Highly-metastatic colorectal cancer cell released miR-181a-5p-rich extracellular vesicles promote liver metastasis by activating hepatic stellate cells and remodelling the tumour microenvironment.

Liver metastasis of colorectal cancer (CRLM) is the most common cause of CRC-related mortality, and is typically caused by interactions between CRC cells and the tumour microenvironment (TME) in the liver. However, the molecular mechanisms underlying the crosstalk between tumour-derived extracellular vesicle (EV) miRNAs and the TME in CRLM have yet to be fully elucidated. The present study demonstrated that highly metastatic CRC cells released more miR-181a-5p-rich EVs than cells which exhibit a low metastatic potential, in-turn promoting CRLM. Additionally, we verified that FUS mediated packaging of miR-181a-5p into CRC EVs, which in-turn persistently activated hepatic stellate cells (HSCs) by targeting SOCS3 and activating the IL6/STAT3 signalling pathway. Activated HSCs could secrete the chemokine CCL20 and further activate a CCL20/CCR6/ERK1/2/Elk-1/miR-181a-5p positive feedback loop, resulting in reprogramming of the TME and the formation of pre-metastatic niches in CRLM. Clinically, high levels of serum EV containing miR-181a-5p was positively correlated with liver metastasis in CRC patients. Taken together, highly metastatic CRC cells-derived EVs rich in miR-181a-5p could activate HSCs and remodel the TME, thereby facilitating liver metastasis in CRC patients. These results provide novel insight into the mechanism underlying liver metastasis in CRC.