Adenosine-to-inosine RNA editing mediated by ADARs in esophageal squamous cell carcinoma

Cancer Res. 2014 Feb 1;74(3):840-51. doi: 10.1158/0008-5472.CAN-13-2545. Epub 2013 Dec 3.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Deaminase / genetics
  • Adenosine Deaminase / metabolism*
  • Adenosine*
  • Carcinoma, Squamous Cell / genetics*
  • Carcinoma, Squamous Cell / metabolism*
  • Carcinoma, Squamous Cell / mortality
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism
  • Cell Line, Tumor
  • Cohort Studies
  • Disease Progression
  • Esophageal Neoplasms / genetics*
  • Esophageal Neoplasms / metabolism*
  • Esophageal Neoplasms / mortality
  • Esophageal Squamous Cell Carcinoma
  • Gene Expression
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Inosine*
  • Oncogene Proteins / genetics
  • Oncogene Proteins / metabolism
  • RNA Editing*
  • RNA-Binding Proteins

Substances

  • Carrier Proteins
  • Oncogene Proteins
  • RNA-Binding Proteins
  • ornithine decarboxylase antizyme inhibitor
  • Inosine
  • ADARB1 protein, human
  • Adenosine Deaminase
  • Adenosine