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

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.