Cancer-derived exosomal miR-25-3p promotes pre-metastatic niche formation by inducing vascular permeability and angiogenesis

TLDR

Cancer‑derived exosomes drive pre‑metastatic niche formation, yet their mechanisms remain unclear. Exosomal miR‑25‑3p targets KLF2/KLF4 to downregulate VEGFR2, ZO‑1, occludin, and Claudin5, thereby increasing vascular permeability and angiogenesis. Exosomal miR‑25‑3p is transferred from colorectal cancer cells to endothelial cells, induces vascular leakiness, promotes liver and lung metastasis in mice, and is elevated in metastatic patients, indicating its potential as a blood‑based biomarker.

Abstract

Cancer-derived exosomes are considered a major driver of cancer-induced pre-metastatic niche formation at foreign sites, but the mechanisms remain unclear. Here, we show that miR-25-3p, a metastasis-promoting miRNA of colorectal cancer (CRC), can be transferred from CRC cells to endothelial cells via exosomes. Exosomal miR-25-3p regulates the expression of VEGFR2, ZO-1, occludin and Claudin5 in endothelial cells by targeting KLF2 and KLF4, consequently promotes vascular permeability and angiogenesis. In addition, exosomal miR-25-3p from CRC cells dramatically induces vascular leakiness and enhances CRC metastasis in liver and lung of mice. Moreover, the expression level of miR-25-3p from circulating exosomes is significantly higher in CRC patients with metastasis than those without metastasis. Our work suggests that exosomal miR-25-3p is involved in pre-metastatic niche formation and may be used as a blood-based biomarker for CRC metastasis.