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Disruption of the C...
Disruption of the Clock Component Bmal1 in Mice Promotes Cancer Metastasis through the PAI-1-TGF-beta-myoCAF-Dependent Mechanism
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- Wu, Jieyu (author)
- Tumor & Cell Biol Karolinska Inst, Sweden
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- Jing, Xu (author)
- Tumor & Cell Biol Karolinska Inst, Sweden
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- Du, Qiqiao (author)
- Tumor & Cell Biol Karolinska Inst, Sweden; Sun Yat Sen Univ, Peoples R China
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- Sun, Xiaoting (author)
- Wenzhou Med Univ, Peoples R China
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- Holgersson, Kristian (author)
- Loma Linda Univ, CA 92350 USA
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- Gao, Juan (author)
- Karolinska Institutet,Tumor & Cell Biol Karolinska Inst, Sweden
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- He, Xingkang (author)
- Zhejiang Univ Med Sch, Peoples R China
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- Hosaka, Kayoko (author)
- Karolinska Institutet,Tumor & Cell Biol Karolinska Inst, Sweden
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- Zhao, Chen (author)
- Fudan Univ, Peoples R China
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- Tao, Wei (author)
- Harvard Med Sch, MA 02115 USA
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- FitzGerald, Garret A. (author)
- Univ Penn, PA 19104 USA
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- Yang, Yunlong (author)
- Karolinska Institutet,Fudan Univ, Peoples R China
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- Jensen, Lasse (author)
- Linköpings universitet,Avdelningen för diagnostik och specialistmedicin,Medicinska fakulteten,Region Östergötland, Klinisk farmakologi
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- Cao, Yihai (author)
- Tumor & Cell Biol Karolinska Inst, Sweden; Sun Yat Sen Univ, Peoples R China
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(creator_code:org_t)
- WILEY, 2023
- 2023
- English.
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In: Advanced Science. - : WILEY. - 2198-3844. ; 10:24
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Abstract
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- The circadian clock in animals and humans plays crucial roles in multiple physiological processes. Disruption of circadian homeostasis causes detrimental effects. Here, it is demonstrated that the disruption of the circadian rhythm by genetic deletion of mouse brain and muscle ARNT-like 1 (Bmal1) gene, coding for the key clock transcription factor, augments an exacerbated fibrotic phenotype in various tumors. Accretion of cancer-associated fibroblasts (CAFs), especially the alpha smooth muscle actin positive myoCAFs, accelerates tumor growth rates and metastatic potentials. Mechanistically, deletion of Bmal1 abrogates expression of its transcriptionally targeted plasminogen activator inhibitor-1 (PAI-1). Consequently, decreased levels of PAI-1 in the tumor microenvironment instigate plasmin activation through upregulation of tissue plasminogen activator and urokinase plasminogen activator. The activated plasmin converts latent TGF-beta into its activated form, which potently induces tumor fibrosis and the transition of CAFs into myoCAFs, the latter promoting cancer metastasis. Pharmacological inhibition of the TGF-beta signaling largely ablates the metastatic potentials of colorectal cancer, pancreatic ductal adenocarcinoma, and hepatocellular carcinoma. Together, these data provide novel mechanistic insights into disruption of the circadian clock in tumor growth and metastasis. It is reasonably speculated that normalization of the circadian rhythm in patients provides a novel paradigm for cancer therapy.
Subject headings
- TEKNIK OCH TEKNOLOGIER -- Kemiteknik -- Annan kemiteknik (hsv//swe)
- ENGINEERING AND TECHNOLOGY -- Chemical Engineering -- Other Chemical Engineering (hsv//eng)
Keyword
- brain and muscle ARNT-like 1; cancer; circadian clock; fibroblasts; metastasis
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Wu, Jieyu
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Jing, Xu
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Du, Qiqiao
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Sun, Xiaoting
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Holgersson, Kris ...
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Gao, Juan
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show more...
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He, Xingkang
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Hosaka, Kayoko
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Zhao, Chen
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Tao, Wei
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FitzGerald, Garr ...
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Yang, Yunlong
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Jensen, Lasse
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Cao, Yihai
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- About the subject
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- ENGINEERING AND TECHNOLOGY
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ENGINEERING AND ...
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and Chemical Enginee ...
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and Other Chemical E ...
- Articles in the publication
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Advanced Science
- By the university
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Linköping University
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Karolinska Institutet