PMID- 35650603 OWN - NLM STAT- MEDLINE DCOM- 20220603 LR - 20240102 IS - 1476-4598 (Electronic) IS - 1476-4598 (Linking) VI - 21 IP - 1 DP - 2022 Jun 1 TI - CircSTX6 promotes pancreatic ductal adenocarcinoma progression by sponging miR-449b-5p and interacting with CUL2. PG - 121 LID - 10.1186/s12943-022-01599-5 [doi] LID - 121 AB - BACKGROUND: circular RNAs (circRNAs) have been reported to play crucial roles in the biology of different cancers. However, little is known about the function of circSTX6 (hsa_circ_0007905) in pancreatic ductal adenocarcinoma (PDAC). METHODS: circSTX6, a circRNA containing exons 4, 5, 6 and 7 of the STX6 gene, was identified by RNA sequencing and detected by quantitative reverse transcription PCR (qRT-PCR). The biological function of circSTX6 was assessed in vitro and in vivo. The relationship between circSTX6 and miR-449b-5p was confirmed by biotin-coupled circRNA capture, fluorescence in situ hybridization (FISH) and luciferase reporter assays. The interaction of circSTX6 with Cullin 2 (CUL2) was verified by RNA-protein RNA pull-down, RNA immunoprecipitation (RIP) and western blotting assays. RESULTS: circSTX6 was frequently upregulated in PDAC tissues, and circSTX6 overexpression promoted tumor proliferation and metastasis both in vitro and in vivo. Furthermore, circSTX6 expression was associated with tumor differentiation and N stage. Mechanistically, circSTX6 regulated the expression of non-muscle myosin heavy chain 9 (MYH9) by sponging miR-449b-5p. Moreover, circSTX6 was confirmed to participate in the ubiquitin-dependent degradation of hypoxia-inducible factor 1-alpha (HIF1A) by interacting with CUL2 and subsequently accelerating the transcription of MYH9. CONCLUSIONS: Our findings indicate that circSTX6 facilitates proliferation and metastasis of PDAC cells by regulating the expression of MYH9 through the circSTX6/miR-449b-5p axis and circSTX6/CUL2/HIF1A signaling pathway. Therefore, circSTX6 could serve as a potential therapeutic target for the treatment of PDAC. CI - (c) 2022. The Author(s). FAU - Meng, Lingdong AU - Meng L AD - Pancreas Center, the First Affiliated Hospital of Nanjing Medical University, Nanjing, PR China. AD - Pancreas Institute, Nanjing Medical University, Nanjing, China. AD - Nanjing Medical University, Nanjing, China. FAU - Zhang, Yihan AU - Zhang Y AD - Pancreas Center, the First Affiliated Hospital of Nanjing Medical University, Nanjing, PR China. AD - Pancreas Institute, Nanjing Medical University, Nanjing, China. AD - Nanjing Medical University, Nanjing, China. FAU - Wu, Pengfei AU - Wu P AD - Pancreas Center, the First Affiliated Hospital of Nanjing Medical University, Nanjing, PR China. AD - Pancreas Institute, Nanjing Medical University, Nanjing, China. AD - Nanjing Medical University, Nanjing, China. FAU - Li, Danrui AU - Li D AD - Pancreas Center, the First Affiliated Hospital of Nanjing Medical University, Nanjing, PR China. AD - Pancreas Institute, Nanjing Medical University, Nanjing, China. AD - Nanjing Medical University, Nanjing, China. FAU - Lu, Yichao AU - Lu Y AD - Pancreas Center, the First Affiliated Hospital of Nanjing Medical University, Nanjing, PR China. AD - Pancreas Institute, Nanjing Medical University, Nanjing, China. AD - Nanjing Medical University, Nanjing, China. FAU - Shen, Peng AU - Shen P AD - Pancreas Center, the First Affiliated Hospital of Nanjing Medical University, Nanjing, PR China. AD - Pancreas Institute, Nanjing Medical