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Follistatin-like 1 mitigates intermittent hypoxia-induced melanoma lung metastasis in mice

  • Basic Science • Original Article
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Abstract

Purpose

Intermittent hypoxia (IH) mimicking obstructive sleep apnea (OSA) has been confirmed to induce tumor lung metastasis via oxidative stress and inflammation responses. Follistatin-like 1 (Fstl1), as a matricellular protein, plays critical roles in inflammatory diseases and cancer. This study aimed to investigate the effect and mechanism of Fstl1 on OSA-IH-induced tumor lung metastasis.

Methods

Fstl1+/+ or Fstl1+/– mice inoculated with B16F10 melanoma cells were exposed to OSA-IH. The number and area of mouse lung metastatic colonies were assessed. Markers for tumor metastasis, oxidative stress, and inflammation in lung melanoma tissue or B16F10 melanoma cells were quantified by western blotting, qRT-PCR, and immunohistochemistry. The migration of B16F10 cells was examined by wound healing assay.

Results

Fstl1 levels are decreased in lung tissues from OSA-IH injured mice inoculated with melanoma cells. Fstl1-deficient mice were highly susceptible to the OSA-IH model of melanoma lung metastasis, as assessed by increased number and area of lung metastatic colonies, and by the elevated levels of HIF-1α, Vegf, N-cadherin, and E-cadherin. Lung melanoma tissue in Fstl1+/– mice provided evidence of increased oxidative stress, as determined by increased levels of NRF2 and P22phox and decreased level of Sod2, as well as increased inflammatory response, as determined by elevated levels of NF-κB P65, Tnf-α and Il-6. Conversely, stable overexpression of Fstl1 in B16F10 cells under OSA-IH exposure attenuated the migration of B16F10 cells and levels of tumor-related markers, as well as decreased oxidative stress and inflammatory responses.

Conclusion

These results suggest that Fstl1 may protect against OSA-IH-induced tumor lung metastasis through oxidative stress and inflammatory responses. Fstl1 may serve as a promising target for OSA-related cancer.

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Data availability

The software and all relevant raw data are freely available to scientists.

Code availability

Not applicable.

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Funding

This work was supported by the grants from the National Natural Science Foundation of China (Nos. 82070077, 81500070, 81970084, 82030001).

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Author notes

  1. Chao Qi and Jie Cao contributed equally to this work.

Authors and Affiliations

  1. State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin, 300071, China

    Chao Qi, Xingzu Liu, Wen Ning & Lian Li

  2. Department of Respiratory and Critical Care Medicine, Tianjin Medical University General Hospital, Tianjin, 300052, China

    Jie Cao, Qianqian Chen, Maoli Liang, Jing Feng & Baoyuan Chen

  3. Department of Radiation Oncology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China

    Zhongjie Chen

Authors
  1. Chao Qi
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  2. Jie Cao
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  5. Maoli Liang
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  9. Wen Ning
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  10. Lian Li
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Contributions

L.L. and W.N. conceived and designed research; C.Q. and X.-Z.L. performed experiments and analyzed the data; J.C., M.-L.L., and Q.-Q.C. analyzed the data; C.Q. and L.L. drafted manuscript; L.L., W.N., B.-Y.C. J.F, and Z.-J.C. edited and revised manuscript; C.Q., J.C., X.-Z.L., Q.-Q.C., M.-L.L., Z.-J.C., J.F, B.-Y.C., W.N., and L.L. approved final version of manuscript.

Corresponding authors

Correspondence to Wen Ning or Lian Li.

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All animal experimental protocols were approved by the Animal Care and Use Committee at Nankai University (Approval Number: 20140008) and were performed in accordance with the guidelines outlined by the committee.

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Qi, C., Cao, J., Liu, X. et al. Follistatin-like 1 mitigates intermittent hypoxia-induced melanoma lung metastasis in mice. Sleep Breath 27, 1165–1173 (2023). https://doi.org/10.1007/s11325-022-02680-5

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  • DOI: https://doi.org/10.1007/s11325-022-02680-5

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