Charles J Cho1, Jaeeun Jung2,3, Lushang Jiang1, Eun Ji Lee1, Dae-Soo Kim2, Byung Sik Kim4, Hee Sung Kim4, Hwoon-Yong Jung5, Ho-June Song5, Sung Wook Hwang5, Yangsoon Park6, Min Kyo Jung7, Chan Gi Pack7, Seung-Jae Myung8,9,10, Suhwan Chang11. 1. Department of Biomedical Sciences, University of Ulsan College of Medicine, Asan Medical Center, Seoul, 05505, Korea. 2. Rare Disease Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea. 3. Department of Bioinformatics, KRIBB School of Bioscience, Korea University of Science and Technology (UST), Daejeon, Korea. 4. Department of Gastric Surgery, University of Ulsan College of Medicine, Asan Medical Center, Seoul, 05505, Korea. 5. Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, 05505, Korea. 6. Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, 05505, Korea. 7. Department of Convergence Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul, 05505, Korea. 8. Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, 05505, Korea. sjmyung@amc.seoul.kr. 9. Department of Convergence Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul, 05505, Korea. sjmyung@amc.seoul.kr. 10. Department of Gastroenterology and Convergence Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul, 05505, Korea. sjmyung@amc.seoul.kr. 11. Department of Biomedical Sciences, University of Ulsan College of Medicine, Asan Medical Center, Seoul, 05505, Korea. suhwan.chang@amc.seoul.kr.
Abstract
BACKGROUND: Adenosine deaminase acting on RNA 1 (ADAR1) is known to mediate deamination of adenosine-to-inosine through binding to double-stranded RNA, the phenomenon known as RNA editing. Currently, the function of ADAR1 in gastric cancer is unclear. AIMS: This study was aimed at investigating RNA editing-dependent and editing-independent functions of ADAR1 in gastric cancer, especially focusing on its influence on editing of 3' untranslated regions (UTRs) and subsequent changes in expression of messenger RNAs (mRNAs) as well as microRNAs (miRNAs). METHODS: RNA-sequencing and small RNA-sequencing were performed on AGS and MKN-45 cells with a stable ADAR1 knockdown. Changed frequencies of editing and mRNA and miRNA expression were then identified by bioinformatic analyses. Targets of RNA editing were further validated in patients' samples. RESULTS: In the Alu region of both gastric cell lines, editing was most commonly of the A-to-I type in 3'-UTR or intron. mRNA and protein levels of PHACTR4 increased in ADAR1 knockdown cells, because of the loss of seed sequences in 3'-UTR of PHACTR4 mRNA that are required for miRNA-196a-3p binding. Immunohistochemical analyses of tumor and paired normal samples from 16 gastric cancer patients showed that ADAR1 expression was higher in tumors than in normal tissues and inversely correlated with PHACTR4 staining. On the other hand, decreased miRNA-148a-3p expression in ADAR1 knockdown cells led to increased mRNA and protein expression of NFYA, demonstrating ADAR1's editing-independent function. CONCLUSIONS: ADAR1 regulates post-transcriptional gene expression in gastric cancer through both RNA editing-dependent and editing-independent mechanisms.
BACKGROUND:Adenosine deaminase acting on RNA 1 (ADAR1) is known to mediate deamination of adenosine-to-inosine through binding to double-stranded RNA, the phenomenon known as RNA editing. Currently, the function of ADAR1 in gastric cancer is unclear. AIMS: This study was aimed at investigating RNA editing-dependent and editing-independent functions of ADAR1 in gastric cancer, especially focusing on its influence on editing of 3' untranslated regions (UTRs) and subsequent changes in expression of messenger RNAs (mRNAs) as well as microRNAs (miRNAs). METHODS: RNA-sequencing and small RNA-sequencing were performed on AGS and MKN-45 cells with a stable ADAR1 knockdown. Changed frequencies of editing and mRNA and miRNA expression were then identified by bioinformatic analyses. Targets of RNA editing were further validated in patients' samples. RESULTS: In the Alu region of both gastric cell lines, editing was most commonly of the A-to-I type in 3'-UTR or intron. mRNA and protein levels of PHACTR4 increased in ADAR1 knockdown cells, because of the loss of seed sequences in 3'-UTR of PHACTR4 mRNA that are required for miRNA-196a-3p binding. Immunohistochemical analyses of tumor and paired normal samples from 16 gastric cancerpatients showed that ADAR1 expression was higher in tumors than in normal tissues and inversely correlated with PHACTR4 staining. On the other hand, decreased miRNA-148a-3p expression in ADAR1 knockdown cells led to increased mRNA and protein expression of NFYA, demonstrating ADAR1's editing-independent function. CONCLUSIONS:ADAR1 regulates post-transcriptional gene expression in gastric cancer through both RNA editing-dependent and editing-independent mechanisms.
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