title: ADAR2 functions as a tumor suppressor via editing IGFBP7 in esophageal squamous cell carcinoma.
abstract: 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.
authors.affiliation: 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.
authors.forename: Yuan-Bin
authors.initials: YB
authors.lastname: Chen
authors.affiliation: 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.
authors.forename: Xiao-Yu
authors.initials: XY
authors.lastname: Liao
authors.affiliation: 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.
authors.forename: Jiang-Bo
authors.initials: JB
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Fang
authors.initials: F
authors.lastname: Wang
authors.affiliation: Unit on Statistical Genomics, Division of Intramural Research Programs, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Hai-De
authors.initials: HD
authors.lastname: Qin
authors.affiliation: 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.
authors.forename: Lanjun
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Unit on Statistical Genomics, Division of Intramural Research Programs, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Yin Yao
authors.initials: YY
authors.lastname: Shugart
authors.affiliation: 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.
authors.forename: Yi-Xin
authors.initials: YX
authors.lastname: Zeng
authors.affiliation: 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.
authors.forename: Wei-Hua
authors.initials: WH
authors.lastname: Jia
mesh_terms: D000243:Adenosine Deaminase / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D001665:Binding Sites; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004938:Esophageal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D000077277:Esophageal Squamous Cell Carcinoma; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D018969:Insulin-Like Growth Factor Binding Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D009368:Neoplasm Transplantation; D055550:Protein Stability; D017393:RNA Editing; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D018969:Insulin-Like Growth Factor Binding Proteins; D016601:RNA-Binding Proteins; C102529:insulin-like growth factor binding protein-related protein 1; C567955:ADARB1 protein, human; D000243:Adenosine Deaminase