PMID- 35459186 OWN - NLM STAT- MEDLINE DCOM- 20220426 LR - 20240102 IS - 1756-9966 (Electronic) IS - 0392-9078 (Print) IS - 0392-9078 (Linking) VI - 41 IP - 1 DP - 2022 Apr 23 TI - Circular RNA circ-MTHFD1L induces HR repair to promote gemcitabine resistance via the miR-615-3p/RPN6 axis in pancreatic ductal adenocarcinoma. PG - 153 LID - 10.1186/s13046-022-02343-z [doi] LID - 153 AB - BACKGROUND: Chemoresistance of pancreatic cancer is the main reason for the poor treatment effect of pancreatic cancer patients. Exploring chemotherapy resistance-related genes has been a difficult and hot topic of oncology. Numerous studies implicate the key roles of circular RNAs (circRNAs) in the development of pancreatic cancer. However, the regulation of circRNAs in the process of pancreatic ductal adenocarcinoma (PDAC) chemotherapy resistance is not yet fully clear. METHODS: Based on the cross-analysis of the Gene Expression Omnibus (GEO) database and the data of our center, we explored a new molecule, hsa_circ_0078297 (circ-MTHFD1L), related to chemotherapy resistance. QRT-PCR was used to detect the expression of circRNAs, miRNAs, and mRNAs in human PDAC tissues and their matched normal tissues. The interaction between circ-MTHFD1L and miR-615-3p/RPN6 signal axis was confirmed by a series of experiments such as Dual-luciferase reporter assay, fluorescence in situ hybridization (FISH) RNA immunoprecipitation (RIP) assays. RESULTS: Circ-MTHFD1L was significantly increased in PDAC tissues and cells. And in PDAC patients, the higher the expression level of circ-MTHFD1L, the worse the prognosis. Mechanism analysis showed that circ-MTHFD1L, as an endogenous miR-615-3p sponge, upregulates the expression of RPN6, thereby promoting DNA damage repair and exerting its effect on enhancing gemcitabine chemotherapy resistance. More importantly, we also found that Silencing circ-MTHFD1L combined with olaparib can increase the sensitivity of pancreatic cancer to gemcitabine. CONCLUSION: Circ-MTHFD1L maintains PDAC gemcitabine resistance through the miR-615-3p/RPN6 signal axis. Circ-MTHFD1L may be a molecular marker for the effective treatment of PDAC. CI - (c) 2022. The Author(s). FAU - Chen, Zhi-Wen AU - Chen ZW AUID- ORCID: 0000-0002-1770-6208 AD - Shengli Clinical Medical College of Fujian Medical University, Fuzhou, 350001, Fujian Province, People's Republic of China. FAU - Hu, Jian-Fei AU - Hu JF AD - Shengli Clinical Medical College of Fujian Medical University, Fuzhou, 350001, Fujian Province, People's Republic of China. FAU - Wang, Zu-Wei AU - Wang ZW AD - Shengli Clinical Medical College of Fujian Medical University, Fuzhou, 350001, Fujian Province, People's Republic of China. FAU - Liao, Cheng-Yu AU - Liao CY AD - Shengli Clinical Medical College of Fujian Medical University, Fuzhou, 350001, Fujian Province, People's Republic of China. FAU - Kang, Feng-Ping AU - Kang FP AD - Shengli Clinical Medical College of Fujian Medical University, Fuzhou, 350001, Fujian Province, People's Republic of China. FAU - Lin, Cai-Feng AU - Lin CF AD - Shengli Clinical Medical College of Fujian Medical University, Fuzhou, 350001, Fujian Province, People's Republic of China. AD - Department of Hepatobiliary Surgery, Jinshan Branch of Fujian Province Hospital, Fuzhou, 350007, Fujian Province, People's Republic of China. FAU - Huang, Yi AU - Huang Y AD - Shengli Clinical Medical College of Fujian Medical University, Fuzhou, 350001, Fujian Province, People's Republic of China. AD - Center for Experimental Research in Clinical