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.
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.
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高转移结直肠癌细胞释放富含miR-181a-5p的细胞外囊泡，通过激活肝星状细胞并重塑肿瘤微环境来促进肝转移。
DOI：
10.1002/jev2.12186
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发表时间：
2022-01
影响因子：
16
通讯作者：
Li D
中科院分区：
文献类型：
--
作者：
Zhao S;Mi Y;Zheng B;Wei P;Gu Y;Zhang Z;Xu Y;Cai S;Li X;Li D
结直肠癌肝转移（CRLM）是CRC相关死亡的最常见原因，通常由CRC细胞与肝脏中的肿瘤微环境（TME）之间的相互作用引起。然而，肿瘤来源的细胞外囊泡（EV）miRNA与CRLM中的TME之间串扰的分子机制尚未完全阐明。目前的研究表明，高转移性CRC细胞比表现出低转移潜力的细胞释放更多富含miR-181 a-5p的EV，从而促进CRLM。此外，我们证实了FUS介导miR-181 a-5p包装到CRC EV中，这反过来又通过靶向SOCS3和激活IL 6/STAT3信号通路持续激活肝星状细胞（HSC）。活化的HSC可以分泌趋化因子CCL20，并进一步激活CCL20/CCR6/ERK 1/2/Elk-1/miR-181 a-5p正反馈环，导致TME的重编程和CRLM中转移前小生境的形成。临床上，高水平的含miR-181 a-5p的血清EV与CRC患者的肝转移呈正相关。总之，富含miR-181 a-5p的高转移性CRC细胞来源的EV可以激活HSC并重塑TME，从而促进CRC患者的肝转移。这些结果提供了新的见解，在CRC肝转移的机制。
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.
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影响因子：
7.4
作者：
Chu X;Jin Q;Chen H;Wood GC;Petrick A;Strodel W;Gabrielsen J;Benotti P;Mirshahi T;Carey DJ;Still CD;DiStefano JK;Gerhard GS
通讯作者：
Gerhard GS
影响因子：
14.9
作者：
Cook KB;Kazan H;Zuberi K;Morris Q;Hughes TR
通讯作者：
Hughes TR
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影响因子：
12.3
作者：
Qin, Xing;Guo, Haiyan;Zhang, Jianjun
通讯作者：
Zhang, Jianjun
影响因子：
30.5
作者：
Yasukawa, H;Ohishi, M;Yoshimura, A
通讯作者：
Yoshimura, A
肿瘤源性外泌体miR-934诱导巨噬细胞M2极化促进结直肠癌肝转移
影响因子：
28.5
作者：
Zhao S;Mi Y;Guan B;Zheng B;Wei P;Gu Y;Zhang Z;Cai S;Xu Y;Li X;He X;Zhong X;Li G;Chen Z;Li D
通讯作者：
Li D