Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China.
Endoscopy Center, Department of Gastroenterology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China.
Toxicol Appl Pharmacol. 2023 Jun 1;468:116516. doi: 10.1016/j.taap.2023.116516. Epub 2023 Apr 15.
Lung cancer remains a common malignant tumor causing death due to the rapid industrialization and serious pollution of the environment. The Von Willebrand Factor (vWF) protein is an endothelial marker and is widely used to diagnose cancer and other inflammations, however its exact mechanism of action remains largely unexplored. In particular, how it plays two opposing roles in tumor development is not clear. Our study aimed to the impact of endothelial-derived vWF on tumor development by co-culturing human umbilical vein endothelial cells (HUVECs) with lung cancer cells (95D and A549). A knockdown of endothelial-derived vWF assisted lung cancer cell in proliferation, migration and inhibited apoptosis in vitro, while overexpression of endothelial-derived vWF inhibited the proliferation, migration and induced apoptosis of lung cancer cells. The results of further experiments indicated that the vWF secreted by endothelial cells could affect lung cancer cell migration and apoptosis via its binding to integrin αvβ3 on the surface of lung cancer cells. Furthermore, a novel finding was the fact that endothelial-derived vWF inhibited lung cancer cell apoptosis by phosphorylating ERK1/2. At the same time, we established experimental lung metastasis model and xenograft model in normal mice and vWF mice, and found that knockout of vWF in mice significantly promoted lung cancer growth and metastasis. In conclusion, our research found that endothelial-derived vWF could directly combine to αvβ3 on the exterior of A549 and 95D, thereby mediating lung cancer proliferation, migration and apoptosis and inhibiting the development of lung cancer.
肺癌仍然是一种常见的恶性肿瘤，由于工业化的快速发展和环境污染的严重，导致其死亡率很高。血管性血友病因子（vWF）蛋白是一种内皮细胞标志物，广泛用于诊断癌症和其他炎症，但它的确切作用机制仍在很大程度上未被探索。特别是，它如何在肿瘤发展中发挥两种相反的作用尚不清楚。我们的研究旨在通过共培养人脐静脉内皮细胞（HUVEC）和肺癌细胞（95D 和 A549）来研究内皮细胞衍生的 vWF 对肿瘤发展的影响。内皮细胞衍生的 vWF 的敲低可协助肺癌细胞在体外增殖、迁移并抑制细胞凋亡，而过表达内皮细胞衍生的 vWF 则抑制肺癌细胞的增殖、迁移并诱导细胞凋亡。进一步实验的结果表明，内皮细胞分泌的 vWF 可以通过与肺癌细胞表面的整合素αvβ3 结合来影响肺癌细胞的迁移和凋亡。此外，一个新的发现是内皮细胞衍生的 vWF 通过磷酸化 ERK1/2 抑制肺癌细胞凋亡。同时，我们在正常小鼠和 vWF 小鼠中建立了实验性肺转移模型和异种移植模型，发现小鼠中 vWF 的敲除显著促进了肺癌的生长和转移。总之，我们的研究发现内皮细胞衍生的 vWF 可以直接与 A549 和 95D 的细胞外 αvβ3 结合，从而介导肺癌的增殖、迁移和凋亡，并抑制肺癌的发展。
