Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Hsa_circ_0000285 functions as a competitive endogenous RNA to promote osteosarcoma progression by sponging hsa-miRNA-599

Gene Therapy volume 27, pages 186–195 (2020)Cite this article

Subjects

Abstract

Circular RNA (circRNA) is important in the pathogenesis of many diseases. By analyzing the GSE96964 microarray, hsa_circ_0000285 (circ-0000285) was found to be highly expressed in osteosarcoma. Recent studies have shown that circ-0000285 is capable of regulating proliferative and migratory potentials. Here, we investigated the potential functions in regulating osteosarcoma cells to proliferate and migrate. First of all, qRT-PCR data revealed a higher level of circ-0000285 in osteosarcoma cell lines relative to normal osteoblasts. Through dual-luciferase reporter gene assay and RIP assay, we confirmed that both circ-0000285 and TGFB2 could directly bind to miRNA-599. Regulatory effects of circ-0000285 and miRNA-599 on proliferative and migratory potentials were evaluated by EdU assay and transwell migration assay. It is indicated that circ-0000285 overexpression enhanced the proliferative and migratory potentials of osteosarcoma, which could be reversed by miRNA-599 overexpression. This study revealed a vital role of circ-0000285/miRNA-599/TGFB2 axis in regulating the progression of osteosarcoma, providing a novel perspective for clarifying its pathogenesis.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Data availability

The datasets used in this study are available from the corresponding author on reasonable request.

References

  1. Zhou W, Hao M, Du X, Chen K, Wang G, Yang J. Advances in targeted therapy for osteosarcoma. Discov Med. 2014;17:301–7.

    PubMed  Google Scholar 

  2. Zhang Y, Lun L, Zhu B, Wang Q, Ding C, Hu Y, et al. Diagnostic accuracy of CD44V6 for osteosarcoma: a meta-analysis. J Orthop Surg Res. 2016;11:133.

    Article  Google Scholar 

  3. Moore DD, Luu HH. Osteosarcoma. Cancer Treat Res. 2014;162:65–92.

    Article  Google Scholar 

  4. Brown HK, Tellez-Gabriel M, Heymann D. Cancer stem cells in osteosarcoma. Cancer Lett. 2017;386:189–95.

    Article  CAS  Google Scholar 

  5. Ottaviani G, Jaffe N. The epidemiology of osteosarcoma. Cancer Treat Res. 2009;152:3–13.

    Article  Google Scholar 

  6. Bielack SS, Kempf-Bielack B, Delling G, Exner GU, Flege S, Helmke K, et al. Prognostic factors in high-grade osteosarcoma of the extremities or trunk: an analysis of 1702 patients treated on neoadjuvant cooperative osteosarcoma study group protocols. J Clin Oncol. 2002;20:776–90.

    Article  Google Scholar 

  7. Meng S, Zhou H, Feng Z, Xu Z, Tang Y, Li P, et al. CircRNA: functions and properties of a novel potential biomarker for cancer. Mol Cancer. 2017;16:94.

    Article  Google Scholar 

  8. Su H, Lin F, Deng X, Shen L, Fang Y, Fei Z, et al. Profiling and bioinformatics analyses reveal differential circular RNA expression in radioresistant esophageal cancer cells. J Transl Med. 2016;14:225.

    Article  Google Scholar 

  9. Chen L, Zhang S, Wu J, Cui J, Zhong L, Zeng L, et al. circRNA_100290 plays a role in oral cancer by functioning as a sponge of the miR-29 family. Oncogene. 2017;36:4551–61.

    Article  CAS  Google Scholar 

  10. Tan WL, Lim BT, Anene-Nzelu CG, Ackers-Johnson M, Dashi A, See K, et al. A landscape of circular RNA expression in the human heart. Cardiovasc Res. 2017;113:298–309.

    CAS  PubMed  Google Scholar 

  11. Zou M, Huang C, Li X, He X, Chen Y, Liao W, et al. Circular RNA expression profile and potential function of hsa_circRNA_101238 in human thoracic aortic dissection. Oncotarget. 2017;8:81825–37.

