Matrix metalloproteinase-2 delivery to extracellular vesicles produced by HPV-positive cervical cancer cells enhances metastasis via the Akt pathway.

Here, we aimed to analyze the effects of matrix metalloproteinase-2 (MMP-2) delivery to extracellular vesicles (EVs) secreted by human papillomavirus (HPV)-associated cervical cancer cells on human umbilical vein endothelial cell (HUVEC) angiogenesis. First, MMP-2 expression was compared among SiHa (HPV16), HeLa (HPV18), and C-33A (negative) cells. Then, EVs were isolated from these cells, and MMP-2 expression in the EVs was compared. SiHa and HeLa cells were transfected with MMP-2 or control siRNA. HUVECs were treated with EVs isolating from transfected cells. Migration and angiogenesis of HUVECs were measured, and p-Akt protein expression in HUVECs was detected. An Akt inhibitor or activator was used to analyze the effect of MMP-2 delivery to EVs on the migration of HUVECs. The SiHa-induced xenograft tumors were treated with 2 µg of EVs every 3 d for a total of 27 d. Tumor growth, and the expression levels of p-Akt, MMP-2, and vascular endothelial growth factor (VEGF) were observed in the tumors. The results showed that MMP-2 expression was higher in SiHa- and HeLa-derived EVs than that in the C-33A-derived EVs. Interference with MMP-2 suppressed the invasion of SiHa and HeLa cells. The migration and angiogenesis of HUVECs were enhanced by MMP-2 delivery to EVs secreted by SiHa and HeLa cells through regulation of the Akt pathway. The growth of xenograft tumors was accelerated by EVs secreted by SiHa cell with differential MMP-2 expression. Our results indicate the delivered MMP-2 in EVs acts as a messenger between HPV-associated cancer cells and HUVECs.