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

Cancer Gene Therapy (2023)Cite this article

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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.

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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.

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.

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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).

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  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

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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.

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Correspondence to Chengfu Yuan.

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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 (2023). https://doi.org/10.1038/s41417-022-00581-z

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