EV-miR-99a–NLRP2 Regulation of Fibroblast Inflammation in CRC Metastasis

A greater activation level of fibroblasts was observed in primary CRC tissues from patients with metastasis than in those from patients without metastasis, and EVs secreted by highly metastatic CRC cells promoted fibroblast activation.EV-encapsulated miR-99a (EV-miR-99a) promotes fibroblast activation by specifically targeting NLR family pyrin domain containing 2 (NLRP2) and activating NF-?B signaling in fibroblasts.EV-miR-99a-activated fibroblasts secrete CCL7 and induce EMT in CRC cells by activating the CCR5-mTOR-p70S6K pathway.EV-miR-99a-activated fibroblasts upregulate miR-99a expression in CRC cells via NF-?B-mediated TGF-ß1 expression, forming a miR-99a/TGF-ß1 positive feedback loop between CAFs and CRC cells that facilitates the formation of a proinflammatory niche.Treatment with the p70S6K inhibitor LY2584702 abolishes the mutual reinforcement between CRC cells and fibroblasts and prevents CRC liver metastasis, and detection of EV-miR-99a levels in the serum provides a promising method to predict the metastasis status of CRC patients.