    Article  Google Scholar 

  12. Zhao Y, Alexandrov PN, Jaber V, Lukiw WJ. Deficiency in the ubiquitin conjugating enzyme UBE2A in Alzheimer’s disease (AD) is linked to deficits in a natural circular miRNA-7 sponge (circRNA; ciRS-7). Genes. 2016;7:116.

    Article  Google Scholar 

  13. Li LJ, Zhao W, Tao SS, Leng RX, Fan YG, Pan HF, et al. Competitive endogenous RNA network: potential implication for systemic lupus erythematosus. Expert Opin Ther Targets. 2017;21:639–48.

    Article  CAS  Google Scholar 

  14. Zhou B, Yu JW. A novel identified circular RNA, circRNA_010567, promotes myocardial fibrosis via suppressing miR-141 by targeting TGF-beta1. Biochem Biophys Res Commun. 2017;487:769–75.

    Article  CAS  Google Scholar 

  15. Xiao-Long M, Kun-Peng Z, Chun-Lin Z. Circular RNA circ_HIPK3 is down-regulated and suppresses cell proliferation, migration and invasion in osteosarcoma. J Cancer. 2018;9:1856–62.

    Article  Google Scholar 

  16. Li Y, Zheng F, Xiao X, Xie F, Tao D, Huang C, et al. CircHIPK3 sponges miR-558 to suppress heparanase expression in bladder cancer cells. EMBO Rep. 2017;18:1646–59.

    Article  CAS  Google Scholar 

  17. Shan K, Liu C, Liu BH, Chen X, Dong R, Liu X, et al. Circular Noncoding RNA HIPK3 Mediates Retinal Vascular Dysfunction in Diabetes Mellitus. Circulation. 2017;136:1629–42.

    Article  CAS  Google Scholar 

  18. Liu H, Bi J, Dong W, Yang M, Shi J, Jiang N, et al. Invasion-related circular RNA circFNDC3B inhibits bladder cancer progression through the miR-1178-3p/G3BP2/SRC/FAK axis. Mol Cancer. 2018;17:161.

    Article  CAS  Google Scholar 

  19. Wang C, Tan S, Liu WR, Lei Q, Qiao W, Wu Y, et al. RNA-Seq profiling of circular RNA in human lung adenocarcinoma and squamous cell carcinoma. Mol Cancer. 2019;18:134.

    Article  Google Scholar 

  20. Zheng S, Qian Z, Jiang F, Ge D, Tang J, Chen H, et al. CircRNA LRP6 promotes the development of osteosarcoma via negatively regulating KLF2 and APC levels. Am J Transl Res. 2019;11:4126–38.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Li S, Pei Y, Wang W, Liu F, Zheng K, Zhang X. Circular RNA 0001785 regulates the pathogenesis of osteosarcoma as a ceRNA by sponging miR-1200 to upregulate HOXB2. Cell Cycle. 2019;18:1281–91.

    Article  CAS  Google Scholar 

  22. Jin J, Chen A, Qiu W, Chen Y, Li Q, Zhou X, et al. Dysregulated circRNA_100876 suppresses proliferation of osteosarcoma cancer cells by targeting microRNA-136. J Cell Biochem. 2019;120:15678–87.

    Article  CAS  Google Scholar 

  23. Xu M, Jin H, Xu CX, Sun B, Mao Z, Bi WZ, et al. miR-382 inhibits tumor growth and enhance chemosensitivity in osteosarcoma. Oncotarget. 2014;5:9472–83.

    Article  Google Scholar 

  24. Bossi L, Figueroa-Bossi N. Competing endogenous RNAs: a target-centric view of small RNA regulation in bacteria. Nat Rev Microbiol. 2016;14:775–84.

    Article  CAS  Google Scholar 

  25. Abdollahzadeh R, Daraei A, Mansoori Y, Sepahvand M, Amoli MM, Tavakkoly-Bazzaz J. Competing endogenous RNA (ceRNA) cross talk and language in ceRNA regulatory networks: a new look at hallmarks of breast cancer. J Cell Physiol. 2019;234:10080–100.

    Article  CAS  Google Scholar 

  26. Zhu Y, Bian Y, Zhang Q, Hu J, Li L, Yang M, et al. Construction and analysis of dysregulated lncRNA-associated ceRNA network in colorectal cancer. J Cell Biochem. 2019;9250–63.

