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. Cancer Res; 74(3); 840-51. Ó2013 AACR.

Organ-wide profiling in mouse reveals high editing levels of Filamin B mRNA in the musculoskeletal system

“…Thus, levels of editing in mature mRNAs may also be regulated by differential splicing. Moreover, Flnb editing has been shown to be altered in esophageal and liver carcinomas due to the increased activity of ADAR1 indicating that this enzyme may also target Flnb , at least under specific conditions [38,39]. Clearly, further investigations concerning the modulation of Flnb RNA editing will be required.…”

ADAR1: a promising new biomarker for esophageal squamous cell carcinoma?

“…The expression of ADAR1 is also downregulated by miRNA-1 (miR-1) [16,17], and the tight regulation of ADAR1 by miR-1 is likely to be critical for heart development [18,19]. In ESCC, we found that ADAR1 gene, which is mapped to chromosome 1q21, was amplified in approximately 70% of ESCC tumors using fluorescent in situ hybridization, and there was a positive correlation between overexpression of ADAR1 and the genomic amplification of ADAR1 gene in ESCC specimens [11], suggesting another mechanism of ADAR1 overexpression in tumors.…”

“…Our recent studies have reported that the differential expression of ADAR1 and/or ADAR2 was observed in HCC and ESCC tumors, leading to a gene-specific hyper or hypo-editing phenotype [11,25,33]. In ESCC, ADAR1 and ADAR2 were abundantly expressed, whereas ADAR3 was undetectable.…”

“…As a common editing target by ADAR1 and ADAR2, the decreased editing frequency of glioma-associated oncogene 1 was observed in basal cell carcinoma tumor samples when compared to normal skin, and RNA editing of glioma-associated oncogene 1 transcription factor are involved in Hedgehog signaling [24]. In contrast, ADAR1 was found to be upregulated in tumor tissues, such as hepatocellular carcinoma (HCC) [25], ESCC [11] and breast cancer [26]. It has been reported that homodimer formation may be necessary for ADAR1 and ADAR2 to act as active deaminases [27].…”

“…The imbalance of ADARs expression/activity is found to be associated with a variety of human diseases, such as amyotrophic lateral sclerosis [4], systemic lupus erythematosus [5,6], neurological disorders [7,8] and cancer [9]. Recently, we have provided the first analyses of expression profiles of ADARs in human ESCC and demonstrated that among all three RNA editing enzymes ADAR1, ADAR2 and ADAR3 [10], only ADAR1 was significantly overexpressed in ESCC tumors, which has great prognostic value and diagnostic potential for ESCC; ADAR1 functions as an oncogene in the development of ESCC; the tight link between the differential expression of ADAR1 and an altered gene-specific editing pattern was investigated to illustrate how the A-to-I RNA editing balance is deregulated in ESCC; and a new functional recurrent RNA editing event, resulting in an amino acid substitution of the AZIN1 gene (antizyme inhibitor 1), was specifically regulated by ADAR1 and found to confer more aggressive tumorigenic behaviors [11]. In this article, we discuss recent studies connecting the differentially expressed ADAR genes with RNA editing alteration in human cancers, with a specific focus on ADAR1-mediated RNA editing in carcinogenesis.…”