Department of Gynecology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, China.
Department of Radiotherapy, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, China.
Cell Biol Int. 2023 Sep;47(9):1558-1572. doi: 10.1002/cbin.12054. Epub 2023 Jun 5.
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.
在这里，我们旨在分析将基质金属蛋白酶 2 (MMP-2) 递送至人乳头瘤病毒 (HPV) 相关宫颈癌细胞分泌的细胞外囊泡 (EVs) 对人脐静脉内皮细胞 (HUVEC) 血管生成的影响。首先，比较了 SiHa (HPV16)、HeLa (HPV18) 和 C-33A(阴性) 细胞中 MMP-2 的表达。然后，从这些细胞中分离 EVs，并比较 EVs 中的 MMP-2 表达。用 MMP-2 或对照 siRNA 转染 SiHa 和 HeLa 细胞。用转染细胞分离的 EVs 处理 HUVECs。测量 HUVECs 的迁移和血管生成，并检测 HUVECs 中 p-Akt 蛋白的表达。使用 Akt 抑制剂或激活剂分析 MMP-2 递送至 EVs 对 HUVECs 迁移的影响。用 2 µg 的 EVs 处理 SiHa 诱导的异种移植瘤，每 3 天一次，共 27 天。观察肿瘤生长以及肿瘤中 p-Akt、MMP-2 和血管内皮生长因子 (VEGF) 的表达水平。结果表明，SiHa 和 HeLa 衍生的 EVs 中的 MMP-2 表达高于 C-33A 衍生的 EVs。干扰 MMP-2 抑制了 SiHa 和 HeLa 细胞的侵袭。通过调节 Akt 途径，SiHa 和 HeLa 细胞分泌的 EVs 中 MMP-2 的递送至增强了 HUVECs 的迁移和血管生成。具有差异 MMP-2 表达的 SiHa 细胞分泌的 EVs 加速了异种移植瘤的生长。我们的结果表明，EVs 中递送至的 MMP-2 充当 HPV 相关癌细胞与 HUVEC 之间的信使。
