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:

LncSNHG14 promotes nutlin3a resistance by inhibiting ferroptosis via the miR-206 /SLC7A11 axis in osteosarcoma cells

Cancer Gene Therapy volume 30, pages 704–715 (2023)Cite this article

Subjects

Abstract

The most prevalent form of primary osseous malignant tumor in adolescents and children is osteosarcoma (OS). A combination of surgery and neoadjuvant/post-surgery chemotherapy is currently the standard therapy. While the chemoresistance associated with OS generally leads to poor efficacy of therapeutic agents, the relevant molecular interaction is still elusive. Here, the lncRNA (long non-coding RNA) SNHG14 was found to be significantly upregulated in the nutlin3a-resistant OS cell line NR-SJSA1 and contributes to treatment resistance by suppressing ferroptosis. In NR-SJSA1 cells, knockdown of LncRNA SNHG14 resulted in a reversal of drug resistance and activation of ferroptosis, which disappeared when ferrostatin-1, a ferroptosis inhibitor, was added. Mechanistically, lncRNA SNHG14 targeted and down-regulated the expression of miR-206, further affecting the common ferroptosis inhibitor SLC7A11, and preventing NR-SJSA1 cells from undergoing ferroptosis. In conclusion, our findings highlight the involvement of lncRNA SNHG14 in ferroptosis and chemotherapy resistance of nutlin3a-resistant NR-SJSA1 cells, thus shedding new insight on how to overcome drug resistance in osteosarcoma cells and improve treatment efficacy.

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: LncRNA SNHG14 knockdown promotes the sensitivity of NR-SJSA1 cells to nutlin3a.
Fig. 2: LncRNA SNHG14 knockdown promotes ferroptosis in NR-SJSA1 cells.
Fig. 3: LncRNA SNHG14 knockdown enhances nutlin3a sensitivity of NR-SJSA1 cells by promoting ferroptosis.
Fig. 4: miR-206 is identified as a downstream target of lncRNA SNHG14.
Fig. 5: miR-206 induces ferroptosis in NR-SJSA1 cells.
Fig. 6: LncSNHG14 promotes nutlin3a resistance in NR-SJSA1 cells via inhibiting ferroptosis by targeting miR-206.
Fig. 7: SLC7A11 is identified as a downstream target of miR-206.
Fig. 8: miR-206 activates ferroptosis by downregulating SLC7A11.

Similar content being viewed by others

Data availability

The datasets generated during and/or analysed during the current study are not publicly available due [REASON WHY DATA ARE NOT PUBLIC] but are available from the corresponding author on reasonable request.

References

  1. Biermann JS, Adkins DR, Agulnik M, Benjamin RS, Brigman B, Butrynski JE, et al. Bone cancer. J Natl Compr Cancer Netw: JNCCN. 2013;11:688–723.

    Article  PubMed  Google Scholar 

  2. Biazzo A, De Paolis M. Multidisciplinary approach to osteosarcoma. Acta orthopaedica Belgica. 2016;82:690–8.

    CAS  PubMed  Google Scholar 

  3. I Lilienthal and N Herold, Targeting Molecular Mechanisms Underlying Treatment Efficacy and Resistance in Osteosarcoma: A Review of Current and Future Strategies, 2020;21.

  4. Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell. 2012;149:1060–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Mao C, Liu X. DHODH-mediated ferroptosis defence is a targetable vulnerability in cancer, 2021;593:586–90.

  6. Wang W, Green M, Choi JE, Gijón M, Kennedy PD, Johnson JK, et al. CD8(+) T cells regulate tumour ferroptosis during cancer immunotherapy. Nature. 2019;569:270–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Lang X, Green MD, Radiotherapy and Immunotherapy Promote Tumoral Lipid Oxidation and Ferroptosis via Synergistic Repression of SLC7A11. 2019;9:1673–85.

  8. JM Ubellacker, A Tasdogan, V Ramesh and B Shen, Lymph protects metastasizing melanoma cells from ferroptosis. 2020;585:113–8.

  9. Jiang L, Kon N, Li T, Wang SJ, Su T, Hibshoosh H, et al. Ferroptosis as a p53-mediated activity during tumour suppression. Nature. 2015;520:57–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Koppula P, Zhuang L, Gan B, Cystine transporter SLC7A11/xCT in cancer: ferroptosis, nutrient dependency, and cancer therapy, Protein & cell, 2020, https://doi.org/10.1007/s13238-020-00789-5.

