Cheon Inyoung, Lee Sieun, Oh Seonyeong, Ahn Young-Ho
Department of Molecular Medicine and Inflammation-Cancer Microenvironment Research Center, College of Medicine, Ewha Womans University, Seoul 07804, Korea.
Mol Ther Nucleic Acids. 2024 Apr 23;35(2):102194. doi: 10.1016/j.omtn.2024.102194. eCollection 2024 Jun 11.
Cancer-associated fibroblasts (CAFs) play a substantial role in promoting cancer cell motility, drug resistance, angiogenesis, and metastasis; therefore, extensive research has been conducted to determine their mode of activation. We aimed to identify whether miRNA-200 (miR-200), a widely recognized suppressor of epithelial-mesenchymal transition, prevents CAFs from promoting cancer progression. Overexpression of miR-200 prevented CAFs from promoting lung cancer cell migration, invasion, tumorigenicity, and metastasis. Additionally, miR-200 suppressed the ability of CAFs to recruit and polarize macrophages toward the M2 phenotype, as well as the migration and tube formation of vascular endothelial cells. NRP2, a co-receptor of vascular endothelial growth factor receptor (VEGFR), was confirmed to be a target of miR-200, which mediates the functional activity of miR-200 in CAFs. NRP2-VEGFR signaling facilitates the secretion of VEGF-D and pleiotrophin from CAFs, leading to the activation of cancer cell migration and invasion. These findings suggest that miR-200 remodels CAFs to impede cancer progression and metastasis and that miR-200 and NRP2 are potential therapeutic targets in the treatment of lung cancer.
癌症相关成纤维细胞（CAFs）在促进癌细胞迁移、耐药性、血管生成和转移方面发挥着重要作用；因此，人们进行了广泛的研究以确定它们的激活方式。我们旨在确定miRNA-200（miR-200）这种广泛认可的上皮-间质转化抑制因子是否能阻止CAFs促进癌症进展。miR-200的过表达可阻止CAFs促进肺癌细胞迁移、侵袭、致瘤性和转移。此外，miR-200抑制了CAFs招募巨噬细胞并使其向M2表型极化的能力，以及血管内皮细胞的迁移和管腔形成。神经纤毛蛋白2（NRP2）是血管内皮生长因子受体（VEGFR）的共受体，被证实是miR-200的靶标，它介导了miR-200在CAFs中的功能活性。NRP2-VEGFR信号通路促进CAFs分泌VEGF-D和多效生长因子，导致癌细胞迁移和侵袭的激活。这些发现表明，miR-200重塑CAFs以阻碍癌症进展和转移，并且miR-200和NRP2是肺癌治疗中的潜在治疗靶点。
