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

Journal of Extracellular Vesicles

Yanzi Gu¹  Senlin Zhao²  Dawei Li²  Xinxiang Li²  Ye Xu²  Sanjun Cai²  Yushuai Mi³  Binbin Zheng⁴  Ping Wei⁵  Zhengxiang Zhang⁶ 

[1] Department of Biobank Fudan University Shanghai Cancer Center Shanghai China;Department of Colorectal Surgery Fudan University Shanghai Cancer Center Shanghai China;Department of Gastrointestinal Surgery The Second Hospital Cheeloo College of Medicine Shandong University Jinan China;Department of General Surgery Shanghai General Hospital School of Medicine Shanghai Jiaotong University Shanghai China;Department of Oncology Shanghai Medical College Fudan University Shanghai China;Department of Oncology Yijishan Hospital of Wannan Medical College Wuhu Anhui China;

关键词: CCL20/CCR6/ERK1/2/Elk‐1/miR‐181a‐5p feedback loop;    colorectal liver metastasis;    extracellular vesicle;    hepatic stellate cell;    miR‐181a‐5p;    tumour microenvironment;   

DOI  :  10.1002/jev2.12186

来源: DOAJ

【 摘 要 】

Abstract 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.

【 授权许可】

Unknown