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Loss of CYLD promotes cell invasion via ALK5 stabilization in oral squamous cell carcinoma
Oral squamous cell carcinoma (OSCC) has a very poor prognosis because of its highly invasive nature, and the 5‐year survival rate has not changed appreciably for the past 30 years. Although cylindromatosis (CYLD), a deubiquitinating enzyme, is thought to be a potent tumour suppressor, its biological...
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Published in: | The Journal of pathology 2018-03, Vol.244 (3), p.367-379 |
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creator | Shinriki, Satoru Jono, Hirofumi Maeshiro, Manabu Nakamura, Takuya Guo, Jianying Li, Jian‐Dong Ueda, Mitsuharu Yoshida, Ryoji Shinohara, Masanori Nakayama, Hideki Matsui, Hirotaka Ando, Yukio |
description | Oral squamous cell carcinoma (OSCC) has a very poor prognosis because of its highly invasive nature, and the 5‐year survival rate has not changed appreciably for the past 30 years. Although cylindromatosis (CYLD), a deubiquitinating enzyme, is thought to be a potent tumour suppressor, its biological and clinical significance in OSCC is largely unknown. This study aimed to clarify the roles of CYLD in OSCC progression. Our immunohistochemical analyses revealed significantly reduced CYLD expression in invasive areas in OSCC tissues, whereas CYLD expression was conserved in normal epithelium and carcinoma in situ. Furthermore, downregulation of CYLD by siRNA led to the acquisition of mesenchymal features and increased migratory and invasive properties in OSCC cells and HaCaT keratinocytes. It is interesting that CYLD knockdown promoted transforming growth factor‐β (TGF‐β) signalling by inducing stabilization of TGF‐β receptor I (ALK5) in a cell autonomous fashion. In addition, the response to exogenous TGF‐β stimulation was enhanced by CYLD downregulation. The invasive phenotypes induced by CYLD knockdown were completely blocked by an ALK5 inhibitor. In addition, lower expression of CYLD was significantly associated with the clinical features of deep invasion and poor overall survival, and also with increased phosphorylation of Smad3, which is an indicator of activation of TGF‐β signalling in invasive OSCC. These findings suggest that downregulation of CYLD promotes invasion with mesenchymal transition via ALK5 stabilization in OSCC cells. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. |
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Although cylindromatosis (CYLD), a deubiquitinating enzyme, is thought to be a potent tumour suppressor, its biological and clinical significance in OSCC is largely unknown. This study aimed to clarify the roles of CYLD in OSCC progression. Our immunohistochemical analyses revealed significantly reduced CYLD expression in invasive areas in OSCC tissues, whereas CYLD expression was conserved in normal epithelium and carcinoma in situ. Furthermore, downregulation of CYLD by siRNA led to the acquisition of mesenchymal features and increased migratory and invasive properties in OSCC cells and HaCaT keratinocytes. It is interesting that CYLD knockdown promoted transforming growth factor‐β (TGF‐β) signalling by inducing stabilization of TGF‐β receptor I (ALK5) in a cell autonomous fashion. In addition, the response to exogenous TGF‐β stimulation was enhanced by CYLD downregulation. The invasive phenotypes induced by CYLD knockdown were completely blocked by an ALK5 inhibitor. In addition, lower expression of CYLD was significantly associated with the clinical features of deep invasion and poor overall survival, and also with increased phosphorylation of Smad3, which is an indicator of activation of TGF‐β signalling in invasive OSCC. These findings suggest that downregulation of CYLD promotes invasion with mesenchymal transition via ALK5 stabilization in OSCC cells. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.</description><identifier>ISSN: 0022-3417</identifier><identifier>EISSN: 1096-9896</identifier><identifier>DOI: 10.1002/path.5019</identifier><identifier>PMID: 29235674</identifier><language>eng</language><publisher>Chichester, UK: John Wiley & Sons, Ltd</publisher><subject>ALK5 ; CYLD ; Epithelium ; Invasiveness ; Keratinocytes ; Medical prognosis ; mesenchymal transition, invasion ; Mesenchyme ; Oral cancer ; Oral squamous cell carcinoma ; Phosphorylation ; siRNA ; Smad3 protein ; Squamous cell carcinoma ; Stabilization ; Tissues ; Transforming growth factor-b ; transforming growth factor‐β ; Tumors</subject><ispartof>The Journal of pathology, 2018-03, Vol.244 (3), p.367-379</ispartof><rights>Copyright © 2017 Pathological Society of Great Britain and Ireland. 