State Key Laboratory of Bioreactor Engineering & Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, PR China.
State Key Laboratory of Bioreactor Engineering & Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, PR China.
Eur J Pharmacol. 2021 May 5;898:173994. doi: 10.1016/j.ejphar.2021.173994. Epub 2021 Mar 3.
Disintegrin and metalloproteinase 28 (ADAM28) is a member of the disintegrin and metalloprotease domain (ADAM) family. It is associated with the growth and metastasis of various malignancies in vivo, but its role in gastric cancer remains unclear. The purpose of this study was to investigate the effect of ADAM28 derived from gastric cancer and endothelium on gastric cancer cells and its related mechanisms. In this study, Western blot analysis and q-PCR results showed that ADAM28 was up-regulated in gastric cancer cell lines. The TCGA database showed that patients with high ADAM28 expression had significantly shorter overall survival than those with low ADAM28 expression. By MTT analysis, wound healing assay, and flow cytometry, we found that overexpression/knockdown of ADAM28 expression in gastric cancer cells can regulate cell proliferation, apoptosis and migration in vitro. In addition, overexpression/knockdown of ADAM28 in human umbilical vein endothelial cells (HUVECs) in the upper ventricle can regulate the apoptosis of lower ventricular gastric cancer cells in the co-culture system. Furthermore, ELISA demonstrated that knockdown of ADAM28 from endothelial cells increased the expression of von Willebrand Factor (vWF) in the supernatant. We found that ADAM28 both from gastric cancer cells and HUVECs eliminated vWF-induced apoptosis of gastric cancer cells by cleaving vWF, and the addition of the vWF knockdown plasmid eliminated the increase of integrin β3, p-TP53 and c-Casp3 caused by ADAM28 knockdown. In conclusion, ADAM28 from endothelium and gastric cancer may cleave vWF to eliminate vWF-induced apoptosis of gastric cancer cells and play an pro-metastasis effect.
解整合素金属蛋白酶 28（ADAM28）是解整合素金属蛋白酶结构域（ADAM）家族的成员。它与体内各种恶性肿瘤的生长和转移有关，但在胃癌中的作用尚不清楚。本研究旨在探讨源自胃癌和内皮细胞的 ADAM28 对胃癌细胞的影响及其相关机制。在这项研究中，Western blot 分析和 q-PCR 结果表明 ADAM28 在胃癌细胞系中上调。TCGA 数据库显示，ADAM28 高表达的患者总生存期明显短于 ADAM28 低表达的患者。通过 MTT 分析、划痕愈合实验和流式细胞术，我们发现过表达/敲低胃癌细胞中的 ADAM28 表达可调节细胞增殖、凋亡和迁移。此外，在共培养系统中，过表达/敲低人脐静脉内皮细胞（HUVEC）中的 ADAM28 可调节下室胃癌细胞的凋亡。此外，ELISA 表明，内皮细胞中 ADAM28 的敲低增加了上清液中血管性血友病因子（vWF）的表达。我们发现来自胃癌细胞和 HUVEC 的 ADAM28 通过切割 vWF 消除了 vWF 诱导的胃癌细胞凋亡，并且添加 vWF 敲低质粒消除了 ADAM28 敲低引起的整合素 β3、p-TP53 和 c-Casp3 的增加。总之，来自内皮细胞和胃癌的 ADAM28 可能会切割 vWF，以消除 vWF 诱导的胃癌细胞凋亡，并发挥促转移作用。
