Transfer of metastatic traits via miR‐200c in extracellular vesicles derived from colorectal cancer stem cells is inhibited by atractylenolide I

Cancer stem cells (CSCs) are important factors contributing to tumorigenesis. We examined whether CSCs isolated from colorectal cancer (CRC) cells possess metastatic properties that can be transferred to non‐CSCs via the delivery of miR‐200c enclosed in extracellular vesicles (EVs). The inhibitory effect of atractylenolide I (ATL‐1), a traditional Chinese medicinal compound, on miR‐200c activity and metastatic transfer was investigated. EVs were isolated from colorectal CSCs. The expression of miR‐200c was evaluated in CSCs and CSC‐derived EVs, and horizontal transfer of metastatic properties via EVs to non‐CSCs was investigated in terms of cell behavior and phosphatidylinositol‐4,5‐bisphosphate 3‐kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling. CSCs isolated from metastatic CRC cells exhibited higher levels of miR‐200c than those in nonmetastatic CRC cells. Overexpression of miR‐200c in CSCs enhanced metastatic potential by promoting proliferation and inhibiting apoptosis, in turn leading to the release of EVs carrying an excess of miR‐200c. Non‐CSCs co‐cultured with miR‐200c‐containing EVs exhibited enhanced invasion and stemness maintenance associated with PI3K/Akt/mTOR activation, demonstrating successful metastatic transfer via EV delivery. Furthermore, ATL‐1 impaired the EV‐mediated transfer of metastatic properties by suppressing miR‐200c activity and disrupting EV uptake by non‐CSCs. EVs are critical signal transducers that facilitate intercellular communication and exchange of metastatic properties, which can be controlled by ATL‐1. The findings are useful in the development of microRNA‐based anticancer strategies by targeting EV‐mediated activity, especially using natural compounds.