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circANKRD17(has_circ_0007883) confers paclitaxel resistance of ovarian cancer via interacting with FUS to stabilize FOXR2

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Abstract

Emerging numbers of endogenous circular RNAs (circRNAs) have gained much attention to serve as essential regulators in the carcinogenesis of human cancers. Unfortunately, the occurrence of paclitaxel (PTX) resistance to ovarian cancer remains to be responsible for the poor prognosis. Herein, the aim of our study is to reveal a dysregulation of a particular circRNA, circANKRD17 (has_circ_0007883), and its exact role involving in chemoresistance of ovarian cancer. Expression patterns of circANKRD17 in PTX-resistant ovarian cancer tissues and cell lines was examined using quantitative real-time PCR analysis. Role of circANKRD17 on drug resistance and cell viability was evaluated by CCK-8 assay. Colony formation was subjected to measure cell proliferation. Flow cytometry was employed to evaluate cell cycle either or cell apoptosis. Xenograft models were constructed for further in vivo confirmation. The cicrANKRD17/FUS/FOXR2 axis was demonstrated using bioinformatics analysis, RNA pull-down, as well as RNA immunoprecipitation assays. Dramatically high expressed circANKRD17 observed in ovarian cancer tissues and cells was correlated with PTX resistance, which indicated the poor prognosis. Functionally, knockdown of circANKRD17 decreased PTX resistance via inhibiting cell viability and inducing cell apoptosis. Mechanistically, circANKRD17 interacted with the RNA-binding protein, fused in sarcoma (FUS) to stabilize FOXR2. In summary, our study uncovered a novel machinery of circANKRD17/FUS/FOXR2 referring to ovarian cancer drug sensitivity and tumorigenesis, highlighting a potential strategy for circRNAs in chemoresistance.

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Data availability

All data generated or analyzed during this study are included in this article. The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

References

  1. Siegel RL, Miller KD, Jemal A (2018) Cancer statistics, 2018. CA Cancer J Clin 68:7–30

    Article  PubMed  Google Scholar 

  2. Pinato DJ, Graham J, Gabra H, Sharma R (2013) Evolving concepts in the management of drug resistant ovarian cancer: dose dense chemotherapy and the reversal of clinical platinum resistance. Cancer Treat Rev 39:153–160

    Article  CAS  PubMed  Google Scholar 

  3. Vaughan S, Coward JI, Bast RC Jr, Berchuck A, Berek JS, Brenton JD, Coukos G, Crum CC, Drapkin R, Etemadmoghadam D, Friedlander M, Gabra H, Kaye SB, Lord CJ, Lengyel E, Levine DA, McNeish IA, Menon U, Mills GB, Nephew KP, Oza AM, Sood AK, Stronach EA, Walczak H, Bowtell DD, Balkwill FR (2011) Rethinking ovarian cancer: recommendations for improving outcomes. Nat Rev Cancer 11:719–725

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Agarwal R, Kaye SB (2003) Ovarian cancer: strategies for overcoming resistance to chemotherapy. Nat Rev Cancer 3:502–516

    Article  CAS  PubMed  Google Scholar 

  5. Sapiezynski J, Taratula O, Rodriguez-Rodriguez L, Minko T (2016) Precision targeted therapy of ovarian cancer. J Control Release 243:250–268

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Zhang XO, Dong R, Zhang Y, Zhang JL, Luo Z, Zhang J, Chen LL, Yang L (2016) Diverse alternative back-splicing and alternative splicing landscape of circular RNAs. Genome Res 26:1277–1287

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Chen LL, Yang L (2015) Regulation of circRNA biogenesis. RNA Biol 12:381–388

    Article  PubMed  PubMed Central  Google Scholar 

  8. Guo M, Li S, Zhao X, Yuan Y, Zhang B, Guan Y (2020) Knockdown of circular RNA hsa_circ_0000714 can regulate RAB17 by sponging miR-370-3p to reduce paclitaxel resistance of ovarian cancer through CDK6/RB pathway. Onco Targets Ther 13:13211–13224

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Xia B, Zhao Z, Wu Y, Wang Y, Zhao Y, Wang J (2020) Circular RNA circTNPO3 regulates paclitaxel resistance of ovarian cancer cells by miR-1299/NEK2 signaling pathway. Mol Ther Nucleic Acids 21:780–791

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Gan X, Zhu H, Jiang X, Obiegbusi SC, Yong M, Long X, Hu J (2020) CircMUC16 promotes autophagy of epithelial ovarian cancer via interaction with ATG13 and miR-199a. Mol Cancer 19:45

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Li Z, Hu S, Wang J, Cai J, Xiao L, Yu L, Wang Z (2010) MiR-27a modulates MDR1/P-glycoprotein expression by targeting HIPK2 in human ovarian cancer cells. Gynecol Oncol 119:125–130

