Hypoxia-inducible factor 1 mediates intermittent hypoxia-induced migration of human breast cancer MDA-MB-231 cells

Metastasis is the major cause of triple-negative breast cancer (TNBC)-associated mortality. Hypoxia promotes cancer cell migration and remote metastasis, which occur with hypoxia inducible factor 1 alpha (HIF-1 alpha) stabilization and vimentin upregulation. However, the evolutionary dynamics that link the changes in HIF-1 alpha and vimentin levels under hypoxic conditions are not well understood. In the present study, the effects of intermittent hypoxia (IH), continuous hypoxia (CH) and normoxia on the migration and proliferation of human TNBC MDA-MB-231 cells were investigated. The results demonstrated that IH significantly increased the migration of MDA-MB-231 cells, and this effect was dependent on the number of cycles of hypoxia-reoxygenation. Unexpectedly, IH significantly inhibited cell proliferation, while CH only caused such an effect if hypoxia extended for >= 3 days. IH and CH induced HIF-1 alpha protein accumulation and vimentin upregulation, with a greater effect observed in IH. Knockdown of HIF-1 alpha with siRNA abolished IH-induced cell migration and vimentin upregulation. In summary, multiple cycles of hypoxia and reoxygenation have a more pronounced effect on the promotion of TNBC invasiveness than CH; HIF-1 alpha activation and downstream vimentin upregulation may account for this phenotypic change.