title: Adenosine-to-inosine RNA editing mediated by ADARs in esophageal squamous cell carcinoma.
abstract: Esophageal squamous cell carcinoma (ESCC), the major histologic form of esophageal cancer, is a heterogeneous tumor displaying a complex variety of genetic and epigenetic changes. Aberrant RNA editing of adenosine-to-inosine (A-to-I), as it is catalyzed by adenosine deaminases acting on RNA (ADAR), represents a common posttranscriptional modification in certain human diseases. In this study, we investigated the status and role of ADARs and altered A-to-I RNA editing in ESCC tumorigenesis. Among the three ADAR enzymes expressed in human cells, only ADAR1 was overexpressed in primary ESCC tumors. ADAR1 overexpression was due to gene amplification. Patients with ESCC with tumoral overexpression of ADAR1 displayed a poor prognosis. In vitro and in vivo functional assays established that ADAR1 functions as an oncogene during ESCC progression. Differential expression of ADAR1 resulted in altered gene-specific editing activities, as reflected by hyperediting of FLNB and AZIN1 messages in primary ESCC. Notably, the edited form of AZIN1 conferred a gain-of-function phenotype associated with aggressive tumor behavior. Our findings reveal that altered gene-specific A-to-I editing events mediated by ADAR1 drive the development of ESCC, with potential implications in diagnosis, prognosis, and treatment of this disease.
authors.affiliation: Authors' Affiliations: Department of Clinical Oncology, the First Affiliated Hospital, Zhengzhou University, Zhengzhou; State Key Laboratory of Oncology in Southern China, Sun Yat-Sen University Cancer Centre; Key Laboratory for Major Obstetric Disease of Guangdong Province, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou; Department of Clinical Oncology, Nanyang city first people's hospital, Henan; Department of Clinical Oncology, The University of Hong Kong, Hong Kong, China; and Cancer Science Institute of Singapore, National University of Singpaore, Singapore.
authors.forename: Yan-Ru
authors.initials: YR
authors.lastname: Qin
authors.forename: Jun-Jing
authors.initials: JJ
authors.lastname: Qiao
authors.forename: Tim Hon Man
authors.initials: TH
authors.lastname: Chan
authors.forename: Ying-Hui
authors.initials: YH
authors.lastname: Zhu
authors.forename: Fang-Fang
authors.initials: FF
authors.lastname: Li
authors.forename: Haibo
authors.initials: H
authors.lastname: Liu
authors.forename: Jing
authors.initials: J
authors.lastname: Fei
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Xin-Yuan
authors.initials: XY
authors.lastname: Guan
authors.forename: Leilei
authors.initials: L
authors.lastname: Chen
mesh_terms: D000241:Adenosine; D000243:Adenosine Deaminase / Q000235:genetics / Q000378:metabolism*; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D015331:Cohort Studies; D018450:Disease Progression; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality; D000077277:Esophageal Squamous Cell Carcinoma; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007288:Inosine; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D017393:RNA Editing; D016601:RNA-Binding Proteins
chemical_list: D002352:Carrier Proteins; D015513:Oncogene Proteins; D016601:RNA-Binding Proteins; C039317:ornithine decarboxylase antizyme inhibitor; D007288:Inosine; C567955:ADARB1 protein, human; D000243:Adenosine Deaminase; D000241:Adenosine