PMID- 37589744 OWN - NLM STAT- MEDLINE DCOM- 20230818 LR - 20230911 IS - 1420-9071 (Electronic) IS - 1420-682X (Linking) VI - 80 IP - 9 DP - 2023 Aug 17 TI - AUF1-induced circular RNA hsa_circ_0010467 promotes platinum resistance of ovarian cancer through miR-637/LIF/STAT3 axis. PG - 256 LID - 10.1007/s00018-023-04906-5 [doi] AB - BACKGROUND: Increasing evidences has indicated that primary and acquired resistance of ovarian cancer (OC) to platinum is mediated by multiple molecular and cellular factors. Understanding these mechanisms could promote the therapeutic efficiency for patients with OC. METHODS: Here, we screened the expression pattern of circRNAs in samples derived from platinum-resistant and platinum-sensitive OC patients using RNA-sequencing (RNA-seq). The expression of hsa_circ_0010467 was validated by Sanger sequencing, RT-qPCR, and fluorescence in situ hybridization (FISH) assays. Overexpression and knockdown experiments were performed to explore the function of hsa_circ_0010467. The effects of hsa_circ_0010467 on enhancing platinum treatment were validated in OC cells, mouse model and patient-derived organoid (PDO). RNA pull-down, RNA immunoprecipitation (RIP), and dual-luciferase reporter assays were performed to investigate the interaction between hsa_circ_0010467 and proteins. RESULTS: Increased expression of hsa_circ_0010467 is observed in platinum-resistant OC cells, tissues and serum exosomes, which is positively correlated with advanced tumor stage and poor prognosis of OC patients. Hsa_circ_0010467 is found to maintain the platinum resistance via inducing tumor cell stemness, and silencing hsa_circ_0010467 substantially increases the efficacy of platinum treatment on inhibiting OC cell proliferation. Further investigation reveals that hsa_circ_0010467 acts as a miR-637 sponge to mediate the repressive effect of miR-637 on leukemia inhibitory factor (LIF) and activates the LIF/STAT3 signaling pathway. We further discover that AUF1 could promote the biogenesis of hsa_circ_0010467 in OC. CONCLUSION: Our study uncovers the mechanism that hsa_circ_0010467 mediates the platinum resistance of OC through AUF1/hsa_circ_0010467/miR-637/LIF/STAT3 axis, and provides potential targets for the treatment of platinum-resistant OC patients. CI - (c) 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG. FAU - Wu, Yangjun AU - Wu Y AD - Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, China. AD - Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. FAU - Xu, Miao AU - Xu M AD - Department of Clinical Nutrition, West China Hospital, Sichuan University, Chengdu, China. FAU - Feng, Zheng AU - Feng Z AD - Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, China. AD - Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. FAU - Wu, Hao AU - Wu H AD - Precision Research Center for Refractory Diseases, Institute for Clinical Research, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201620, China. FAU - Wu, Jingni AU - Wu J AD - Precision Research Center for Refractory Diseases, Institute for Clinical Research, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201620, China. FAU - Ha, Xinyu AU - Ha X AD - Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, China. AD - Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. FAU - Wu, Yong AU - Wu Y AD - Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, China. AD - Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. FAU - Chen, Siyu AU - Chen S AD - Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, China. AD - Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. FAU - Xu, Fei AU - Xu F AD - Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, China. AD - Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. FAU - Wen, Hao AU - Wen H AD - Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, China. AD - Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. FAU - Li, Shengli AU - Li S AUID- ORCID: 0000-0001-5430-303X AD - Precision Research Center for Refractory Diseases, Institute for Clinical Research, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201620, China. shengli.li@sjtu.edu.cn. FAU - Wu, Xiaohua AU - Wu X AD - Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, China. wu.xh@fudan.edu.cn. AD - Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. wu.xh@fudan.edu.cn. LA - eng GR - 81972431/National Natural Science Foundation of China/ GR - 32100517/National Natural Science Foundation of China/ GR - 21ZR1415000/General Project of Natural Science Foundation of Shanghai/ PT - Journal Article DEP - 20230817 PL - Switzerland TA - Cell Mol Life Sci JT - Cellular and molecular life sciences : CMLS JID - 9705402 RN - 0 (Leukemia Inhibitory Factor) RN - 0 (MicroRNAs) RN - 0 (MIRN637 microRNA, human) RN - 0 (RNA, Circular) RN - 0 (STAT3 protein, human) RN - 0 (STAT3 Transcription Factor) RN - 0 (HNRNPD protein, human) RN - 0 (Heterogeneous Nuclear Ribonucleoprotein D0) SB - IM MH - Animals MH - Female MH - Humans MH - Mice MH - In Situ Hybridization, Fluorescence MH - Leukemia Inhibitory Factor MH - *MicroRNAs/genetics MH - *Ovarian Neoplasms/drug therapy/genetics MH - *RNA, Circular/genetics MH - STAT3 Transcription Factor/genetics MH - *Heterogeneous Nuclear Ribonucleoprotein D0/genetics OTO - NOTNLM OT - AUF1 OT - EIF4G3 OT - Hsa_circ_0010467 OT - LIF OT - Ovarian cancer OT - Platinum resistance OT - miR-637 EDAT- 2023/08/17 12:41 MHDA- 2023/08/18 06:43 CRDT- 2023/08/17 11:04 PHST- 2023/03/12 00:00 [received] PHST- 2023/08/02 00:00 [accepted] PHST- 2023/07/12 00:00 [revised] PHST- 2023/08/18 06:43 [medline] PHST- 2023/08/17 12:41 [pubmed] PHST- 2023/08/17 11:04 [entrez] AID - 10.1007/s00018-023-04906-5 [pii] AID - 10.1007/s00018-023-04906-5 [doi] PST - epublish SO - Cell Mol Life Sci. 2023 Aug 17;80(9):256. doi: 10.1007/s00018-023-04906-5.