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Although cylindromatosis (CYLD), a deubiquitinating enzyme, is thought to be a potent tumour suppressor, its biological and clinical significance in OSCC is largely unknown. This study aimed to clarify the roles of CYLD in OSCC progression. Our immunohistochemical analyses revealed significantly reduced CYLD expression in invasive areas in OSCC tissues, whereas CYLD expression was conserved in normal epithelium and carcinoma in situ. Furthermore, downregulation of CYLD by siRNA led to the acquisition of mesenchymal features and increased migratory and invasive properties in OSCC cells and HaCaT keratinocytes. It is interesting that CYLD knockdown promoted transforming growth factor‐β (TGF‐β) signalling by inducing stabilization of TGF‐β receptor I (ALK5) in a cell autonomous fashion. In addition, the response to exogenous TGF‐β stimulation was enhanced by CYLD downregulation. The invasive phenotypes induced by CYLD knockdown were completely blocked by an ALK5 inhibitor. In addition, lower expression of CYLD was significantly associated with the clinical features of deep invasion and poor overall survival, and also with increased phosphorylation of Smad3, which is an indicator of activation of TGF‐β signalling in invasive OSCC. These findings suggest that downregulation of CYLD promotes invasion with mesenchymal transition via ALK5 stabilization in OSCC cells. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.</description><subject>ALK5</subject><subject>CYLD</subject><subject>Epithelium</subject><subject>Invasiveness</subject><subject>Keratinocytes</subject><subject>Medical prognosis</subject><subject>mesenchymal transition, invasion</subject><subject>Mesenchyme</subject><subject>Oral cancer</subject><subject>Oral squamous cell carcinoma</subject><subject>Phosphorylation</subject><subject>siRNA</subject><subject>Smad3 protein</subject><subject>Squamous cell carcinoma</subject><subject>Stabilization</subject><subject>Tissues</subject><subject>Transforming growth factor-b</subject><subject>transforming growth factor‐β</subject><subject>Tumors</subject><issn>0022-3417</issn><issn>1096-9896</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><recordid>eNp1kE1LxDAURYMoOn4s_AMScKOLatImabMcxk8s6EIXugkvmRQjbTM2raK_3tQZXQiuHuSdXO47CO1TckIJSU8X0D-fcELlGppQIkUiCynW0STu0iRjNN9C2yG8EEKk5HwTbaUyzbjI2QQ9lT4E7Cs8eyzP8KLzje9twMbWNXbtGwTnW_zmAE_LG45DD9rV7hP68dm12HdQ4_A6QOOH1S8DnXGtb2AXbVRQB7u3mjvo4eL8fnaVlLeX17NpmRhGpUxEqhmfV7YCw62xugDCoOBaZFrqwpg5kCrTXBesyAQX0giRxUOgEgWVhrFsBx0tc2P718GGXjUujFWgtbGVojIXjLFc5hE9_IO--KFrYzuVEkJFITM6UsdLynRRTmcrtehcA92HokSNwtUoXI3CI3uwShx0Y-e_5I_hCJwugXdX24__k9Td9P7qO_IL4lCKAA</recordid><startdate>201803</startdate><enddate>201803</enddate><creator>Shinriki, Satoru</creator><creator>Jono, Hirofumi</creator><creator>Maeshiro, Manabu</creator><creator>Nakamura, Takuya</creator><creator>Guo, Jianying</creator><creator>Li, Jian‐Dong</creator><creator>Ueda, Mitsuharu</creator><creator>Yoshida, Ryoji</creator><creator>Shinohara, Masanori</creator><creator>Nakayama, Hideki</creator><creator>Matsui, Hirotaka</creator><creator>Ando, Yukio</creator><general>John Wiley & Sons, Ltd</general><general>Wiley Subscription Services, Inc</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QP</scope><scope>7QR</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>8FD</scope><scope>FR3</scope><scope>H94</scope><scope>K9.</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0002-1688-5769</orcidid></search><sort><creationdate>201803</creationdate><title>Loss of CYLD promotes cell invasion via ALK5 stabilization in oral squamous cell carcinoma</title><author>Shinriki, Satoru ; Jono, Hirofumi ; Maeshiro, Manabu ; Nakamura, Takuya ; Guo, Jianying ; Li, Jian‐Dong ; Ueda, Mitsuharu ; Yoshida, Ryoji ; Shinohara, Masanori ; Nakayama, Hideki ; Matsui, Hirotaka ; Ando, Yukio</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4199-62b45dfefac5eceb8a04a85b63b9b8ccda0f3b5b84836569c663009af6819c443</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>ALK5</topic><topic>CYLD</topic><topic>Epithelium</topic><topic>Invasiveness</topic><topic>Keratinocytes</topic><topic>Medical