Effects of Wnt signaling on epithelial to mesenchymal transition in chronic rhinosinusitis with nasal polyp
BackgroundEpithelial to mesenchymal transition (EMT) is associated with the pathophysiology of chronic rhinosinusitis with nasal polyp (CRSwNP). Wnt signaling is causative for EMT, whereas the mechanism in CRSwNP is not fully understood.ObjectiveWe sought to evaluate the role of Wnt signaling in EMT...
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| Veröffentlicht in: | Thorax 2020-11, Vol.75 (11), p.982-993 |
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| creator | Bae, Jun-Sang Ryu, Gwanghui Kim, Ji Hye Kim, Eun Hee Rhee, Yun Hee Chung, Young-Jun Kim, Dae Woo Lim, Suha Chung, Phil-Sang Shin, Hyun-Woo Mo, Ji-Hun |
| description | BackgroundEpithelial to mesenchymal transition (EMT) is associated with the pathophysiology of chronic rhinosinusitis with nasal polyp (CRSwNP). Wnt signaling is causative for EMT, whereas the mechanism in CRSwNP is not fully understood.ObjectiveWe sought to evaluate the role of Wnt signaling in EMT of CRSwNP using a murine nasal polyp (NP) model and human tissues.MethodsInflammatory markers and EMT-related molecules were evaluated in NP models using adenomatosis polyposis coli (Apc)Min/+ mice with activated Wnt signaling and NP models treated with Wnt signaling inhibitor, indocyanine green-001 (ICG-001). EMT markers and Wnt signaling-associated mediators were analysed using human sinonasal tissues from control subjects and CRSwNP patients.ResultsApcMin/+ mice-induced NPs exhibited more frequent polypoid lesions and upregulation of Wnt-related molecules, including nuclear β-catenin, WNT3A and cyclin D1. Markers of EMT were significantly overexpressed in the ApcMin/+ NP mice (p |
| doi_str_mv | 10.1136/thoraxjnl-2019-213916 |
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Wnt signaling is causative for EMT, whereas the mechanism in CRSwNP is not fully understood.ObjectiveWe sought to evaluate the role of Wnt signaling in EMT of CRSwNP using a murine nasal polyp (NP) model and human tissues.MethodsInflammatory markers and EMT-related molecules were evaluated in NP models using adenomatosis polyposis coli (Apc)Min/+ mice with activated Wnt signaling and NP models treated with Wnt signaling inhibitor, indocyanine green-001 (ICG-001). EMT markers and Wnt signaling-associated mediators were analysed using human sinonasal tissues from control subjects and CRSwNP patients.ResultsApcMin/+ mice-induced NPs exhibited more frequent polypoid lesions and upregulation of Wnt-related molecules, including nuclear β-catenin, WNT3A and cyclin D1. Markers of EMT were significantly overexpressed in the ApcMin/+ NP mice (p<0.001 for E-cadherin and α-smooth muscle actin), and interleukin (IL)-17A+ cells and neutrophilic infiltration were increased in ApcMin/+ NP mice (p<0.001). Inhibition of Wnt signaling via ICG-001 resulted in significantly decreased nasal polypoid lesions (p<0.001), EMT-related markers (p=0.019 for E-cadherin and p=0.002 for vimentin) and the mRNA levels of IL-4 (p<0.001) and IL-17A (p=0.004) compared with the positive control group. Finally, nuclear β-catenin (p=0.042) was significantly increased compared with the control, and the expression levels of Wnt ligands and receptors were upregulated in human NP tissues (p=0.045 for WNT3A and p=0.042 for FZD2), suggesting increased Wnt signaling and EMT in CRSwNP.ConclusionWnt signaling may contribute to the pathogenesis of NPs through EMT. Therefore, inhibition of Wnt signaling may be a potential therapeutic strategy for patients with CRSwNP.</description><identifier>ISSN: 0040-6376</identifier><identifier>EISSN: 1468-3296</identifier><identifier>DOI: 10.1136/thoraxjnl-2019-213916</identifier><identifier>PMID: 33023995</identifier><language>eng</language><publisher>England: BMJ Publishing Group Ltd and British Thoracic Society</publisher><subject>Actins - metabolism ; Adenomatous Polyposis Coli Protein ; airway epithelium ; Animals ; Asthma ; beta Catenin - metabolism ; Biomarkers - metabolism ; Cadherins - metabolism ; Cell adhesion & migration ; Chronic obstructive pulmonary disease ; Cyclin D1 - metabolism ; cytokine biology ; Cytokines ; Disease Models, Animal ; Epithelial-Mesenchymal Transition - physiology ; Gene expression ; histology/cytology ; Humans ; Indocyanine Green - pharmacology ; Inflammation ; innate immunity ; Mice ; Nasal Polyps - drug therapy ; Nasal Polyps - physiopathology ; Neutrophils ; Polyps ; Respiratory research ; Rhinitis ; Rhinitis - physiopathology ; Sinusitis ; Sinusitis - physiopathology ; Twist-Related Protein 1 - metabolism ; Up-Regulation ; Wnt Signaling Pathway - physiology</subject><ispartof>Thorax, 2020-11, Vol.75 (11), p.982-993</ispartof><rights>Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.