and in vivo. ADAR2 knockdown inhibited apoptosis in ADAR2 highly expressing tumor cells. RNA-seq assay showed that ADAR2, not ADAR1 or active-site-mutated ADAR2, could edit insulin-like growth factor binding protein 7 (IGFBP7) mRNA in ESCC. IGFBP7 knockdown or ADAR2 catalytic activity destruction abolished the pro-apoptotic function of ADAR2. Mechanistically, RNA editing may stabilize IGFBP7 protein by changing the protease recognition site of matriptase and this is essential for IGFBP7 to induce apoptosis. Western blotting revealed that ADAR2 overexpression could induce IGFBP7-dependent inhibition of Akt signaling. Thus, our data indicate that ADAR2 suppresses tumor growth and induces apoptosis by editing and stabilizing IGFBP7 in ESCC, and this may represent a novel therapeutic target for treating ESCC.
食管鳞状细胞癌（ESCC）是最具侵袭性的癌症之一，其特征在于基因和表观遗传变化的异质性。最近，由作用于RNA的腺苷脱氨酶（ADARs）催化的A到I RNA编辑被发现在肿瘤发生过程中受到异常调控。我们之前报道过ADAR2在ESCC中表达下调，但其作用尚不清楚。因此，我们在此报告，ADAR2的过表达可诱导ESCC细胞系凋亡，并在体外和体内抑制肿瘤生长。ADAR2敲低抑制了ADAR2高表达肿瘤细胞的凋亡。RNA测序分析表明，在ESCC中，ADAR2而非ADAR1或活性位点突变的ADAR2可编辑胰岛素样生长因子结合蛋白7（IGFBP7）mRNA。IGFBP7敲低或ADAR2催化活性破坏消除了ADAR2的促凋亡功能。从机制上讲，RNA编辑可能通过改变matriptase的蛋白酶识别位点来稳定IGFBP7蛋白，这对IGFBP7诱导凋亡至关重要。蛋白质印迹分析显示，ADAR2过表达可诱导IGFBP7依赖的Akt信号通路抑制。因此，我们的数据表明，ADAR2通过编辑和稳定ESCC中的IGFBP7来抑制肿瘤生长并诱导凋亡，这可能代表了治疗ESCC的一个新的治疗靶点。
