A positive feedback loop between miR-574-3p and HIF-1α in promoting angiogenesis under hypoxia

In our previous report, we presented evidence supporting the role of miR-574-3p in downregulating the expression of cullin 2 (CUL2) in gastric cancer (GC) cells. Expanding on those findings, the present study aims to confirm the direct interaction between miR-574-3p and the 3' untranslated region (3'UTR) of CUL2, which leads to the suppression of CUL2 expression and destabilization of the VCBCR complex. Based on these discoveries, we propose a novel pathway involving miR-574-3p, HIF-1α, and VEGF that contributes to angiogenesis. Through a series of meticulous experiments, we successfully validate this hypothesis. Specifically, our observations indicate that overexpression of miR-574-3p in GC cells induces an upregulation of HIF-1α and VEGF, resulting in enhanced proliferation, migration, invasion, and tube formation of HUVEC cells. Furthermore, employing a mouse model, we demonstrate that miR-574-3p facilitates the recruitment of endothelial cells towards matrigel xenografts. Additionally, we note a parallel increase in miR-574-3p and HIF-1α levels across multiple cell lines (including AGS, SGC-7901, Hela, and 293T cells) subjected to hypoxic conditions (2 % O2 or CoCl2 treatment), as well as in the myocardial muscles of sodium nitrite-induced hypoxic mice. Further investigations reveal that HIF-1α upregulates miR-574-3p expression by directly binding to the miR-574 promoter. Collectively, these findings strongly support the existence of a positive feedback loop between miR-574-3p and HIF-1α, which facilitates angiogenesis under hypoxic conditions.