Shear Stress Drives the Cleavage Activation of Protease‐Activated Receptor 2 by PRSS3/Mesotrypsin to Promote Invasion and Metastasis of Circulating Lung Cancer Cells
Abstract When circulating tumor cells (CTCs) travel in circulation, they can be killed by detachment‐induced anoikis and fluidic shear stress (SS)‐mediated apoptosis. Circulatory treatment, which can make CTCs detached but also generate SS, can increase metastasis of cancer cells. To identify SS‐spe...
| Main Authors: | , , |
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| Format: | Article |
| Language: | English |
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Wiley
2023-09-01
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| Series: | Advanced Science |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/advs.202301059 |
| _version_ | 1797692639899811840 |
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| author | Muya Zhou Koukou Li Kathy Qian Luo |
| author_facet | Muya Zhou Koukou Li Kathy Qian Luo |
| author_sort | Muya Zhou |
| collection | DOAJ |
| description | Abstract When circulating tumor cells (CTCs) travel in circulation, they can be killed by detachment‐induced anoikis and fluidic shear stress (SS)‐mediated apoptosis. Circulatory treatment, which can make CTCs detached but also generate SS, can increase metastasis of cancer cells. To identify SS‐specific mechanosensors without detachment impacts, a microfluidic circulatory system is used to generate arteriosus SS and compare transcriptome profiles of circulating lung cancer cells with suspended cells. Half of the cancer cells can survive SS damage and show higher invasion ability. Mesotrypsin (PRSS3), protease‐activated receptor 2 (PAR2), and the subunit of activating protein 1, Fos‐related antigen 1 (FOSL1), are upregulated by SS, and their high expression is responsible for promoting invasion and metastasis. SS triggers PRSS3 to cleave the N‐terminal inhibitory domain of PAR2 within 2 h. As a G protein‐coupled receptor, PAR2 further activates the Gαi protein to turn on the Src‐ERK/p38/JNK‐FRA1/cJUN axis to promote the expression of epithelial–mesenchymal transition markers, and also PRSS3, which facilitates metastasis. Enriched PRSS3, PAR2, and FOSL1 in human tumor samples and their correlations with worse outcomes reveal their clinical significance. PAR2 may serve as an SS‐specific mechanosensor cleavable by PRSS3 in circulation, which provides new insights for targeting metastasis‐initiating CTCs. |
| first_indexed | 2024-03-12T02:31:30Z |
| format | Article |
| id | doaj.art-07736b6c5b4c4cec9c05e45ebffd67c7 |
| institution | Directory Open Access Journal |
| issn | 2198-3844 |
| language | English |
| last_indexed | 2024-03-12T02:31:30Z |
| publishDate | 2023-09-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj.art-07736b6c5b4c4cec9c05e45ebffd67c72023-09-05T07:49:09ZengWileyAdvanced Science2198-38442023-09-011025n/an/a10.1002/advs.202301059Shear Stress Drives the Cleavage Activation of Protease‐Activated Receptor 2 by PRSS3/Mesotrypsin to Promote Invasion and Metastasis of Circulating Lung Cancer CellsMuya Zhou0Koukou Li1Kathy Qian Luo2Department of Biomedical Sciences, Faculty of Health Sciences University of Macau Taipa Macao SAR 999078 ChinaDepartment of Biomedical Sciences, Faculty of Health Sciences University of Macau Taipa Macao SAR 999078 ChinaDepartment of Biomedical Sciences, Faculty of Health Sciences University of Macau Taipa Macao SAR 999078 ChinaAbstract When circulating tumor cells (CTCs) travel in circulation, they can be killed by detachment‐induced anoikis and fluidic shear stress (SS)‐mediated apoptosis. Circulatory treatment, which can make CTCs detached but also generate SS, can increase metastasis of cancer cells. To identify SS‐specific mechanosensors without detachment impacts, a microfluidic circulatory system is used to generate arteriosus SS and compare transcriptome profiles of circulating lung cancer cells with suspended cells. Half of the cancer cells can survive SS damage and show higher invasion ability. Mesotrypsin (PRSS3), protease‐activated receptor 2 (PAR2), and the subunit of activating protein 1, Fos‐related antigen 1 (FOSL1), are upregulated by SS, and their high expression is responsible for promoting invasion and metastasis. SS triggers PRSS3 to cleave the N‐terminal inhibitory domain of PAR2 within 2 h. As a G protein‐coupled receptor, PAR2 further activates the Gαi protein to turn on the Src‐ERK/p38/JNK‐FRA1/cJUN axis to promote the expression of epithelial–mesenchymal transition markers, and also PRSS3, which facilitates metastasis. Enriched PRSS3, PAR2, and FOSL1 in human tumor samples and their correlations with worse outcomes reveal their clinical significance. PAR2 may serve as an SS‐specific mechanosensor cleavable by PRSS3 in circulation, which provides new insights for targeting metastasis‐initiating CTCs.https://doi.org/10.1002/advs.202301059cancer metastasiscirculating tumor cellsprotease‐activated receptor 2PRSS3/mesotrypsinshear stress |
| spellingShingle | Muya Zhou Koukou Li Kathy Qian Luo Shear Stress Drives the Cleavage Activation of Protease‐Activated Receptor 2 by PRSS3/Mesotrypsin to Promote Invasion and Metastasis of Circulating Lung Cancer Cells Advanced Science cancer metastasis circulating tumor cells protease‐activated receptor 2 PRSS3/mesotrypsin shear stress |
| title | Shear Stress Drives the Cleavage Activation of Protease‐Activated Receptor 2 by PRSS3/Mesotrypsin to Promote Invasion and Metastasis of Circulating Lung Cancer Cells |
| title_full | Shear Stress Drives the Cleavage Activation of Protease‐Activated Receptor 2 by PRSS3/Mesotrypsin to Promote Invasion and Metastasis of Circulating Lung Cancer Cells |
| title_fullStr | Shear Stress Drives the Cleavage Activation of Protease‐Activated Receptor 2 by PRSS3/Mesotrypsin to Promote Invasion and Metastasis of Circulating Lung Cancer Cells |
| title_full_unstemmed | Shear Stress Drives the Cleavage Activation of Protease‐Activated Receptor 2 by PRSS3/Mesotrypsin to Promote Invasion and Metastasis of Circulating Lung Cancer Cells |
| title_short | Shear Stress Drives the Cleavage Activation of Protease‐Activated Receptor 2 by PRSS3/Mesotrypsin to Promote Invasion and Metastasis of Circulating Lung Cancer Cells |
| title_sort | shear stress drives the cleavage activation of protease activated receptor 2 by prss3 mesotrypsin to promote invasion and metastasis of circulating lung cancer cells |
| topic | cancer metastasis circulating tumor cells protease‐activated receptor 2 PRSS3/mesotrypsin shear stress |
| url | https://doi.org/10.1002/advs.202301059 |
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