关键词: 高级别浆液性卵巢癌, 基质金属蛋白酶2, 奥拉帕尼, 药物敏感性, 血管内皮生长因子/磷脂酰肌醇3-激酶/蛋白激酶B通路

Abstract: Objective To investigate the effect of matrix metalloproteinase 2(MMP2)on the sensitivity of poly-ADP ribose polymerase inhibitor(PARPi)in high-grade serous ovarian cancer(HGSOC)cells and the underlying mechanism.Methods The HGSOC cell line HeyA8 cells were divided into 3 groups:control group,sh-NC group,sh-MMP2 group.RT-qPCR and Western blotting were used to detect the expression of MMP2.CCK-8 method was used to detect the cell survival rate under different concentrations of Olaparib.Then HeyA8 cells were divided into 4 groups:sh-NC group,sh-MMP2 group,sh-NC+PARPi group,sh-MMP2+PARPi group.Wound-healing assay,Annexin V-FITC/PI method and Hochest 33258 staining were used to detect cell migration and apoptosis,respectively.Western blotting was used to determine the expression levels of proteins related to the vascular endothelial growth factor(VEGF)/phosphatidylinositol 3-kinase(PI3K)/protein kinase B(Akt).Results Compared with those in the control group and the sh-NC group,the relative expression levels of MMP2 mRNA and protein of HeyA8 cells in the sh-MMP2 group were downregulated,and the cell survival rate after Olaparib treatment was reduced(P<0.05).Compared with those in the sh-NC group,the wound-healing rate of HeyA8 cells in the sh-MMP2 group was decreased,the apoptosis rate was increased,nuclear condensation and fragmentation of apoptotic cells were observed,the relative protein expression levels of vascular endothelial growth factor A(VEGFA),vascular endothelial growth factor receptor 2(VEGFR-2),phosphorylated PI3K(Tyr458)[p-PI3K(Tyr458)]and phosphorylated Akt(Ser473)[p-Akt(Ser473)]were all downregulated(P<0.05).Compared with those in the sh-NC+PARPi group,the wound-healing rate of HeyA8 cells in the sh-MMP2+PARPi group was decreased,the apoptosis rate was increased,more apoptotic cells with nuclear condensation and fragmentation were observed,the relative protein expression levels of VEGFA,VEGFR2,p-PI3K(Tyr458)and p-Akt(Ser473)were downregulated(P<0.05).Conclusion Silencing MMP2 expression can promote PARPi-induced apoptosis in HGSOC cells,and increase PARPi sensitivity.

Key words: high-grade serous ovarian cancer, matrix metalloproteinase 2, olaparib, drug sensitivity, vascular endothelial growth factor/phosphatidylinositol 3-kinase/protein kinase B pathway