A dual role for miR-210-3p in hypoxia-driven signaling and mitotic regulation in cancer.

miR-210-3p is a well-established hypoxia-induced microRNA that is commonly upregulated in a wide range of solid tumors, traditionally linked to mitochondrial repression and hypoxia-inducible factor (HIF) signaling. However, its functional role in cancer remains complex and highly context dependent. Here we perform a comprehensive pan-cancer transcriptomic analysis together with functional assays, revealing that miR-210-3p not only mediates classical hypoxic responses but also amplifies mitotic gene expression through activation of FOXM1. Mechanistically, this effect is shown to be dependent on HIF1α but not on HIF2α and, importantly, it has not been recapitulated by hypoxia alone. Notably, activation of the mitotic program is observed in breast cancer cells but not in head and neck squamous carcinoma models, highlighting a strong degree of context dependency across tumor types. In breast cancer cells, miR-210-3p overexpression enhances FOXM1 phosphorylation, upregulates kinetochore regulators, and induces mitotic defects, correlating with poor prognosis in aggressive tumors. Together, these findings position miR-210-3p as a molecular integrator linking pseudohypoxia to mitotic dysregulation, contributing to tumor aggressiveness by sustaining HIF activity and promoting mitotic stress. This dual functionality reconciles its paradoxical effects on proliferation and highlights its potential as a therapeutic target in cancers characterized by pseudohypoxia and mitotic abnormalities.