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 P22^phox 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.

中文翻译：

---

Follistatin-like 1 减轻小鼠间歇性缺氧诱导的黑色素瘤肺转移

目的

模拟阻塞性睡眠呼吸暂停 (OSA) 的间歇性缺氧 (IH) 已被证实可通过氧化应激和炎症反应诱导肿瘤肺转移。Follistatin-like 1 (Fstl1) 作为一种基质细胞蛋白，在炎症性疾病和癌症中起着关键作用。本研究旨在探讨Fstl1对OSA-IH诱导的肿瘤肺转移的影响及机制。

方法

接种 B16F10 黑色素瘤细胞的Fstl1 ^{+ / +}或Fstl1 ^{+ / –}小鼠暴露于 OSA-IH。评估了小鼠肺转移集落的数量和面积。通过蛋白质印迹、qRT-PCR 和免疫组织化学对肺黑色素瘤组织或 B16F10 黑色素瘤细胞中肿瘤转移、氧化应激和炎症的标志物进行定量。通过伤口愈合试验检查 B16F10 细胞的迁移。

结果

接种黑色素瘤细胞的 OSA-IH 损伤小鼠的肺组织中 Fstl1 水平降低。Fstl1缺陷小鼠对黑色素瘤肺转移的 OSA-IH 模型高度敏感，这是通过肺转移集落的数量和面积增加以及 HIF-1α、Vegf、N-钙粘蛋白和 E-钙粘蛋白水平升高来评估的. Fstl1 ^{+ / –}小鼠的肺黑色素瘤组织提供了氧化应激增加的证据，这由 NRF2 和P22 ^phox水平升高和Sod2水平降低所确定，以及炎症反应增加，由 NF-κB P65 水平升高所确定，肿瘤坏死因子-α和IL-6。相反，在 OSA-IH 暴露下， Fstl1在 B16F10 细胞中的稳定过表达减弱了 B16F10 细胞的迁移和肿瘤相关标志物的水平，并降低了氧化应激和炎症反应。

结论

这些结果表明 Fstl1 可能通过氧化应激和炎症反应来防止 OSA-IH 诱导的肿瘤肺转移。Fstl1 可作为 OSA 相关癌症的有希望的靶点。