Angelol-A exerts anti-metastatic and anti-angiogenic effects on human cervical carcinoma cells by modulating the phosphorylated-ERK/miR-29a-3p that targets the MMP2/VEGFA axis

Abstract

AimsAngelol-A (Ang-A), a kind of coumarins, is isolated from the roots of Angelica pubescens f. biserrata. However, AA exerts antitumor effects and molecular mechanism on cervical cancer cells is unknown. Main methodsCell viability was determined using the MTT assay, and the cell cycle phase was assessed by PI staining with flow cytometry. Ang-A-treated cells with/without Antago-miR-29a-3p (miR-29a-3p inhibitor) or U0126 (MEK inhibitor) were assessed for the expression of miR-29a-3p, in vitro migration/invasion, and angiogenesis using qRT-PCR, a chemotaxis assay, and tube formation assay, respectively. The expression of mitogen-activated protein kinases/MMP2/MMP9/VEGFA was determined by western blot analysis with applicable antibodies. Key findingsAng-A significantly inhibited MMP2 and VEGFA expression, cell migration, and invasive motility in human cervical cancer cells. Conditioned medium inhibited tube formation in HUVECs. Ang-A principally inhibited invasive motility and angiogenesis by upregulating the expression of miR-29a-3p that targets the VEGFA-3′ UTR. The role of miR-29a-3p was confirmed using Antago-miR-29a-3p, which reversed the Ang-A-inhibited expression of MMP2 and VEGFA, invasive motility, and angiogenesis in human cervical cancer cells. The ERK pathway was implicated in mediating the metastatic and angiogenic action of Ang-A. Combined treatment with Ang-A treated and U0126 exerted a synergistic inhibitory effect on the expression of MMP2 and VEGFA and the metastatic and angiogenic properties of human cervical cancer cells. SignificanceThese findings are the first to indicate that in human cervical cancer cells, Ang-A exerts anti-metastatic and anti-angiogenic effects via targeting the miR-29a-3p/MMP2/VEGFA axis, mediated through the ERK pathway.