PMID- 30927924 OWN - NLM STAT- MEDLINE DCOM- 20190819 LR - 20201209 IS - 1476-4598 (Electronic) IS - 1476-4598 (Linking) VI - 18 IP - 1 DP - 2019 Mar 30 TI - Circular RNA AKT3 upregulates PIK3R1 to enhance cisplatin resistance in gastric cancer via miR-198 suppression. PG - 71 LID - 10.1186/s12943-019-0969-3 [doi] LID - 71 AB - BACKGROUND: Cisplatin (CDDP) treatment is one of the most predominant chemotherapeutic strategies for patients with gastric cancer (GC). A better understanding of the mechanisms of CDDP resistance can greatly improve therapeutic efficacy in patients with GC. Circular RNAs (circRNAs) are a class of noncoding RNAs whose functions are related to the pathogenesis of cancer, but, in CDDP resistance of GC remains unknown. METHODS: circAKT3 (hsa_circ_0000199, a circRNA originating from exons 8, 9, 10, and 11 of the AKT3 gene) was identified by RNA sequencing and verified by quantitative reverse transcription PCR. The role of circAKT3 in CDDP resistance in GC was assessed both in vitro and in vivo. Luciferase reporter assay, biotin-coupled RNA pull-down and fluorescence in situ hybridization (FISH) were conducted to evaluate the interaction between circAKT3 and miR-198. Functional experiments were measured by western blotting, a cytotoxicity assay, clonogenic assay and flow cytometry. RESULTS: The expression of circAKT3 was higher in CDDP-resistant GC tissues and cells than in CDDP-sensitive samples. The upregulation of circAKT3 in GC patients receiving CDDP therapy was significantly associated with aggressive characteristics and was an independent risk factor for disease-free survival (DFS). Our data indicated that circAKT3 promotes DNA damage repair and inhibits the apoptosis of GC cells in vivo and in vitro. Mechanistically, we verified that circAKT3 could promote PIK3R1 expression by sponging miR-198. CONCLUSIONS: circAKT3 plays an important role in the resistance of GC to CDDP. Thus, our results highlight the potential of circAKT3 as a therapeutic target for GC patients receiving CDDP therapy. FAU - Huang, Xiaoxu AU - Huang X AD - Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu province, China. AD - Department of Gastrointestinal Surgery, The First Affiliated Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, China. FAU - Li, Zheng AU - Li Z AD - Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu province, China. FAU - Zhang, Qiang AU - Zhang Q AD - Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu province, China. FAU - Wang, Weizhi AU - Wang W AD - Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu province, China. FAU - Li, Bowen AU - Li B AD - Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu province, China. FAU - Wang, Lu AU - Wang L AD - Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu province, China. FAU - Xu, Zhipeng AU - Xu Z AD - Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu province, China. FAU - Zeng, Ailiang AU - Zeng A AD - Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China. FAU - Zhang, Xing AU - Zhang X AD - Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu province, China. FAU - Zhang, Xuan AU - Zhang X AD - Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu province, China. FAU - He, Zhongyuan AU - He Z AD - Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu province, China. FAU - Li, Qiang AU - Li Q AD - Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu province, China. FAU - Sun, Guangli AU - Sun G AD - Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu province, China. FAU - Wang, Sen AU - Wang S AD - Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu province, China. FAU - Li, Qing AU - Li Q AD - Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu province, China. FAU - Wang, Linjun AU - Wang L AD - Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu province, China. FAU - Zhang, Lu AU - Zhang L AD - Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu province, China. FAU - Xu, Hao AU - Xu H AD - Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu province, China. FAU - Xu, Zekuan AU - Xu Z AUID- ORCID: 0000-0001-5179-4128 AD - Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu province, China. xuzekuan@njmu.edu.cn. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20190330 PL - England TA - Mol Cancer JT - Molecular cancer JID - 101147698 RN - 0 (MIRN198 microRNA, human) RN - 0 (MicroRNAs) RN - 0 (RNA, Circular) RN - 63231-63-0 (RNA) RN - EC 2.7.1.- (PIK3R1 protein, human) RN - EC 2.7.1.137 (Class Ia Phosphatidylinositol 3-Kinase) RN - Q20Q21Q62J (Cisplatin) MH - Animals MH - Cell Line, Tumor MH - Cell Survival MH - Cisplatin/administration & dosage MH - Class Ia Phosphatidylinositol 3-Kinase MH - *Drug Resistance, Neoplasm MH - Female MH - Gene Expression Profiling MH - Gene Expression Regulation, Neoplastic MH - Humans MH - Male MH - Mice MH - MicroRNAs/*genetics MH - Phosphatidylinositol 3-Kinases/*genetics/metabolism MH - Prognosis MH - RNA/*genetics MH - RNA, Circular MH - Sequence Analysis, RNA MH - Stomach Neoplasms/*drug therapy/genetics/metabolism MH - Survival Analysis MH - *Up-Regulation MH - Xenograft Model Antitumor Assays PMC - PMC6441201 OTO - NOTNLM OT - Circular RNA OT - Cisplatin resistance OT - Gastric cancer OT - PIK3R1 OT - circAKT3 OT - miR-198 COIS- ETHICS APPROVAL AND CONSENT TO PARTICIPATE: The present study was approved by the Hospital's Protection of Human Subjects Committee. CONSENT FOR PUBLICATION: We have received consents from individual patients who have participated in this study. The consent forms will be provided upon request. COMPETING INTERESTS: The authors declare that they have no competing interests. PUBLISHER'S NOTE: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. EDAT- 2019/04/01 06:00 MHDA- 2019/08/20 06:00 PMCR- 2019/03/30 CRDT- 2019/04/01 06:00 PHST- 2018/11/21 00:00 [received] PHST- 2019/02/21 00:00 [accepted] PHST- 2019/04/01 06:00 [entrez] PHST- 2019/04/01 06:00 [pubmed] PHST- 2019/08/20 06:00 [medline] PHST- 2019/03/30 00:00 [pmc-release] AID - 10.1186/s12943-019-0969-3 [pii] AID - 969 [pii] AID - 10.1186/s12943-019-0969-3 [doi] PST - epublish SO - Mol Cancer. 2019 Mar 30;18(1):71. doi: 10.1186/s12943-019-0969-3.