Abstract
BackgroundAdenosine-to-inosine (A-to-I) RNA editing is catalyzed by adenosine deaminases acting on RNA (ADAR) enzymes. Recent evidence suggests that RNA editing of antizyme inhibitor 1 (AZIN1) RNA is emerging as a key epigenetic alteration underlying cancer pathogenesis.MethodsWe evaluated AZIN1 RNA editing levels, and the expression of its regulator, ADAR1, in 280 gastric tissues from 140 patients, using a RNA editing site-specific quantitative polymerase chain reaction assays. We also analyzed the clinical significance of these results as disease biomarkers in gastric cancer (GC) patients.ResultsBoth AZIN1 RNA editing levels and ADAR1 expression were significantly elevated in GC tissues compared with matched normal mucosa (P < 0.0001, 0.0008, respectively); and AZIN1 RNA editing was positively correlated with ADAR1 expression. Elevated expression of ADAR1 significantly correlated with poor overall survival (P = 0.034), while hyper-edited AZIN1 emerged as an independent prognostic factor for OS and disease-free survival in GC patients [odds ratio (OR):1.98, 95% CI 1.17–3.35, P = 0.011, OR: 4.55, 95% CI 2.12–9.78, P = 0.0001, respectively]. Increased AZIN1 RNA editing and ADAR1 over-expression were significantly correlated with key clinicopathological factors, such as advanced T stage, presence of lymph node metastasis, distant metastasis, and higher TNM stages in GC patients. Logistic regression analysis revealed that hyper-editing status of AZIN1 RNA was an independent risk factor for lymph node metastasis in GC patients [hazard ratio (HR):3.03, 95% CI 1.19–7.71, P = 0.02]. Conclusions: AZIN1 RNA editing levels may be an important prognostic biomarker in GC patients, and may serve as a key clinical decision-making tool for determining preoperative treatment strategies in GC patients.
Highlights
Adenosine-to-inosine (A-to-I) RNA editing is catalyzed by adenosine deaminases acting on RNA (ADAR) enzymes
Profiling analysis revealed that antizyme inhibitor 1 (AZIN1) RNA editing levels were significantly elevated in gastric cancer (GC) tissues compared with matched normal mucosa (P < 0.0001, Fig. 1a)
(See figure on page.) Fig. 1 Dysregulation of AZIN1 RNA editing and ADAR1 expression status in tissues from GC patients. a AZIN1 RNA editing levels and ADAR1 expression levels were significantly increased in primary cancer tissues compared with adjacent normal mucosa. b Receiver operating characteristic (ROC) curve analysis for AZIN1 RNA editing levels and ADAR1 expression levels for distinguishing between GC and normal gastric mucosa
Summary
Adenosine-to-inosine (A-to-I) RNA editing is catalyzed by adenosine deaminases acting on RNA (ADAR) enzymes. Recent evidence suggests that RNA editing of antizyme inhibitor 1 (AZIN1) RNA is emerging as a key epigenetic alteration underlying cancer pathogenesis. RNA editing refers to the post-transcriptional epigenetic modification of RNA sequences through insertion, deletion, or nucleotide conversion, resulting in an increased diversity of the transcriptomic repertoire. Adenosine-toinosine (A-to-I) RNA editing is primarily mediated by adenosine deaminase acting on RNA (ADAR) enzymes, and is the predominant form of RNA editing in humans [1]. Genome-wide A-to-I editing was initially thought to be a rare event which was limited to coding exons, advances in next-generation sequencing technologies and bioinformatic tools have allowed revealed identification of hundreds of thousands of RNA editing sites throughout the human transcriptome. The selective distribution of RNA editing loci and their biological roles indicate the potential for clinically relevant diagnostic and prognostic tools capable of accurately assessing aberrant RNA editing involved in cancer progression and therapeutic resistance
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