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Plasma Exosomal CircNEK9 Accelerates the Progression of Gastric Cancer via miR-409-3p/MAP7 Axis

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Abstract

Background

Exosome-mediated transfer of circular RNAs (circRNAs) is related to gastric cancer (GC) development. CircRNA NIMA-related kinase 9 (circNEK9; hsa_circ_0032683) was reported to be up-regulated in GC.

Aims

The biological role of circNEK9 and its underlying mechanisms in GC progression were explored.

Methods

The levels of RNAs and proteins were determined by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot assay. Cell proliferation was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, colony formation assay, and flow cytometry. Wound healing assay and transwell assays were conducted to analyze cell motility. Intermolecular interaction was verified by dual-luciferase reporter assay and RNA pull-down assay. Animal experiments were used to evaluate the role of circNEK9 in the growth of xenograft tumors in vivo.

Results

CircNEK9 was up-regulated in GC tissues and cell lines. CircNEK9 interference suppressed the proliferation and motility of GC cells. CircNEK9 silencing enhanced microRNA-409-3p (miR-409-3p) level through direct interaction. CircNEK9 silencing-mediated influences on the proliferation and metastasis of GC cells were partly overturned by the interference of miR-409-3p. MiR-409-3p directly interacted with microtubule-associated protein 7 (MAP7) messenger RNA (mRNA). MiR-409-3p-induced effects in GC cells were largely counteracted by the overexpression of MAP7. CircNEK9 silencing blocked GC tumor growth in vivo. Exosome-mediated transfer of circNEK9 promoted the motility of recipient GC cells.

Conclusions

CircNEK9 accelerated the proliferation, migration, and invasion of GC cells through targeting miR-409-3p/MAP7 axis. Plasma exosomal circNEK9 promoted the migration and invasion of recipient GC cells.

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References

  1. Olmi S, Giorgi R, Cioffi SPB, et al. Total and subtotal laparoscopic gastrectomy for the treatment of advanced gastric cancer: morbidity and oncological outcomes. J Laparoendosc Adv Surg Tech A. 2018;28:278–285. https://doi.org/10.1089/lap.2017.0372.

    Article  PubMed  Google Scholar 

  2. Yu L, Zhou GQ, Li DC. MiR-136 triggers apoptosis in human gastric cancer cells by targeting AEG-1 and BCL2. Eur Rev Med Pharmacol Sci. 2018;22:7251–7256. https://doi.org/10.26355/eurrev_201811_16259.

    Article  CAS  PubMed  Google Scholar 

  3. Ferlay J, Soerjomataram I, Dikshit R, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136:E359–E386. https://doi.org/10.1002/ijc.29210.

    Article  CAS  PubMed  Google Scholar 

  4. Memczak S, Jens M, Elefsinioti A, et al. Circular RNAs are a large class of animal RNAs with regulatory potency. Nature. 2013;495:333–338. https://doi.org/10.1038/nature11928.

    Article  CAS  PubMed  Google Scholar 

  5. Tang Q, Hann SS. Biological roles and mechanisms of circular RNA in human cancers. Onco Targets Ther. 2020;13:2067–2092. https://doi.org/10.2147/ott.s233672.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Li R, Jiang J, Shi H, et al. CircRNA: a rising star in gastric cancer. Cell Mol Life Sci. 2019;. https://doi.org/10.1007/s00018-019-03345-5.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Bao Q, Li F, Zheng H, et al. Prognostic role of dysregulated circRNAs in patients with non-small cell lung cancer: a meta-analysis. J Thorac Dis. 2020;12:823–829. https://doi.org/10.21037/jtd.2019.12.71.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Tran AM, Chalbatani GM, Berland L, et al. A new world of biomarkers and therapeutics for female reproductive system and breast cancers: circular RNAs. Front Cell Dev Biol. 2020;8:50. https://doi.org/10.3389/fcell.2020.00050.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Zhang Q, Miao Y, Fu Q, et al. CircRNACCDC66 regulates cisplatin resistance in gastric cancer via the miR-618/BCL2 axis. Biochem Biophys Res Commun. 2020;. https://doi.org/10.1016/j.bbrc.2020.03.156.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Sun H, Wang Q, Yuan G, et al. Hsa_circ_0001649 restrains gastric carcinoma growth and metastasis by downregulation of miR-20a. J Clin Lab Anal. 2020;. https://doi.org/10.1002/jcla.23235.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Lugea A, Waldron RT. Exosome-mediated intercellular communication between stellate cells and cancer cells in pancreatic ductal adenocarcinoma. Pancreas. 2017;46:1–4. https://doi.org/10.1097/mpa.0000000000000686.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Geng X, Lin X, Zhang Y, et al. Exosomal circular RNA sorting mechanisms and their function in promoting or inhibiting cancer. Oncol Lett. 2020;19:3369–3380. https://doi.org/10.3892/ol.2020.11449.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Sohel MMH. Circulating microRNAs as biomarkers in cancer diagnosis. Life Sci. 2020;248:117473. https://doi.org/10.1016/j.lfs.2020.117473.

