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
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 ext...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2022-01-01
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| Series: | Journal of Extracellular Vesicles |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/jev2.12186 |
| _version_ | 1811335142279479296 |
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| author | Senlin Zhao Yushuai Mi Binbin Zheng Ping Wei Yanzi Gu Zhengxiang Zhang Ye Xu Sanjun Cai Xinxiang Li Dawei Li |
| author_facet | Senlin Zhao Yushuai Mi Binbin Zheng Ping Wei Yanzi Gu Zhengxiang Zhang Ye Xu Sanjun Cai Xinxiang Li Dawei Li |
| author_sort | Senlin Zhao |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-13T17:19:44Z |
| format | Article |
| id | doaj.art-c2662c718b5d4a1b9df7911a9f7b3aeb |
| institution | Directory Open Access Journal |
| issn | 2001-3078 |
| language | English |
| last_indexed | 2024-04-13T17:19:44Z |
| publishDate | 2022-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of Extracellular Vesicles |
| spelling | doaj.art-c2662c718b5d4a1b9df7911a9f7b3aeb2022-12-22T02:38:02ZengWileyJournal of Extracellular Vesicles2001-30782022-01-01111n/an/a10.1002/jev2.12186Highly‐metastatic colorectal cancer cell released miR‐181a‐5p‐rich extracellular vesicles promote liver metastasis by activating hepatic stellate cells and remodelling the tumour microenvironmentSenlin Zhao0Yushuai Mi1Binbin Zheng2Ping Wei3Yanzi Gu4Zhengxiang Zhang5Ye Xu6Sanjun Cai7Xinxiang Li8Dawei Li9Department of Colorectal Surgery Fudan University Shanghai Cancer Center Shanghai ChinaDepartment of Gastrointestinal Surgery The Second Hospital Cheeloo College of Medicine Shandong University Jinan ChinaDepartment of General Surgery Shanghai General Hospital School of Medicine Shanghai Jiaotong University Shanghai ChinaDepartment of Oncology Shanghai Medical College Fudan University Shanghai ChinaDepartment of Biobank Fudan University Shanghai Cancer Center Shanghai ChinaDepartment of Oncology Yijishan Hospital of Wannan Medical College Wuhu Anhui ChinaDepartment of Colorectal Surgery Fudan University Shanghai Cancer Center Shanghai ChinaDepartment of Colorectal Surgery Fudan University Shanghai Cancer Center Shanghai ChinaDepartment of Colorectal Surgery Fudan University Shanghai Cancer Center Shanghai ChinaDepartment of Colorectal Surgery Fudan University Shanghai Cancer Center Shanghai ChinaAbstract 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.https://doi.org/10.1002/jev2.12186CCL20/CCR6/ERK1/2/Elk‐1/miR‐181a‐5p feedback loopcolorectal liver metastasisextracellular vesiclehepatic stellate cellmiR‐181a‐5ptumour microenvironment |
| spellingShingle | Senlin Zhao Yushuai Mi Binbin Zheng Ping Wei Yanzi Gu Zhengxiang Zhang Ye Xu Sanjun Cai Xinxiang Li Dawei Li 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 CCL20/CCR6/ERK1/2/Elk‐1/miR‐181a‐5p feedback loop colorectal liver metastasis extracellular vesicle hepatic stellate cell miR‐181a‐5p tumour microenvironment |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | CCL20/CCR6/ERK1/2/Elk‐1/miR‐181a‐5p feedback loop colorectal liver metastasis extracellular vesicle hepatic stellate cell miR‐181a‐5p tumour microenvironment |
| url | https://doi.org/10.1002/jev2.12186 |
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