Abstract 152P
Background
AT-rich interactive domain 1A (ARID1A) is a tumor suppressor gene, which is frequently mutated in Epstein-Barr virus-positive gastric cancer (EBV (+) GC). While most ARID1Amutations in GC are truncating mutations, leading to loss of ARID1A protein expression, epigenetic modifications appear to contribute to ARID1A deficiency in EBV (+) GC harboring wild-type ARID1A.
Methods
Based on the hypothesis that DNA promotor hypermethylation is a significant epigenetic modification in EBV (+) GC that contributes to ARID1A deficiency, the methylation status of ARID1Awas evaluated in EBV-infected cells and GC patients using a publicly available microarray database and the Cancer Genome Atlas (TCGA) database. EBV-encoded miRNAs that potentially target ARID1Awere identified as an additional epigenetic modulator by computational prediction. In vitro experiments were conducted to evaluate how EBV-encoded miRNAs affected ARID1A mRNA and protein levels. In clinical GC samples, expression of the predicted miRNAs was evaluated by qRT-PCR and correlated with ARID1A expression, as assessed by IHC staining.
Results
ARID1Awas not hypermethylated in EBV (+) GC samples or EBV-infected GC cells. EBV infection did not alter ARID1AmRNA levels, suggesting that ARID1A protein deficiency was caused by post-transcriptional gene silencing in ARID1A-WT EBV (+) GC. Overexpression of miR-BART-X and miR-BART-Y, which were identified as miRNAs that potentially bind ARID1A, suppressed ARID1A protein expression in MKN7 and NCI-N87 cells. Highly expressed miR-BART-X and miR-BART-Y were correlated with decreased ARID1A levels in GC tumors.
Conclusions
The present findings revealed a pivotal role for epigenetic modifications that EBV-encoded miRNAs contribute to gastric carcinogenesis via ARID1A suppression.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Fukushima Medical University.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.
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