    Article  CAS  PubMed  Google Scholar 

  14. Zhao W, Liu Y, Zhang C, et al. Multiple roles of exosomal long noncoding RNAs in cancers. Biomed Res Int. 2019;2019:1460572. https://doi.org/10.1155/2019/1460572.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Hwang HW, Mendell JT. MicroRNAs in cell proliferation, cell death, and tumorigenesis. Br J Cancer. 2006;94:776–780. https://doi.org/10.1038/sj.bjc.6603023.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Kloosterman WP, Plasterk RH. The diverse functions of microRNAs in animal development and disease. Dev Cell. 2006;11:441–450. https://doi.org/10.1016/j.devcel.2006.09.009.

    Article  CAS  PubMed  Google Scholar 

  17. Li C, Nie H, Wang M, et al. MicroRNA-409-3p regulates cell proliferation and apoptosis by targeting PHF10 in gastric cancer. Cancer Lett. 2012;320:189–197. https://doi.org/10.1016/j.canlet.2012.02.030.

    Article  CAS  PubMed  Google Scholar 

  18. Zheng B, Liang L, Huang S, et al. MicroRNA-409 suppresses tumour cell invasion and metastasis by directly targeting radixin in gastric cancers. Oncogene. 2012;31:4509–4516. https://doi.org/10.1038/onc.2011.581.

    Article  CAS  PubMed  Google Scholar 

  19. Zhang L, Liu X, Song L, et al. MAP7 promotes migration and invasion and progression of human cervical cancer through modulating the autophagy. Cancer Cell Int. 2020;20:17. https://doi.org/10.1186/s12935-020-1095-4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Wang Z, Ma K, Pitts S, et al. Novel circular RNA circNF1 acts as a molecular sponge, promoting gastric cancer by absorbing miR-16. Endocr Relat Cancer. 2019;26:265–277. https://doi.org/10.1530/erc-18-0478.

    Article  CAS  PubMed  Google Scholar 

  21. Zeng K, Chen X, Xu M, et al. CircHIPK3 promotes colorectal cancer growth and metastasis by sponging miR-7. Cell Death Dis. 2018;9:417. https://doi.org/10.1038/s41419-018-0454-8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Wang SH, Ma F, Tang ZH, et al. Long non-coding RNA H19 regulates FOXM1 expression by competitively binding endogenous miR-342-3p in gallbladder cancer. J Exp Clin Cancer Res. 2016;35:160. https://doi.org/10.1186/s13046-016-0436-6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Wang S, Zhang Y, Cai Q, et al. Circular RNA FOXP1 promotes tumor progression and Warburg effect in gallbladder cancer by regulating PKLR expression. Mol Cancer. 2019;18:145. https://doi.org/10.1186/s12943-019-1078-z.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Kang M, Ren M, Li Y, et al. Exosome-mediated transfer of lncRNA PART1 induces gefitinib resistance in esophageal squamous cell carcinoma via functioning as a competing endogenous RNA. J Exp Clin Cancer Res. 2018;37:171. https://doi.org/10.1186/s13046-018-0845-9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Liang H, Huang H, Li Y, et al. CircRNA_0058063 functions as a ceRNA in bladder cancer progression via targeting miR-486-3p/FOXP4 axis. Biosci Rep. 2020;. https://doi.org/10.1042/bsr20193484.

