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On-line Access: 2021-06-11

Received: 2020-12-24

Revision Accepted: 2021-03-05

Crosschecked: 0000-00-00

Cited: 0

Clicked: 2068

Citations:  Bibtex RefMan EndNote GB/T7714

 ORCID:

Ke HAO

https://orcid.org/0000-0002-8013-9277

Bin LU

https://orcid.org/0000-0002-6247-571X

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Journal of Zhejiang University SCIENCE B 2021 Vol.22 No.6 P.492-503

http://doi.org/10.1631/jzus.B2000842


Blocking the JAK2/STAT3 and ERK pathways suppresses the proliferation of gastrointestinal cancers by inducing apoptosis


Author(s):  Xi WANG, Chunyan DAI, Yifei YIN, Lin WU, Weiyang JIN, Yufei FU, Zhe CHEN, Ke HAO, Bin LU

Affiliation(s):  Key Laboratory of Digestive Pathophysiology of Zhejiang Province, the First Affiliated Hospital of Zhejiang Chinese Medical University, Zhejiang Chinese Medical University, Hangzhou 310006, China; more

Corresponding email(s):   haoke@hmc.edu.cn, Lvbin@medmail.com.cn

Key Words:  Gastrointestinal cancers, JAK2/STAT3 pathway, ERK pathway, Crosstalk, Apoptosis


Xi WANG, Chunyan DAI, Yifei YIN, Lin WU, Weiyang JIN, Yufei FU, Zhe CHEN, Ke HAO, Bin LU. Blocking the JAK2/STAT3 and ERK pathways suppresses the proliferation of gastrointestinal cancers by inducing apoptosis[J]. Journal of Zhejiang University Science B, 2021, 22(6): 492-503.

@article{title="Blocking the JAK2/STAT3 and ERK pathways suppresses the proliferation of gastrointestinal cancers by inducing apoptosis",
author="Xi WANG, Chunyan DAI, Yifei YIN, Lin WU, Weiyang JIN, Yufei FU, Zhe CHEN, Ke HAO, Bin LU",
journal="Journal of Zhejiang University Science B",
volume="22",
number="6",
pages="492-503",
year="2021",
publisher="Zhejiang University Press & Springer",
doi="10.1631/jzus.B2000842"
}

%0 Journal Article
%T Blocking the JAK2/STAT3 and ERK pathways suppresses the proliferation of gastrointestinal cancers by inducing apoptosis
%A Xi WANG
%A Chunyan DAI
%A Yifei YIN
%A Lin WU
%A Weiyang JIN
%A Yufei FU
%A Zhe CHEN
%A Ke HAO
%A Bin LU
%J Journal of Zhejiang University SCIENCE B
%V 22
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%P 492-503
%@ 1673-1581
%D 2021
%I Zhejiang University Press & Springer
%DOI 10.1631/jzus.B2000842

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T1 - Blocking the JAK2/STAT3 and ERK pathways suppresses the proliferation of gastrointestinal cancers by inducing apoptosis
A1 - Xi WANG
A1 - Chunyan DAI
A1 - Yifei YIN
A1 - Lin WU
A1 - Weiyang JIN
A1 - Yufei FU
A1 - Zhe CHEN
A1 - Ke HAO
A1 - Bin LU
J0 - Journal of Zhejiang University Science B
VL - 22
IS - 6
SP - 492
EP - 503
%@ 1673-1581
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PB - Zhejiang University Press & Springer
ER -
DOI - 10.1631/jzus.B2000842


Abstract: 
Dysregulated crosstalk between different signaling pathways contributes to tumor development, including resistance to cancer therapy. In the present study, we found that the mitogen-activated extracellular signal-regulated kinase (MEK) inhibitor trametinib failed to suppress the proliferation of PANC-1 and MGC803 cells by activating the Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling pathway, while the JAK2 inhibitor fedratinib failed to inhibit the growth of the PANC-1 cells upon stimulation of extracellular signal-regulated kinase (ERK) signaling. In particular, the most prominent enhancement of the anti-proliferative effect resulted from the concurrent blockage of the JAK2/STAT3 and ERK signaling pathways. Furthermore, the combination of the two inhibitors resulted in a reduced tumor burden in mice. Our evidence suggests novel crosstalk between JAK2/STAT3 and ERK signaling in gastric cancer (GC) and pancreatic ductal adenocarcinoma (PDAC) cells and provides a therapeutic strategy to overcome potential resistance in gastrointestinal cancer.

阻断JAK2/STAT3和ERK通路诱发凋亡抑制胃肠道癌的增殖

目的:探索在胃肠道肿瘤细胞中的JAK2/STAT3和MEK/ERK信号通路之间的交互作用,明确两者相互作用在肿瘤细胞增殖和凋亡的作用。
创新点:发现JAK2/STAT3和ERK信号在胃癌(GC)和胰腺导管腺癌(PDAC)细胞内的相互作用,为克服胃肠道肿瘤的化疗耐药提供新的治疗策略。
方法:在GC和PDAC细胞系中,应用MEK抑制剂--曲美替尼(Trametinib)和JAK2抑制剂--费德拉替尼(Fedratinib)单独或共同抑制MEK和JAK2/STAT3信号通路,利用CCK-8和蛋白质印迹(western blot)方法检测细胞增殖和凋亡,及相关信号通路的激活情况;同时利用荷瘤小鼠检测JAK2/STAT3和MEK信号通路的抑制对肿瘤生长的影响。
结论:本研究发现,MEK抑制剂--曲美替尼在抑制MEK信号通路的同时却对JAK2/STAT3信号通路有较强的激活作用,无法有效抑制胃癌细胞和胰腺癌细胞的增殖;而JAK2抑制剂--费德拉替尼虽可以有效抑制JAK/STAT3信号通路的激活,但显著促进ERK信号通路的异常活化,导致对胃癌细胞和胰腺癌细胞的生长抑制作用失效。而当JAK2/STAT3和ERK信号通路同时被抑制后,抗增殖效果显著增强,且该作用效应与促进肿瘤细胞的凋亡进程密切相关。此外,这两种抑制剂的结合有效阻止了荷瘤小鼠的肿瘤生长,有很好的抗肿瘤效果,避免了化疗耐药的发生。

关键词:胃肠道肿瘤;JAK2/STAT3通路;ERK通路;交互作用;凋亡

Darkslateblue:Affiliate; Royal Blue:Author; Turquoise:Article

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