Shear Stress Drives the Cleavage Activation of Protease-Activated Receptor 2 by PRSS3/Mesotrypsin to Promote Invasion and Metastasis of Circulating Lung Cancer Cells

Overview

Journal Adv Sci (Weinh)

Specialty Biomedical Engineering

Date 2023 Jul 3

PMID 37395651

Authors

Muya Zhou

Koukou Li

Kathy Qian Luo

Affiliations

Soon will be listed here.

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 Gα 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.

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Shear Stress Drives the Cleavage Activation of Protease-Activated Receptor 2 by PRSS3/Mesotrypsin to Promote Invasion and Metastasis of Circulating Lung Cancer Cells.

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References

Ma H, Hockla A, Mehner C, Coban M, Papo N, Radisky D . PRSS3/Mesotrypsin and kallikrein-related peptidase 5 are associated with poor prognosis and contribute to tumor cell invasion and growth in lung adenocarcinoma. Sci Rep. 2019; 9(1):1844. PMC: 6372636. DOI: 10.1038/s41598-018-38362-0. View

Lee H, Diaz M, Price K, Ozuna J, Zhang S, Sevick-Muraca E . Fluid shear stress activates YAP1 to promote cancer cell motility. Nat Commun. 2017; 8:14122. PMC: 5253685. DOI: 10.1038/ncomms14122. View

Darmoul D, Gratio V, Devaud H, Laburthe M . Protease-activated receptor 2 in colon cancer: trypsin-induced MAPK phosphorylation and cell proliferation are mediated by epidermal growth factor receptor transactivation. J Biol Chem. 2004; 279(20):20927-34. DOI: 10.1074/jbc.M401430200. View

Nasri I, Bonnet D, Zwarycz B, dAldebert E, Khou S, Mezghani-Jarraya R . PAR2-dependent activation of GSK3β regulates the survival of colon stem/progenitor cells. Am J Physiol Gastrointest Liver Physiol. 2016; 311(2):G221-36. PMC: 5007290. DOI: 10.1152/ajpgi.00328.2015. View

Tanaka H, Shimizu S, Ohmori F, Muraoka Y, Kumagai M, Yoshizawa M . Increases in blood flow and shear stress to nonworking limbs during incremental exercise. Med Sci Sports Exerc. 2006; 38(1):81-5. DOI: 10.1249/01.mss.0000191166.81789.de. View

Roy Choudhury K, Yagle K, Swanson P, Krohn K, Rajendran J . A robust automated measure of average antibody staining in immunohistochemistry images. J Histochem Cytochem. 2009; 58(2):95-107. PMC: 2803710. DOI: 10.1369/jhc.2009.953554. View

Jiang G, Cao F, Ren G, Gao D, Bhakta V, Zhang Y . PRSS3 promotes tumour growth and metastasis of human pancreatic cancer. Gut. 2010; 59(11):1535-44. DOI: 10.1136/gut.2009.200105. View

Aceto N, Bardia A, Miyamoto D, Donaldson M, Wittner B, Spencer J . Circulating tumor cell clusters are oligoclonal precursors of breast cancer metastasis. Cell. 2014; 158(5):1110-1122. PMC: 4149753. DOI: 10.1016/j.cell.2014.07.013. View

de Bono J, Scher H, Montgomery R, Parker C, Miller M, Tissing H . Circulating tumor cells predict survival benefit from treatment in metastatic castration-resistant prostate cancer. Clin Cancer Res. 2008; 14(19):6302-9. DOI: 10.1158/1078-0432.CCR-08-0872. View

10.

Kayode O, Huang Z, Soares A, Caulfield T, Dong Z, Bode A . Small molecule inhibitors of mesotrypsin from a structure-based docking screen. PLoS One. 2017; 12(5):e0176694. PMC: 5413004. DOI: 10.1371/journal.pone.0176694. View

11.

Mussbach F, Ungefroren H, Gunther B, Katenkamp K, Henklein P, Westermann M . Proteinase-activated receptor 2 (PAR2) in hepatic stellate cells - evidence for a role in hepatocellular carcinoma growth in vivo. Mol Cancer. 2016; 15(1):54. PMC: 4966804. DOI: 10.1186/s12943-016-0538-y. View

12.

Ye D, Liang W, Dai L, Yao Y . Moderate Fluid Shear Stress Could Regulate the Cytoskeleton of Nucleus Pulposus and Surrounding Inflammatory Mediators by Activating the FAK-MEK5-ERK5-cFos-AP1 Signaling Pathway. Dis Markers. 2018; 2018:9405738. PMC: 6020454. DOI: 10.1155/2018/9405738. View

13.

Follain G, Osmani N, Azevedo A, Allio G, Mercier L, Karreman M . Hemodynamic Forces Tune the Arrest, Adhesion, and Extravasation of Circulating Tumor Cells. Dev Cell. 2018; 45(1):33-52.e12. DOI: 10.1016/j.devcel.2018.02.015. View

14.

Zhao B, Lv Y . Suspension state and shear stress enhance breast tumor cells EMT through YAP by microRNA-29b. Cell Biol Toxicol. 2021; 39(3):1037-1052. DOI: 10.1007/s10565-021-09661-6. View

15.

Yamashita K, Mimori K, Inoue H, Mori M, Sidransky D . A tumor-suppressive role for trypsin in human cancer progression. Cancer Res. 2003; 63(20):6575-8. View

16.

Lan Q, Mercurius K, Davies P . Stimulation of transcription factors NF kappa B and AP1 in endothelial cells subjected to shear stress. Biochem Biophys Res Commun. 1994; 201(2):950-6. DOI: 10.1006/bbrc.1994.1794. View

17.

Thamilselvan V, Patel A, van der Voort van Zyp J, Basson M . Colon cancer cell adhesion in response to Src kinase activation and actin-cytoskeleton by non-laminar shear stress. J Cell Biochem. 2004; 92(2):361-71. DOI: 10.1002/jcb.20072. View

18.

Cottrell G, Amadesi S, Grady E, Bunnett N . Trypsin IV, a novel agonist of protease-activated receptors 2 and 4. J Biol Chem. 2004; 279(14):13532-9. DOI: 10.1074/jbc.M312090200. View

19.

Luo K, Chang D . The gene-silencing efficiency of siRNA is strongly dependent on the local structure of mRNA at the targeted region. Biochem Biophys Res Commun. 2004; 318(1):303-10. DOI: 10.1016/j.bbrc.2004.04.027. View

20.

Darmoul D, Marie J, Devaud H, Gratio V, Laburthe M . Initiation of human colon cancer cell proliferation by trypsin acting at protease-activated receptor-2. Br J Cancer. 2001; 85(5):772-9. PMC: 2364111. DOI: 10.1054/bjoc.2001.1976. View