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CLC number: R73-37

On-line Access: 2020-10-12

Received: 2020-04-20

Revision Accepted: 2020-08-16

Crosschecked: 2020-09-09

Cited: 0

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Citations:  Bibtex RefMan EndNote GB/T7714

 ORCID:

Fei-yan Liu

https://orcid.org/0000-0003-1007-1366

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Journal of Zhejiang University SCIENCE B 2020 Vol.21 No.10 P.779-795

http://doi.org/10.1631/jzus.B2000190


Verticillin A inhibits colon cancer cell migration and invasion by targeting c-Met


Author(s):  Qian-qian Liu, Xue-li Zeng, Yue-lin Guan, Jing-xin Lu, Kai Tu, Fei-yan Liu

Affiliation(s):  Deparement of Internal Medicine, Zhejiang University Hospital, Hangzhou 310027, China; more

Corresponding email(s):   liuf64@zju.edu.cn

Key Words:  Verticillin A, Colon cancer, Migration, Invasion, c-Mesenchymal-epithelial transition factor (c-MET)


Qian-qian Liu, Xue-li Zeng, Yue-lin Guan, Jing-xin Lu, Kai Tu, Fei-yan Liu. Verticillin A inhibits colon cancer cell migration and invasion by targeting c-Met[J]. Journal of Zhejiang University Science B, 2020, 21(10): 779-795.

@article{title="Verticillin A inhibits colon cancer cell migration and invasion by targeting c-Met",
author="Qian-qian Liu, Xue-li Zeng, Yue-lin Guan, Jing-xin Lu, Kai Tu, Fei-yan Liu",
journal="Journal of Zhejiang University Science B",
volume="21",
number="10",
pages="779-795",
year="2020",
publisher="Zhejiang University Press & Springer",
doi="10.1631/jzus.B2000190"
}

%0 Journal Article
%T Verticillin A inhibits colon cancer cell migration and invasion by targeting c-Met
%A Qian-qian Liu
%A Xue-li Zeng
%A Yue-lin Guan
%A Jing-xin Lu
%A Kai Tu
%A Fei-yan Liu
%J Journal of Zhejiang University SCIENCE B
%V 21
%N 10
%P 779-795
%@ 1673-1581
%D 2020
%I Zhejiang University Press & Springer
%DOI 10.1631/jzus.B2000190

TY - JOUR
T1 - Verticillin A inhibits colon cancer cell migration and invasion by targeting c-Met
A1 - Qian-qian Liu
A1 - Xue-li Zeng
A1 - Yue-lin Guan
A1 - Jing-xin Lu
A1 - Kai Tu
A1 - Fei-yan Liu
J0 - Journal of Zhejiang University Science B
VL - 21
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SP - 779
EP - 795
%@ 1673-1581
Y1 - 2020
PB - Zhejiang University Press & Springer
ER -
DOI - 10.1631/jzus.B2000190


Abstract: 
verticillin A is a diketopiperazine compound which was previously isolated from Amanita flavorubescens Alk (containing parasitic fungi Hypomyces hyalines (Schw.) Tul.). Here, we initially found, by wound healing assay and Transwell assay in vitro, that verticillin A possesses an inhibitory effect against the migration and invasion of the human colon cancer cell. Subsequently, c-mesenchymal-epithelial transition factor (c-Met) was identified as a molecular target of verticillin A by screening key genes related to cell migration. verticillin A-mediated c-Met suppression is at the transcriptional level. Further study demonstrated that verticillin A suppressed c-MET phosphorylation and decreased c-MET protein level. In addition, verticillin A inhibited the phosphorylation of c-MET downstream molecules including rat sarcoma (Ras)-associated factor (Raf), extracellular signal-regulated kinase (ERK), and protein kinase B (AKT). Overexpression of Erk partially reversed the verticillin A-mediated anti-metastasis action in the human colon cancer cell. More importantly, verticillin A also inhibited cancer cell metastasis in vivo. Thus, verticillin A can significantly inhibit the migration and invasion of colon cancer cells by targeting c-Met and inhibiting Ras/Raf/mitogen-activated extracellular signal-regulated kinase (MEK)/ERK signaling pathways. Therefore, we determined that verticillin A is a natural compound that can be further developed as an anti-metastatic drug in human cancers.

轮枝孢菌素A靶向c-Met抑制结肠癌细胞的迁移和侵袭

目的:结肠癌是全球第三大常见癌症,转移是结肠癌患者死亡的主要原因,因此迫切需要寻找能够抑制结肠癌转移新方法.在前期研究中,我们证明了轮枝孢菌素A在各种类型的癌症中均具有强大的抗肿瘤增殖作用.在本研究中,我们试图确定轮枝孢菌素A对结肠癌细胞的抗转移作用,并阐明其潜在的分子机制.
创新点:首次发现轮枝孢菌素A可以有效地抑制结肠癌细胞在体内外的迁移和侵袭.在分子水平上,沉默c-Met显著降低了结肠细胞的侵袭,而轮枝孢菌素A正是有效的c-Met抑制剂;同时,轮枝孢菌素A还可以通过削弱c-MET磷酸化来抑制c-MET下游Ras/Raf/MEK/ERK信号通路,从而达到抗肿瘤转移效果.
方法:采用划痕分析和Transwell法来证明轮枝孢菌素A对结肠癌细胞体外迁移和侵袭的影响;采用蛋白质印迹法来确定c-MET及其下游分子的表达水平和活性;采用实时定量聚合酶链式反应(qRT-PCR)分析以评估c-Met的mRNA表达水平;采用RNA干扰测定用于沉默细胞中c-Met的表达;采用质粒瞬时转染以过度表达Erk.
结论:轮枝孢菌素A显著抑制结肠癌细胞的迁移和侵袭,抑制c-Met转录表达,削弱c-MET磷酸化,从而抑制其下游Ras/Raf/MEK/ERK信号通路,这是轮枝孢菌素A抗结肠癌细胞转移的主要分子机制.根据本研究结果,我们确定天然产物轮枝孢菌素A具有进一步开发抗癌症转移的巨大潜力.

关键词:轮枝孢菌素A;结肠癌;迁移;侵袭;c-MET

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