  11. Drayton RM, Dudziec E, Peter S, Bertz S, Hartmann A, Bryant HE, et al. Reduced expression of miRNA-27a modulates cisplatin resistance in bladder cancer by targeting the cystine/glutamate exchanger SLC7A11. Clin Cancer Res. 2014;20:1990–2000.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Roh JL, Kim EH, Jang HJ, Park JY, Shin D. Induction of ferroptotic cell death for overcoming cisplatin resistance of head and neck cancer. Cancer Lett. 2016;381:96–103.

    Article  CAS  PubMed  Google Scholar 

  13. Wang Z, Ding Y, Wang X, Lu S, Wang C, He C, et al. Pseudolaric acid B triggers ferroptosis in glioma cells via activation of Nox4 and inhibition of xCT. Cancer Lett. 2018;428:21–33.

    Article  CAS  PubMed  Google Scholar 

  14. Wang KC, Chang HY. Molecular mechanisms of long noncoding RNAs. Mol cell. 2011;43:904–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Beermann J, Piccoli MT, Viereck J, Thum T. Non-coding RNAs in Development and Disease: Background, Mechanisms, and Therapeutic Approaches. Physiological Rev. 2016;96:1297–325.

    Article  CAS  Google Scholar 

  16. Fu D, Lu C, Qu X, Li P, Chen K, Shan L, et al. LncRNA TTN-AS1 regulates osteosarcoma cell apoptosis and drug resistance via the miR-134-5p/MBTD1 axis. Aging. 2019;11:8374–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Zhang CL, Zhu KP, Ma XL. Antisense lncRNA FOXC2-AS1 promotes doxorubicin resistance in osteosarcoma by increasing the expression of FOXC2. Cancer Lett. 2017;396:66–75.

    Article  CAS  PubMed  Google Scholar 

  18. Sun ZY, Jian YK, Zhu HY, Li B. lncRNAPVT1 targets miR-152 to enhance chemoresistance of osteosarcoma to gemcitabine through activating c-MET/PI3K/AKT pathway. Pathol, Res Pract. 2019;215:555–63.

    Article  CAS  PubMed  Google Scholar 

  19. Dong H, Wang W, Mo S, Liu Q, Chen X, Chen R, et al. Long non-coding RNA SNHG14 induces trastuzumab resistance of breast cancer via regulating PABPC1 expression through H3K27 acetylation. J Cell Mol Med. 2018;22:4935–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Han Y, Zhou S, Wang X, Mao E, Huang L. SNHG14 stimulates cell autophagy to facilitate cisplatin resistance of colorectal cancer by regulating miR-186/ATG14 axis. Biomedicine Pharmacother = Biomedecine pharmacotherapie. 2020;121:109580.

    Article  CAS  Google Scholar 

  21. Xu L, Xu Y, Yang M, Li, J, Xu F, Chen BL, LncRNA SNHG14 regulates the DDP-resistance of non-small cell lung cancer cell through miR-133a/HOXB13 pathway, 2020;20:266.

  22. Haronikova L, Bonczek O, Zatloukalova P, Kokas-Zavadil F, Kucerikova M, Coates PJ, et al. Resistance mechanisms to inhibitors of p53-MDM2 interactions in cancer therapy: can we overcome them? Cell Mol Biol Lett. 2021;26:53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Valente LJ, Aubrey BJ, Herold MJ, Kelly GL, Happo L, Scott CL, et al. Therapeutic Response to Non-genotoxic Activation of p53 by Nutlin3a Is Driven by PUMA-Mediated Apoptosis in Lymphoma Cells. Cell Rep. 2016;14:1858–66.

    Article  CAS  PubMed  Google Scholar 

  24. Yokota E, Iwai M, Yukawa T, Yoshida M, Naomoto Y, Haisa M, et al. Clinical application of a lung cancer organoid (tumoroid) culture system, 2021;5:29.

  25. Moran DM, Maki CG. Nutlin-3a induces cytoskeletal rearrangement and inhibits the migration and invasion capacity of p53 wild-type cancer cells. Mol cancer therapeutics. 2010;9:895–905.

    Article  CAS  Google Scholar 

  26. Bauleth-Ramos T, Feijão T, Gonçalves A, Shahbazi MA, Liu Z, Barrias C, et al. Colorectal cancer triple co-culture spheroid model to assess the biocompatibility and anticancer properties of polymeric nanoparticles. J Controlled Release. 2020;323:398–411.

