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AUF1-induced circular RNA hsa_circ_0010467 promotes platinum resistance of ovarian cancer through miR-637/LIF/STAT3 axis

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Abstract

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.

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Availability of data and material

Raw RNA-seq data are deposited in the Gene Expression Omnibus (GEO) database under the accession number of GSE214302. Software and resources used for data analysis and visualization are described in the method section.

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Funding

This study was supported by the National Natural Science Foundation of China (81972431 and 32100517) and General Project of Natural Science Foundation of Shanghai (21ZR1415000).

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Author notes

  1. Yangjun Wu, Miao Xu and Zheng Feng authors contributed equally to this work.

Authors and Affiliations

  1. Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, China

    Yangjun Wu, Zheng Feng, Xinyu Ha, Yong Wu, Siyu Chen, Fei Xu, Hao Wen & Xiaohua Wu

  2. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China

    Yangjun Wu, Zheng Feng, Xinyu Ha, Yong Wu, Siyu Chen, Fei Xu, Hao Wen & Xiaohua Wu

  3. Department of Clinical Nutrition, West China Hospital, Sichuan University, Chengdu, China

    Miao Xu

  4. Precision Research Center for Refractory Diseases, Institute for Clinical Research, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201620, China

    Hao Wu, Jingni Wu & Shengli Li

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  1. Yangjun Wu
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Contributions

X.W. and S.L. conceived and supervised the project; Y.W., and Z.F. collected clinical samples; Y.W. and M.X. conducted the experiments; S.L. and W.H. performed the computational analysis; J.W., X. H., Y.W., S.C., F.X., and H.W. interpreted the results; Y.W., S.L., and X.W. wrote the manuscript with comments from all the other authors; All authors read and approved the final version of the manuscript.

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Correspondence to Shengli Li or Xiaohua Wu.

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All animal experiments were approved by the Animal Care Committee of Fudan University, and were performed in accordance with the light of NIH Guidelines for the Care and Use of Laboratory Animals. The Ethics Committee of Fudan University Shanghai Cancer Center approved the study, and all participants signed informed consent statements.

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Wu, Y., Xu, M., Feng, Z. et al. AUF1-induced circular RNA hsa_circ_0010467 promotes platinum resistance of ovarian cancer through miR-637/LIF/STAT3 axis. Cell. Mol. Life Sci. 80, 256 (2023). https://doi.org/10.1007/s00018-023-04906-5

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