University, Nanjing, China. AD - Nanjing Medical University, Nanjing, China. FAU - Yang, Taoyue AU - Yang T AD - Pancreas Center, the First Affiliated Hospital of Nanjing Medical University, Nanjing, PR China. AD - Pancreas Institute, Nanjing Medical University, Nanjing, China. AD - Nanjing Medical University, Nanjing, China. FAU - Shi, Guodong AU - Shi G AD - Pancreas Center, the First Affiliated Hospital of Nanjing Medical University, Nanjing, PR China. AD - Pancreas Institute, Nanjing Medical University, Nanjing, China. AD - Nanjing Medical University, Nanjing, China. FAU - Chen, Qun AU - Chen Q AD - Pancreas Center, the First Affiliated Hospital of Nanjing Medical University, Nanjing, PR China. AD - Pancreas Institute, Nanjing Medical University, Nanjing, China. AD - Nanjing Medical University, Nanjing, China. FAU - Yuan, Hao AU - Yuan H AD - Pancreas Center, the First Affiliated Hospital of Nanjing Medical University, Nanjing, PR China. AD - Pancreas Institute, Nanjing Medical University, Nanjing, China. AD - Nanjing Medical University, Nanjing, China. FAU - Ge, Wanli AU - Ge W AD - Pancreas Center, the First Affiliated Hospital of Nanjing Medical University, Nanjing, PR China. AD - Pancreas Institute, Nanjing Medical University, Nanjing, China. AD - Nanjing Medical University, Nanjing, China. FAU - Miao, Yi AU - Miao Y AD - Pancreas Center, the First Affiliated Hospital of Nanjing Medical University, Nanjing, PR China. AD - Pancreas Institute, Nanjing Medical University, Nanjing, China. AD - Nanjing Medical University, Nanjing, China. FAU - Tu, Min AU - Tu M AD - Pancreas Center, the First Affiliated Hospital of Nanjing Medical University, Nanjing, PR China. tumin1215@163.com. AD - Pancreas Institute, Nanjing Medical University, Nanjing, China. tumin1215@163.com. AD - Nanjing Medical University, Nanjing, China. tumin1215@163.com. FAU - Jiang, Kuirong AU - Jiang K AD - Pancreas Center, the First Affiliated Hospital of Nanjing Medical University, Nanjing, PR China. jiangkuirong@njmu.edu.cn. AD - Pancreas Institute, Nanjing Medical University, Nanjing, China. jiangkuirong@njmu.edu.cn. AD - Nanjing Medical University, Nanjing, China. jiangkuirong@njmu.edu.cn. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20220601 PL - England TA - Mol Cancer JT - Molecular cancer JID - 101147698 RN - 0 (CUL2 protein, human) RN - 0 (Cullin Proteins) RN - 0 (MIRN449 microRNA, human) RN - 0 (MicroRNAs) RN - 0 (Qa-SNARE Proteins) RN - 0 (RNA, Circular) RN - 0 (STX6 protein, human) SB - IM MH - *Carcinoma, Pancreatic Ductal/pathology MH - Cell Line, Tumor MH - *Cullin Proteins/genetics MH - Gene Expression Regulation, Neoplastic MH - Humans MH - In Situ Hybridization, Fluorescence MH - *MicroRNAs/genetics MH - *Pancreatic Neoplasms/pathology MH - Qa-SNARE Proteins MH - RNA, Circular/genetics PMC - PMC9158112 OTO - NOTNLM OT - HIF1A OT - MYH9 OT - Pancreatic ductal adenocarcinoma OT - circSTX6 OT - miR-449b-5p COIS- The authors declare that they have no competing interests. EDAT- 2022/06/02 06:00 MHDA- 2022/06/07 06:00 PMCR- 2022/06/01 CRDT- 2022/06/01 23:48 PHST- 2022/03/17 00:00 [received] PHST- 2022/05/18 00:00 [accepted] PHST- 2022/06/01 23:48 [entrez] PHST- 2022/06/02 06:00 [pubmed] PHST- 2022/06/07 06:00 [medline] PHST- 2022/06/01 00:00 [pmc-release] AID - 10.1186/s12943-022-01599-5 [pii] AID - 1599 [pii] AID - 10.1186/s12943-022-01599-5 [doi] PST - epublish SO - Mol Cancer. 2022 Jun 1;21(1):121. doi: 10.1186/s12943-022-01599-5.