Open AccessHighly‐metastatic colorectal cancer cell released miR‐181a‐5p‐rich extracellular vesicles promote liver metastasis by activating hepatic stellate cells and remodelling the tumour microenvironment
Author(s) -
Zhao Senlin,
Mi Yushuai,
Zheng Binbin,
Wei Ping,
Gu Yanzi,
Zhang Zhengxiang,
Xu Ye,
Cai Sanjun,
Li Xinxiang,
Li Dawei
Publication year - 2022
Publication title -
journal of extracellular vesicles
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.94
H-Index - 68
ISSN - 2001-3078
DOI - 10.1002/jev2.12186
Subject(s) - hepatic stellate cell , metastasis , tumor microenvironment , cancer research , ccl20 , colorectal cancer , microvesicles , chemokine , biology , microrna , medicine , cancer , immune system , immunology , chemokine receptor , pathology , biochemistry , tumor cells , gene
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.