MicroRNA‑203a‑3p improves bleomycin and pingyangmycin sensitivity by inactivating the PI3K/AKT pathway in hemangioma

Abstract

MicroRNAs (miRs) have been found to play a fundamental role in the pathology and progression of hemangioma. Of note, miR-203a-3p prevents hemangioma progression via inactivation of the PI3K/AKT pathway. Bleomycin and pingyangmycin are drugs used in sclerotherapy, but certain hemangioma patients experience drug resistance, leading to poor clinical outcomes. The present study aimed to explore the impact of miR-203a-3p on bleomycin and pingyangmycin sensitivity in hemangioma, as well as the involvement of the PI3K/AKT pathway. miR-203a-3p or negative control mimics were transfected into human hemangioma endothelial cells, which were treated with 0-20 µM bleomycin or pingyangmycin. Subsequently, 740 Y-P, a PI3K/AKT pathway agonist, was added. Cell viability, rate of apoptosis and the expression levels of proteins involved in the PI3K/AKT pathway, including phosphorylated (p)-PI3K, PI3K, p-AKT and AKT, were detected. miR-203a-3p overexpression significantly decreased the half-maximal inhibitory concentration (IC₅₀) values of bleomycin (5.84±0.87 vs. 14.23±2.17 µM; P<0.01) and pingyangmycin (5.13±0.55 vs. 12.04±1.86 µM; P<0.01), compared with untreated cells. In addition, under bleomycin or pingyangmycin treatment, miR-203a-3p overexpression significantly reduced the proportion of EdU positive cells (both P<0.05) and B-cell leukemia/lymphoma-2 (BCL2) protein expression levels (both P<0.05), whilst increasing cell apoptosis rate (both P<0.05) and cleaved caspase 3 protein expression levels (both P<0.05) compared with untreated controls. Furthermore, miR-203a-3p overexpression significantly inhibited the phosphorylation of PI3K and AKT (both P<0.05), an effect that was significantly diminished by 740 Y-P treatment (both P<0.01). In addition, 740 Y-P significantly increased IC₅₀ values of bleomycin (P<0.01) and pingyangmycin (P<0.001) and also significantly increased the proportion of EdU-positive cells and BCL2 protein expression levels, while decreasing the apoptosis rate and cleaved caspase 3 protein expression levels in cells treated with bleomycin or pingyangmycin (all P<0.05). Of note, 740 Y-P weakened the effect of miR-203a-3p overexpression on the aforementioned cellular characteristics. The present study demonstrated that miR-203a-3p improved the sensitivity of cells to bleomycin and pingyangmycin treatment by inhibiting PI3K/AKT signaling in hemangioma.

Keywords: PI3K/AKT pathway; bleomycin; hemangioma; microRNA-203a-3p; pingyangmycin.