    Article  CAS  PubMed  Google Scholar 

  12. Li X, Wang W, Xi Y, Gao M, Tran M, Aziz KE, Qin J, Li W, Chen J (2016) FOXR2 interacts with MYC to promote its transcriptional activities and tumorigenesis. Cell Rep 16:487–497

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Li B, Huang W, Cao N, Lou G (2018) Forkhead-box R2 promotes metastasis and growth by stimulating angiogenesis and activating hedgehog signaling pathway in ovarian cancer. J Cell Biochem 119:7780–7789

    Article  CAS  PubMed  Google Scholar 

  14. Asadollahi S, Mazaheri MN, Karimi-Zarchi M, Fesahat F (2020) The relationship of FOXR2 gene expression profile with epithelial-mesenchymal transition related markers in epithelial ovarian cancer. Klin Onkol 33:201–207

    PubMed  Google Scholar 

  15. Zang J, Lu D, Xu A (2020) The interaction of circRNAs and RNA binding proteins: an important part of circRNA maintenance and function. J Neurosci Res 98:87–97

    Article  CAS  PubMed  Google Scholar 

  16. Okholm TLH, Sathe S, Park SS, Kamstrup AB, Rasmussen AM, Shankar A, Chua ZM, Fristrup N, Nielsen MM, Vang S, Dyrskjot L, Aigner S, Damgaard CK, Yeo GW, Pedersen JS (2020) Transcriptome-wide profiles of circular RNA and RNA-binding protein interactions reveal effects on circular RNA biogenesis and cancer pathway expression. Genome Med 12:112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Weidle UH, Birzele F, Kollmorgen G, Rueger R (2016) Mechanisms and targets involved in dissemination of ovarian cancer. Cancer Genomics Proteomics 13:407–423

    Article  CAS  PubMed  Google Scholar 

  18. Gao D, Qi X, Zhang X, Fang K, Guo Z, Li L (2019) hsa_circRNA_0006528 as a competing endogenous RNA promotes human breast cancer progression by sponging miR-7-5p and activating the MAPK/ERK signaling pathway. Mol Carcinog 58:554–564

    Article  CAS  PubMed  Google Scholar 

  19. Wei W, Birrer MJ (2015) Spleen tyrosine kinase confers paclitaxel resistance in ovarian cancer. Cancer Cell 28:7–9

    Article  CAS  PubMed  Google Scholar 

  20. Mantia-Smaldone GM, Edwards RP, Vlad AM (2011) Targeted treatment of recurrent platinum-resistant ovarian cancer: current and emerging therapies. Cancer Manag Res 3:25–38

    CAS  PubMed  Google Scholar 

  21. Sheng R, Li X, Wang Z, Wang X (2020) Circular RNAs and their emerging roles as diagnostic and prognostic biomarkers in ovarian cancer. Cancer Lett 473:139–147

    Article  CAS  PubMed  Google Scholar 

  22. Shi Y, He R, Yang Y, He Y, Shao K, Zhan L, Wei B (2020) Circular RNAs: novel biomarkers for cervical, ovarian and endometrial cancer (Review). Oncol Rep 44:1787–1798

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Xu Q, Deng B, Li M, Chen Y, Zhuan L (2020) circRNA-UBAP2 promotes the proliferation and inhibits apoptosis of ovarian cancer though miR-382-5p/PRPF8 axis. J Ovarian Res 13:81

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Zhang L, Zhou Q, Qiu Q, Hou L, Wu M, Li J, Li X, Lu B, Cheng X, Liu P, Lu W, Lu Y (2019) CircPLEKHM3 acts as a tumor suppressor through regulation of the miR-9/BRCA1/DNAJB6/KLF4/AKT1 axis in ovarian cancer. Mol Cancer 18:144

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Zeng XY, Yuan J, Wang C, Zeng D, Yong JH, Jiang XY, Lan H, Xiao SS (2020) circCELSR1 facilitates ovarian cancer proliferation and metastasis by sponging miR-598 to activate BRD4 signals. Mol Med 26:70

    Article  PubMed  PubMed Central  Google Scholar 

  26. Militello G, Weirick T, John D, Doring C, Dimmeler S, Uchida S (2017) Screening and validation of lncRNAs and circRNAs as miRNA sponges. Brief Bioinform 18:780–788

    CAS  PubMed  Google Scholar 

  27. Guo JU, Agarwal V, Guo H, Bartel DP (2014) Expanded identification and characterization of mammalian circular RNAs. Genome Biol 15:409

    Article  PubMed  PubMed Central  Google Scholar 

  28. Abdelmohsen K, Panda AC, Munk R, Grammatikakis I, Dudekula DB, De S, Kim J, Noh JH, Kim KM, Martindale JL, Gorospe M (2017) Identification of HuR target circular RNAs uncovers suppression of PABPN1 translation by CircPABPN1. RNA Biol 14:361–369