    Article  CAS  Google Scholar 

  27. Karreth FA, Pandolfi PP. ceRNA cross-talk in cancer: when ce-bling rivalries go awry. Cancer Discov. 2013;3:1113–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Tay Y, Rinn J, Pandolfi PP. The multilayered complexity of ceRNA crosstalk and competition. Nature. 2014;505:344–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Chen Y, Zhang X, An Y, Liu B, Lu M. LncRNA HCP5 promotes cell proliferation and inhibits apoptosis via miR-27a-3p/IGF-1 axis in human granulosa-like tumor cell line KGN. Mol Cell Endocrinol. 2020;503:110697.

    Article  CAS  PubMed  Google Scholar 

  30. Hou XK, Mao JS. Long noncoding RNA SNHG14 promotes osteosarcoma progression via miR-433-3p/FBXO22 axis. Biochemical biophysical Res Commun. 2020;523:766–72.

    Article  CAS  Google Scholar 

  31. Wang M, Mao C, Ouyang L, Liu Y, Lai W, Liu N, et al. Long noncoding RNA LINC00336 inhibits ferroptosis in lung cancer by functioning as a competing endogenous. RNA. 2019;26:2329–43.

    CAS  Google Scholar 

  32. Ji N, Wang Y, Bao G, Yan J, Ji S. LncRNA SNHG14 promotes the progression of cervical cancer by regulating miR-206/YWHAZ. Pathol, Res Pract. 2019;215:668–75.

    Article  CAS  PubMed  Google Scholar 

  33. Wu K, Li J, Qi Y, Zhang C, Zhu D, Liu D, et al. SNHG14 confers gefitinib resistance in non-small cell lung cancer by up-regulating ABCB1 via sponging miR-206-3p. Biomedicine Pharmacother = Biomedecine pharmacotherapie. 2019;116:108995.

    Article  Google Scholar 

Download references

Acknowledgements

We thank Prof. T.C. He of University of Chicago for providing pSEH-Flag plasmid, pSEB-61 plasmid and pMOK1 plasmid. The work was supported by the grants from National Natural Science Foundation of China (Grant No. 81974528 to C.F. Yuan, No. 82174035 to C.F. Yuan, and No. 81773959 to C.F. Yuan), the innovational group project of Hubei Province Natural Science Foundation in China (Grant No. 2021CFA015 to C.F. Yuan), and the Central Funds Guiding the Local Science and Technology Development (Grant No. 2020ZYYD016 to C.F. Yuan).

Author information

Author notes

  1. These authors contributed equally: Luoying Li, Yifan Zhang.

Authors and Affiliations

  1. Third-grade Pharmacological Laboratory on Traditional Chinese Medicine, State Administration of Traditional Chinese Medicine, China Three Gorges University, Yichang, China

    Luoying Li, Yifan Zhang, Yan Gao, Yaqi Hu, Rui Wang, Shuwen Wang, Yuanyang Li, Yumin He & Chengfu Yuan

  2. Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, China Three Gorges University, Yichang, 443002, China

    Luoying Li, Yifan Zhang, Yan Gao, Yaqi Hu, Rui Wang, Shuwen Wang, Yuanyang Li & Chengfu Yuan

  3. College of Basic Medical Science, China Three Gorges University, Yichang, 443002, China

    Luoying Li, Yifan Zhang, Yan Gao, Yaqi Hu, Rui Wang, Shuwen Wang, Yuanyang Li, Yumin He & Chengfu Yuan

Authors
  1. Luoying Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yifan Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yan Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yaqi Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Rui Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Shuwen Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yuanyang Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yumin He
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Chengfu Yuan
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

CY and LL designed research; LL and YZ performed research; LL, YZ, SW, YH, and YL analyzed and interpreted the data; and LL and YZ wrote and edited manuscript. CY acquired of the financial support for the project leading to this publication. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Chengfu Yuan.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

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

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, L., Zhang, Y., Gao, Y. et al. LncSNHG14 promotes nutlin3a resistance by inhibiting ferroptosis via the miR-206 /SLC7A11 axis in osteosarcoma cells. Cancer Gene Ther 30, 704–715 (2023). https://doi.org/10.1038/s41417-022-00581-z

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41417-022-00581-z

This article is cited by

Search

Advanced search

Quick links