    Article  Google Scholar 

  27. Zhang Y, Ke X, Liu J, Ma X, Liu Y, Liang D, et al. Characterization of circRNAassociated ceRNA networks in patients with nonvalvular persistent atrial fibrillation. Mol Med Rep. 2019;19:638–50.

    CAS  PubMed  Google Scholar 

  28. Wang WL, Yang Z, Zhang YJ, Lu P, Ni YK, Sun CF, et al. Competing endogenous RNA analysis reveals the regulatory potency of circRNA_036186 in HNSCC. Int J Oncol. 2018;53:1529–43.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Wang Y, Sui Y, Zhu Q, Sui X. Hsa-miR-599 suppresses the migration and invasion by targeting BRD4 in breast cancer. Oncol Lett. 2017;14:3455–62.

    Article  Google Scholar 

  30. Zhang T, Ma G, Zhang Y, Huo H, Zhao Y. miR-599 inhibits proliferation and invasion of glioma by targeting periostin. Biotechnol Lett. 2017;39:1325–33.

    Article  CAS  Google Scholar 

  31. Hernandez H, Medina-Ortiz WE, Luan T, Clark AF, McDowell CM. Crosstalk between transforming growth factor Beta-2 and toll-like receptor 4 in the trabecular meshwork. Invest Ophthalmol Vis Sci. 2017;58:1811–23.

    Article  CAS  Google Scholar 

  32. Poniatowski LA, Wojdasiewicz P, Gasik R, Szukiewicz D. Transforming growth factor Beta family: insight into the role of growth factors in regulation of fracture healing biology and potential clinical applications. Mediators Inflamm. 2015;2015:137823.

    Article  Google Scholar 

  33. Bi JG, Zheng JF, Li Q, Bao SY, Yu XF, Xu P, et al. MicroRNA-181a-5p suppresses cell proliferation by targeting Egr1 and inhibiting Egr1/TGF-beta/Smad pathway in hepatocellular carcinoma. Int J Biochem Cell Biol. 2019;106:107–16.

    Article  CAS  Google Scholar 

  34. Tao S, Liu M, Shen D, Zhang W, Wang T, Bai Y. TGF-beta/Smads signaling affects radiation response and prolongs survival by regulating DNA repair genes in malignant glioma. DNA Cell Biol. 2018;37:909–16.

    Article  CAS  Google Scholar 

  35. Li J, Wang W, Chen S, Cai J, Ban Y, Peng Q, et al. FOXA1 reprograms the TGF-beta-stimulated transcriptional program from a metastasis promoter to a tumor suppressor in nasopharyngeal carcinoma. Cancer Lett. 2019;442:1–14.

    Article  CAS  Google Scholar 

  36. Xie B, Zhang C, Kang K, Jiang S. miR-599 inhibits vascular smooth muscle cells proliferation and migration by targeting TGFB2. PLoS ONE. 2015;10:e0141512.

    Article  Google Scholar 

  37. Lu R, Ji Z, Li X, Qin J, Cui G, Chen J, et al. Tumor suppressive microRNA-200a inhibits renal cell carcinoma development by directly targeting TGFB2. Tumour Biol. 2015;36:6691–700.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China

    Zhicai Zhang, Feifei Pu, Baichuan Wang, Qiang Wu, Jianxiang Liu & Zengwu Shao

Authors
  1. Zhicai Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Feifei Pu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Baichuan Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Qiang Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jianxiang Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Zengwu Shao
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

JL and ZS designed and supervised the study; ZZ and FP performed the experiments; BW and QW collected and analyzed the data; BW supported administration, technique and materials; ZZ prepared the manuscript; JL and ZS revised the manuscript; All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Jianxiang Liu or Zengwu Shao.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhang, Z., Pu, F., Wang, B. et al. Hsa_circ_0000285 functions as a competitive endogenous RNA to promote osteosarcoma progression by sponging hsa-miRNA-599. Gene Ther 27, 186–195 (2020). https://doi.org/10.1038/s41434-019-0112-5

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41434-019-0112-5

This article is cited by

Search

Advanced search

Quick links