    Article  PubMed  PubMed Central  Google Scholar 

  29. Schneider T, Hung LH, Schreiner S, Starke S, Eckhof H, Rossbach O, Reich S, Medenbach J, Bindereif A (2016) CircRNA-protein complexes: IMP3 protein component defines subfamily of circRNPs. Sci Rep 6:31313

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Feng Y, Yang Y, Zhao X, Fan Y, Zhou L, Rong J, Yu Y (2019) Circular RNA circ0005276 promotes the proliferation and migration of prostate cancer cells by interacting with FUS to transcriptionally activate XIAP. Cell Death Dis 10:792

    Article  PubMed  PubMed Central  Google Scholar 

  31. Svec D, Dolatabadi S, Thomsen C, Cordes N, Shannon M, Fitzpatrick P, Landberg G, Aman P, Stahlberg A (2018) Identification of inhibitors regulating cell proliferation and FUS-DDIT3 expression in myxoid liposarcoma using combined DNA, mRNA, and protein analyses. Lab Invest 98:957–967

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. He Z, Ruan X, Liu X, Zheng J, Liu Y, Liu L, Ma J, Shao L, Wang D, Shen S, Yang C, Xue Y (2019) FUS/circ_002136/miR-138-5p/SOX13 feedback loop regulates angiogenesis in glioma. J Exp Clin Cancer Res 38:65

    Article  PubMed  PubMed Central  Google Scholar 

  33. Sun S, Kong Q, Cai Z, Wang M, Zhao H, Zhao C (2021) circGrm1 promotes pulmonary artery smooth muscle cell proliferation and migration via suppression of GRM1 expression by FUS. Int J Mol Med. https://doi.org/10.3892/ijmm.2021.5035

    Article  PubMed  PubMed Central  Google Scholar 

  34. Garikipati VNS, Verma SK, Cheng Z, Liang D, Truongcao MM, Cimini M, Yue Y, Huang G, Wang C, Benedict C, Tang Y, Mallaredy V, Ibetti J, Grisanti L, Schumacher SM, Gao E, Rajan S, Wilusz JE, Goukassian D, Houser SR, Koch WJ, Kishore R (2019) Circular RNA CircFndc3b modulates cardiac repair after myocardial infarction via FUS/VEGF-A axis. Nat Commun 10:4317

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Katoh M, Katoh M (2004) Identification and characterization of human FOXN6, mouse Foxn6, and rat Foxn6 genes in silico. Int J Oncol 25:219–223

    Article  CAS  PubMed  Google Scholar 

  36. Liao CW, Zheng C, Wang L (2020) Down-regulation of FOXR2 inhibits hypoxia-driven ROS-induced migration and invasion of thyroid cancer cells via regulation of the hedgehog pathway. Clin Exp Pharmacol Physiol 47:1076–1082

    Article  CAS  PubMed  Google Scholar 

  37. Lu SQ, Qiu Y, Dai WJ, Zhang XY (2017) FOXR2 Promotes the proliferation, invasion, and epithelial-mesenchymal transition in human colorectal cancer cells. Oncol Res 25:681–689

    Article  PubMed  PubMed Central  Google Scholar 

  38. Zhang S, Cheng J, Quan C, Wen H, Feng Z, Hu Q, Zhu J, Huang Y, Wu X (2020) circCELSR1 (hsa_circ_0063809) contributes to paclitaxel resistance of ovarian cancer cells by regulating FOXR2 expression via miR-1252. Mol Ther Nucleic Acids 19:718–730

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Affiliated Hospital of Youjiang Medical University for Nationalities, No.18, Zhongshan 2nd Road, Youjiang District, Baise, 533000, Guangxi, People’s Republic of China

    Yue-Xiu Liang, Lian-Ling Zhang & Li Yang

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  1. Yue-Xiu Liang
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  2. Lian-Ling Zhang
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  3. Li Yang
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Contributions

YXL: conception and design of the work. YXL, LLZ: data acquisition, Drafting the work. YXL, LY: data analysis and data interpretation, revising it critically for important intellectual content.

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Correspondence to Li Yang.

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All study on the clinical samples was approved by the Institutional Review Boards of the Affiliated Hospital of Youjiang Medical College for Nationalities. None of the patients had undergone chemotherapy or radiotherapy prior to surgery, and informed consent was obtained from all of the patients.

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Liang, YX., Zhang, LL. & Yang, L. circANKRD17(has_circ_0007883) confers paclitaxel resistance of ovarian cancer via interacting with FUS to stabilize FOXR2. Mol Cell Biochem 478, 835–850 (2023). https://doi.org/10.1007/s11010-022-04548-4

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