</rights><rights>2020 Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-b467t-fe77bb7b30c2c418add31617ad37f768ba6446437ead96cc6844f7ce1b62b7cd3</citedby><cites>FETCH-LOGICAL-b467t-fe77bb7b30c2c418add31617ad37f768ba6446437ead96cc6844f7ce1b62b7cd3</cites><orcidid>0000-0001-5166-3072 ; 0000-0003-1331-364X ; 0000-0002-4038-9992</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27923,27924</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33023995$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Bae, Jun-Sang</creatorcontrib><creatorcontrib>Ryu, Gwanghui</creatorcontrib><creatorcontrib>Kim, Ji Hye</creatorcontrib><creatorcontrib>Kim, Eun Hee</creatorcontrib><creatorcontrib>Rhee, Yun Hee</creatorcontrib><creatorcontrib>Chung, Young-Jun</creatorcontrib><creatorcontrib>Kim, Dae Woo</creatorcontrib><creatorcontrib>Lim, Suha</creatorcontrib><creatorcontrib>Chung, Phil-Sang</creatorcontrib><creatorcontrib>Shin, Hyun-Woo</creatorcontrib><creatorcontrib>Mo, Ji-Hun</creatorcontrib><title>Effects of Wnt signaling on epithelial to mesenchymal transition in chronic rhinosinusitis with nasal polyp</title><title>Thorax</title><addtitle>Thorax</addtitle><addtitle>Thorax</addtitle><description>BackgroundEpithelial to mesenchymal transition (EMT) is associated with the pathophysiology of chronic rhinosinusitis with nasal polyp (CRSwNP). Wnt signaling is causative for EMT, whereas the mechanism in CRSwNP is not fully understood.ObjectiveWe sought to evaluate the role of Wnt signaling in EMT of CRSwNP using a murine nasal polyp (NP) model and human tissues.MethodsInflammatory markers and EMT-related molecules were evaluated in NP models using adenomatosis polyposis coli (Apc)Min/+ mice with activated Wnt signaling and NP models treated with Wnt signaling inhibitor, indocyanine green-001 (ICG-001). EMT markers and Wnt signaling-associated mediators were analysed using human sinonasal tissues from control subjects and CRSwNP patients.ResultsApcMin/+ mice-induced NPs exhibited more frequent polypoid lesions and upregulation of Wnt-related molecules, including nuclear β-catenin, WNT3A and cyclin D1. Markers of EMT were significantly overexpressed in the ApcMin/+ NP mice (p<0.001 for E-cadherin and α-smooth muscle actin), and interleukin (IL)-17A+ cells and neutrophilic infiltration were increased in ApcMin/+ NP mice (p<0.001). Inhibition of Wnt signaling via ICG-001 resulted in significantly decreased nasal polypoid lesions (p<0.001), EMT-related markers (p=0.019 for E-cadherin and p=0.002 for vimentin) and the mRNA levels of IL-4 (p<0.001) and IL-17A (p=0.004) compared with the positive control group. Finally, nuclear β-catenin (p=0.042) was significantly increased compared with the control, and the expression levels of Wnt ligands and receptors were upregulated in human NP tissues (p=0.045 for WNT3A and p=0.042 for FZD2), suggesting increased Wnt signaling and EMT in CRSwNP.ConclusionWnt signaling may contribute to the pathogenesis of NPs through EMT. Therefore, inhibition of Wnt signaling may be a potential therapeutic strategy for patients with CRSwNP.