    Article  PubMed  PubMed Central  Google Scholar 

  26. He Y, Wang Y, Liu L, et al. Circular RNA circ_0006282 contributes to the progression of gastric cancer by sponging miR-155 to upregulate the expression of FBXO22. Onco Targets Ther. 2020;13:1001–1010. https://doi.org/10.2147/ott.s228216.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Feng J, Guo J, Wang JP, et al. MiR-129-5p inhibits proliferation of gastric cancer cells through targeted inhibition on HMGB1 expression. Eur Rev Med Pharmacol Sci. 2020;24:3665–3673. https://doi.org/10.26355/eurrev_202004_20829.

    Article  CAS  PubMed  Google Scholar 

  28. Ren R, Wu J, Zhou MY. MiR-135b-5p affected malignant behaviors of ovarian cancer cells by targeting KDM5B. Eur Rev Med Pharmacol Sci. 2020;24:3548–3554. https://doi.org/10.26355/eurrev_202004_20815.

    Article  CAS  PubMed  Google Scholar 

  29. Zhou LH, Yang YC, Zhang RY, et al. CircRNA_0023642 promotes migration and invasion of gastric cancer cells by regulating EMT. Eur Rev Med Pharmacol Sci. 2018;22:2297–2303. https://doi.org/10.26355/eurrev_201804_14818.

    Article  PubMed  Google Scholar 

  30. Lu J, Zhang PY, Li P, et al. Circular RNA hsa_circ_0001368 suppresses the progression of gastric cancer by regulating miR-6506-5p/FOXO3 axis. Biochem Biophys Res Commun. 2019;512:29–33. https://doi.org/10.1016/j.bbrc.2019.02.111.

    Article  CAS  PubMed  Google Scholar 

  31. Xia T, Pan Z, Zhang J. CircSMC3 regulates gastric cancer tumorigenesis by targeting miR-4720-3p/TJP1 axis. Cancer Med. 2020;. https://doi.org/10.1002/cam4.3057.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Wang J, Lv W, Lin Z, et al. Hsa_circ_0003159 inhibits gastric cancer progression by regulating miR-223-3p/NDRG1 axis. Cancer Cell Int. 2020;20:57. https://doi.org/10.1186/s12935-020-1119-0.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Tymanskyj SR, Yang B, Falnikar A, et al. MAP7 regulates axon collateral branch development in dorsal root ganglion neurons. J Neurosci. 2017;37:1648–1661. https://doi.org/10.1523/jneurosci.3260-16.2017.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Fu L, Fu H, Zhou L, et al. High expression of MAP7 predicts adverse prognosis in young patients with cytogenetically normal acute myeloid leukemia. Sci Rep. 2016;6:34546. https://doi.org/10.1038/srep34546.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Hou J, Jiang W, Zhu L, et al. Circular RNAs and exosomes in cancer: a mysterious connection. Clin Transl Oncol. 2018;20:1109–1116. https://doi.org/10.1007/s12094-018-1839-y.

    Article  CAS  PubMed  Google Scholar 

  36. Li Y, Zheng Q, Bao C, et al. Circular RNA is enriched and stable in exosomes: a promising biomarker for cancer diagnosis. Cell Res. 2015;25:981–984. https://doi.org/10.1038/cr.2015.82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Chen W, Quan Y, Fan S, et al. Exosome-transmitted circular RNA hsa_circ_0051443 suppresses hepatocellular carcinoma progression. Cancer Lett. 2020;475:119–128. https://doi.org/10.1016/j.canlet.2020.01.022.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Health Medicine, Second Medical Center of Chinese PLA General Hospital, No.28, Fuxing Road, Beijing, 100853, China

    Li Yu, Jie Xie, Yan Yu & Siping Wang

  2. Key Laboratory of Animal Ecology and Conservation Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China

    Xiaoming Liu

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Yu, L., Xie, J., Liu, X. et al. Plasma Exosomal CircNEK9 Accelerates the Progression of Gastric Cancer via miR-409-3p/MAP7 Axis. Dig Dis Sci 66, 4274–4289 (2021). https://doi.org/10.1007/s10620-020-06816-z

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