Molecular Therapy: Nucleic Acids (Jun 2024)

miR-200-mediated inactivation of cancer-associated fibroblasts via targeting of NRP2-VEGFR signaling attenuates lung cancer invasion and metastasis

  • Inyoung Cheon,
  • Sieun Lee,
  • Seonyeong Oh,
  • Young-Ho Ahn

Journal volume & issue
Vol. 35, no. 2
p. 102194

Abstract

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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.

Keywords