</description><subject>Actins - metabolism</subject><subject>Adenomatous Polyposis Coli Protein</subject><subject>airway epithelium</subject><subject>Animals</subject><subject>Asthma</subject><subject>beta Catenin - metabolism</subject><subject>Biomarkers - metabolism</subject><subject>Cadherins - metabolism</subject><subject>Cell adhesion & migration</subject><subject>Chronic obstructive pulmonary disease</subject><subject>Cyclin D1 - metabolism</subject><subject>cytokine biology</subject><subject>Cytokines</subject><subject>Disease Models, Animal</subject><subject>Epithelial-Mesenchymal Transition - physiology</subject><subject>Gene expression</subject><subject>histology/cytology</subject><subject>Humans</subject><subject>Indocyanine Green - pharmacology</subject><subject>Inflammation</subject><subject>innate immunity</subject><subject>Mice</subject><subject>Nasal Polyps - drug therapy</subject><subject>Nasal Polyps - physiopathology</subject><subject>Neutrophils</subject><subject>Polyps</subject><subject>Respiratory research</subject><subject>Rhinitis</subject><subject>Rhinitis - physiopathology</subject><subject>Sinusitis</subject><subject>Sinusitis - physiopathology</subject><subject>Twist-Related Protein 1 - metabolism</subject><subject>Up-Regulation</subject><subject>Wnt Signaling Pathway - physiology</subject><issn>0040-6376</issn><issn>1468-3296</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><recordid>eNqNkc1q3DAYRUVoSSY_j5AiyCYbt_osjWQvyzBpAwPZtGRpJFmONbElV7Jp5-0j42QKXYSuhNA5F3EvQtdAPgNQ_mVsfZB_9q7LcgJllgMtgZ-gFTBeZDQv-Qe0IoSRjFPBz9B5jHtCSAEgTtEZpSSnZbleoedt0xg9Ruwb_OhGHO2Tk511T9g7bAY7tqazssOjx72Jxun20M_XIF20o02QdVi3wTurcWit89G6aX6K-HeysZMx8YPvDsMl-tjILpqr1_MC_bzb_th8z3YP3-43X3eZYlyMWWOEUEooSnSuGRSyrilwELKmohG8UJIzxhkVRtYl15oXjDVCG1A8V0LX9ALdLrlD8L8mE8eqt1GbrpPO-ClWOWMlFCQveEJv_kH3fgqpgZlaAytpqjJR64XSwccYTFMNwfYyHCog1bxGdVyjmteoljWS9-k1fVK9qY_WW_0JIAug-v1_Z8Jf5fjZ950XHJ6qBA</recordid><startdate>20201101</startdate><enddate>20201101</enddate><creator>Bae, Jun-Sang</creator><creator>Ryu, Gwanghui</creator><creator>Kim, Ji Hye</creator><creator>Kim, Eun Hee</creator><creator>Rhee, Yun Hee</creator><creator>Chung, Young-Jun</creator><creator>Kim, Dae Woo</creator><creator>Lim, Suha</creator><creator>Chung, Phil-Sang</creator><creator>Shin, Hyun-Woo</creator><creator>Mo, Ji-Hun</creator><general>BMJ Publishing Group Ltd and British Thoracic Society</general><general>BMJ Publishing Group LTD</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>BENPR</scope><scope>BTHHO</scope><scope>CCPQU</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0001-5166-3072</orcidid><orcidid>https://orcid.org/0000-0003-1331-364X</orcidid><orcidid>https://orcid.org/0000-0002-4038-9992</orcidid></search><sort><creationdate>20201101</creationdate><title>Effects of Wnt signaling on epithelial to mesenchymal transition in chronic rhinosinusitis with nasal polyp</title><author>Bae, Jun-Sang ; Ryu, Gwanghui ; Kim, Ji Hye ; Kim, Eun Hee ; Rhee, Yun Hee ; Chung, Young-Jun ; Kim, Dae Woo ; Lim, Suha ; Chung, Phil-Sang ; Shin, Hyun-Woo ; Mo, Ji-Hun</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-b467t-fe77bb7b30c2c418add31617ad37f768ba6446437ead96cc6844f7ce1b62b7cd3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Actins - metabolism</topic><topic>Adenomatous Polyposis Coli Protein</topic><topic>airway epithelium</topic><topic>Animals</topic><topic>Asthma</topic><topic>beta Catenin - metabolism</topic><topic>Biomarkers - metabolism</topic><topic>Cadherins - metabolism</topic><topic>Cell adhesion & migration</topic><topic>Chronic obstructive pulmonary disease</topic><topic>Cyclin D1 - metabolism</topic><topic>cytokine biology</topic><topic>Cytokines</topic><topic>Disease Models, Animal</topic><topic>Epithelial-Mesenchymal Transition - physiology</topic><topic>Gene expression</topic><topic>histology/cytology</topic><topic>Humans</topic><topic>Indocyanine Green - pharmacology</topic><topic>Inflammation</topic><topic>innate immunity</topic><topic>Mice</topic><topic>Nasal Polyps - drug therapy</topic><topic>Nasal Polyps - physiopathology</topic><topic>Neutrophils</topic><topic>Polyps</topic><topic>Respiratory research</topic><topic>Rhinitis</topic><topic>Rhinitis - physiopathology</topic><topic>Sinusitis</topic><topic>Sinusitis - physiopathology</topic><topic>Twist-Related Protein 1 - metabolism</topic><topic>Up-Regulation</topic><topic>Wnt Signaling Pathway - physiology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Bae, Jun-Sang</creatorcontrib><creatorcontrib>Ryu, Gwanghui</creatorcontrib><creatorcontrib>Kim, Ji Hye</creatorcontrib><creatorcontrib>Kim, Eun Hee</creatorcontrib><creatorcontrib>Rhee, Yun Hee</creatorcontrib><creatorcontrib>Chung, Young-Jun</creatorcontrib><creatorcontrib>Kim, Dae