Medicine, Fujian Provincial Hospital, Fuzhou, 350001, Fujian Province, People's Republic of China. FAU - Huang, Long AU - Huang L AD - Shengli Clinical Medical College of Fujian Medical University, Fuzhou, 350001, Fujian Province, People's Republic of China. haloze@163.com. AD - Department of Hepatopancreatobiliary Surgery, Fujian Provincial Hospital, Fujian Medical University, No. 134, East Street, Fuzhou, 350001, Fujian Province, People's Republic of China. haloze@163.com. FAU - Tian, Yi-Feng AU - Tian YF AD - Shengli Clinical Medical College of Fujian Medical University, Fuzhou, 350001, Fujian Province, People's Republic of China. yifeng0887@126.com. AD - Department of Hepatopancreatobiliary Surgery, Fujian Provincial Hospital, Fujian Medical University, No. 134, East Street, Fuzhou, 350001, Fujian Province, People's Republic of China. yifeng0887@126.com. FAU - Chen, Shi AU - Chen S AD - Shengli Clinical Medical College of Fujian Medical University, Fuzhou, 350001, Fujian Province, People's Republic of China. wawljwalj@163.com. AD - Department of Hepatopancreatobiliary Surgery, Fujian Provincial Hospital, Fujian Medical University, No. 134, East Street, Fuzhou, 350001, Fujian Province, People's Republic of China. wawljwalj@163.com. LA - eng GR - 82173250/National Natural Science Foundation of China/ GR - 2021J01365/Fujian Natural Science Foundation/ GR - 2020J011097/Fujian Natural Science Foundation/ GR - 2060402/Education and Scientific Research Foundation of Fujian Province/ GR - 2019-cx-3/Fujian Provincial Health and Family Planning Research Medical Innovation Project/ GR - 2018Y9098/Joint Funds for the innovation of science and technology, Fujian Province/ GR - 2020CXA001/Fujian Medical Innovation Project/ PT - Journal Article DEP - 20220423 PL - England TA - J Exp Clin Cancer Res JT - Journal of experimental & clinical cancer research : CR JID - 8308647 RN - 0 (MIRN615 microRNA, human) RN - 0 (MicroRNAs) RN - 0 (Minor Histocompatibility Antigens) RN - 0 (RNA, Circular) RN - 0W860991D6 (Deoxycytidine) RN - EC 1.5.1.5 (MTHFD1 protein, human) RN - EC 1.5.1.5 (Methylenetetrahydrofolate Dehydrogenase (NADP)) RN - 0 (Gemcitabine) SB - IM MH - *Carcinoma, Pancreatic Ductal/drug therapy/genetics/metabolism MH - Cell Line, Tumor MH - Cell Proliferation MH - Deoxycytidine/analogs & derivatives MH - Humans MH - In Situ Hybridization, Fluorescence MH - *Methylenetetrahydrofolate Dehydrogenase (NADP)/genetics MH - *MicroRNAs/genetics/metabolism MH - *Minor Histocompatibility Antigens/genetics MH - *Pancreatic Neoplasms/drug therapy/genetics/metabolism MH - RNA, Circular/genetics MH - Gemcitabine PMC - PMC9034615 OTO - NOTNLM OT - Circ-MTHFD1L OT - Gemcitabine resistance OT - Pancreatic cancer OT - RPN6 OT - miR-615-3p COIS- Zhi-Wen Chen, Jian-Fei Hu, Zu-Wei Wang contributed equally to this work and all should be considered co-first authors. Shi Chen, Yi-Feng Tian, Long Huang, also contributed equally, and all should be considered the co-corresponding author. The authors declare that they have no competing interests. EDAT- 2022/04/24 06:00 MHDA- 2022/04/27 06:00 PMCR- 2022/04/23 CRDT- 2022/04/23 05:08 PHST- 2022/01/26 00:00 [received] PHST- 2022/03/25 00:00 [accepted] PHST- 2022/04/23 05:08 [entrez] PHST- 2022/04/24 06:00 [pubmed] PHST- 2022/04/27 06:00 [medline] PHST- 2022/04/23 00:00 [pmc-release] AID - 10.1186/s13046-022-02343-z [pii] AID - 2343 [pii] AID - 10.1186/s13046-022-02343-z [doi] PST - epublish SO - J Exp Clin Cancer Res. 2022 Apr 23;41(1):153. doi: 10.1186/s13046-022-02343-z.