prognosis</topic><topic>mesenchymal transition, invasion</topic><topic>Mesenchyme</topic><topic>Oral cancer</topic><topic>Oral squamous cell carcinoma</topic><topic>Phosphorylation</topic><topic>siRNA</topic><topic>Smad3 protein</topic><topic>Squamous cell carcinoma</topic><topic>Stabilization</topic><topic>Tissues</topic><topic>Transforming growth factor-b</topic><topic>transforming growth factor‐β</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Shinriki, Satoru</creatorcontrib><creatorcontrib>Jono, Hirofumi</creatorcontrib><creatorcontrib>Maeshiro, Manabu</creatorcontrib><creatorcontrib>Nakamura, Takuya</creatorcontrib><creatorcontrib>Guo, Jianying</creatorcontrib><creatorcontrib>Li, Jian‐Dong</creatorcontrib><creatorcontrib>Ueda, Mitsuharu</creatorcontrib><creatorcontrib>Yoshida, Ryoji</creatorcontrib><creatorcontrib>Shinohara, Masanori</creatorcontrib><creatorcontrib>Nakayama, Hideki</creatorcontrib><creatorcontrib>Matsui, Hirotaka</creatorcontrib><creatorcontrib>Ando, Yukio</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>The Journal of pathology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Shinriki, Satoru</au><au>Jono, Hirofumi</au><au>Maeshiro, Manabu</au><au>Nakamura, Takuya</au><au>Guo, Jianying</au><au>Li, Jian‐Dong</au><au>Ueda, Mitsuharu</au><au>Yoshida, Ryoji</au><au>Shinohara, Masanori</au><au>Nakayama, Hideki</au><au>Matsui, Hirotaka</au><au>Ando, Yukio</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Loss of CYLD promotes cell invasion via ALK5 stabilization in oral squamous cell carcinoma</atitle><jtitle>The Journal of pathology</jtitle><addtitle>J Pathol</addtitle><date>2018-03</date><risdate>2018</risdate><volume>244</volume><issue>3</issue><spage>367</spage><epage>379</epage><pages>367-379</pages><issn>0022-3417</issn><eissn>1096-9896</eissn><notes>ObjectType-Article-1</notes><notes>SourceType-Scholarly Journals-1</notes><notes>ObjectType-Feature-2</notes><notes>content type line 23</notes><abstract>Oral squamous cell carcinoma (OSCC) has a very poor prognosis because of its highly invasive nature, and the 5‐year survival rate has not changed appreciably for the past 30 years. Although cylindromatosis (CYLD), a deubiquitinating enzyme, is thought to be a potent tumour suppressor, its biological and clinical significance in OSCC is largely unknown. This study aimed to clarify the roles of CYLD in OSCC progression. Our immunohistochemical analyses revealed significantly reduced CYLD expression in invasive areas in OSCC tissues, whereas CYLD expression was conserved in normal epithelium and carcinoma in situ. Furthermore, downregulation of CYLD by siRNA led to the acquisition of mesenchymal features and increased migratory and invasive properties in OSCC cells and HaCaT keratinocytes. It is interesting that CYLD knockdown promoted transforming growth factor‐β (TGF‐β) signalling by inducing stabilization of TGF‐β receptor I (ALK5) in a cell autonomous fashion. In addition, the response to exogenous TGF‐β stimulation was enhanced by CYLD downregulation. The invasive phenotypes induced by CYLD knockdown were completely blocked by an ALK5 inhibitor. In addition, lower expression of CYLD was significantly associated with the clinical features of deep invasion and poor overall survival, and also with increased phosphorylation of Smad3, which is an indicator of activation of TGF‐β signalling in invasive OSCC. These findings suggest that downregulation of CYLD promotes invasion with mesenchymal transition via ALK5 stabilization in OSCC cells. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.</abstract><cop>Chichester, UK</cop><pub>John Wiley & Sons, Ltd</pub><pmid>29235674</pmid><doi>10.1002/path.5019</doi><tpages>13</tpages><orcidid>https://orcid.org/0000-0002-1688-5769</orcidid></addata></record> |
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subjects | ALK5 CYLD Epithelium Invasiveness Keratinocytes Medical prognosis mesenchymal transition, invasion Mesenchyme Oral cancer Oral squamous cell carcinoma Phosphorylation siRNA Smad3 protein Squamous cell carcinoma Stabilization Tissues Transforming growth factor-b transforming growth factor‐β Tumors |
title | Loss of CYLD promotes cell invasion via ALK5 stabilization in oral squamous cell carcinoma |
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