Woo</creatorcontrib><creatorcontrib>Lim, Suha</creatorcontrib><creatorcontrib>Chung, Phil-Sang</creatorcontrib><creatorcontrib>Shin, Hyun-Woo</creatorcontrib><creatorcontrib>Mo, Ji-Hun</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central</collection><collection>BMJ Journals</collection><collection>ProQuest One Community College</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>MEDLINE - Academic</collection><jtitle>Thorax</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Bae, Jun-Sang</au><au>Ryu, Gwanghui</au><au>Kim, Ji Hye</au><au>Kim, Eun Hee</au><au>Rhee, Yun Hee</au><au>Chung, Young-Jun</au><au>Kim, Dae Woo</au><au>Lim, Suha</au><au>Chung, Phil-Sang</au><au>Shin, Hyun-Woo</au><au>Mo, Ji-Hun</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Effects of Wnt signaling on epithelial to mesenchymal transition in chronic rhinosinusitis with nasal polyp</atitle><jtitle>Thorax</jtitle><stitle>Thorax</stitle><addtitle>Thorax</addtitle><date>2020-11-01</date><risdate>2020</risdate><volume>75</volume><issue>11</issue><spage>982</spage><epage>993</epage><pages>982-993</pages><issn>0040-6376</issn><eissn>1468-3296</eissn><abstract>BackgroundEpithelial to mesenchymal transition (EMT) is associated with the pathophysiology of chronic rhinosinusitis with nasal polyp (CRSwNP). Wnt signaling is causative for EMT, whereas the mechanism in CRSwNP is not fully understood.ObjectiveWe sought to evaluate the role of Wnt signaling in EMT of CRSwNP using a murine nasal polyp (NP) model and human tissues.MethodsInflammatory markers and EMT-related molecules were evaluated in NP models using adenomatosis polyposis coli (Apc)Min/+ mice with activated Wnt signaling and NP models treated with Wnt signaling inhibitor, indocyanine green-001 (ICG-001). EMT markers and Wnt signaling-associated mediators were analysed using human sinonasal tissues from control subjects and CRSwNP patients.ResultsApcMin/+ mice-induced NPs exhibited more frequent polypoid lesions and upregulation of Wnt-related molecules, including nuclear β-catenin, WNT3A and cyclin D1. Markers of EMT were significantly overexpressed in the ApcMin/+ NP mice (p<0.001 for E-cadherin and α-smooth muscle actin), and interleukin (IL)-17A+ cells and neutrophilic infiltration were increased in ApcMin/+ NP mice (p<0.001). Inhibition of Wnt signaling via ICG-001 resulted in significantly decreased nasal polypoid lesions (p<0.001), EMT-related markers (p=0.019 for E-cadherin and p=0.002 for vimentin) and the mRNA levels of IL-4 (p<0.001) and IL-17A (p=0.004) compared with the positive control group. Finally, nuclear β-catenin (p=0.042) was significantly increased compared with the control, and the expression levels of Wnt ligands and receptors were upregulated in human NP tissues (p=0.045 for WNT3A and p=0.042 for FZD2), suggesting increased Wnt signaling and EMT in CRSwNP.ConclusionWnt signaling may contribute to the pathogenesis of NPs through EMT. Therefore, inhibition of Wnt signaling may be a potential therapeutic strategy for patients with CRSwNP.</abstract><cop>England</cop><pub>BMJ Publishing Group Ltd and British Thoracic Society</pub><pmid>33023995</pmid><doi>10.1136/thoraxjnl-2019-213916</doi><tpages>12</tpages><orcidid>https://orcid.org/0000-0001-5166-3072</orcidid><orcidid>https://orcid.org/0000-0003-1331-364X</orcidid><orcidid>https://orcid.org/0000-0002-4038-9992</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Actins - metabolism Adenomatous Polyposis Coli Protein airway epithelium Animals Asthma beta Catenin - metabolism Biomarkers - metabolism Cadherins - metabolism Cell adhesion & migration Chronic obstructive pulmonary disease Cyclin D1 - metabolism cytokine biology Cytokines Disease Models, Animal Epithelial-Mesenchymal Transition - physiology Gene expression histology/cytology Humans Indocyanine Green - pharmacology Inflammation innate immunity Mice Nasal Polyps - drug therapy Nasal Polyps - physiopathology Neutrophils Polyps Respiratory research Rhinitis Rhinitis - physiopathology Sinusitis Sinusitis - physiopathology Twist-Related Protein 1 - metabolism Up-Regulation Wnt Signaling Pathway - physiology |
| title | Effects of Wnt signaling on epithelial to mesenchymal transition in chronic rhinosinusitis with nasal polyp |
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