Merkel cell polyomavirus–negative Merkel cell carcinoma is associated with JAK‐STAT and MEK‐ERK pathway activation
Merkel cell polyomavirus (MCPyV) is monoclonally integrated into the genomes of approximately 80% of Merkel cell carcinomas (MCCs). While the presence of MCPyV affects the clinicopathological features of MCC, the molecular mechanisms of MCC pathogenesis after MCPyV infection are unclear. This study...
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| Veröffentlicht in: | Cancer science 2022-01, Vol.113 (1), p.251-260 |
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| creator | Iwasaki, Takeshi Hayashi, Kazuhiko Matsushita, Michiko Nonaka, Daisuke Kohashi, Kenichi Kuwamoto, Satoshi Umekita, Yoshihisa Oda, Yoshinao |
| description | Merkel cell polyomavirus (MCPyV) is monoclonally integrated into the genomes of approximately 80% of Merkel cell carcinomas (MCCs). While the presence of MCPyV affects the clinicopathological features of MCC, the molecular mechanisms of MCC pathogenesis after MCPyV infection are unclear. This study investigates the association between MCPyV infection and activation of the MEK‐ERK and JAK‐STAT signaling pathways in MCC to identify new molecular targets for MCC treatment. The clinicopathological characteristics of 30 MCPyV‐positive and 20 MCPyV‐negative MCC cases were analyzed. The phosphorylation status of MEK, ERK, JAK, and STAT was determined by immunohistochemical analysis. The activation status of the MEK‐ERK and JAK‐STAT pathways and the effects of a JAK inhibitor (ruxolitinib) was analyzed in MCC cell lines. Immunohistochemically, the expression of pJAK2 (P = .038) and pERK1/2 (P = .019) was significantly higher in MCPyV‐negative than in MCPyV‐positive MCCs. Male gender (hazard ratio [HR] 2.882, P = .039), older age (HR 1.137, P |
| doi_str_mv | 10.1111/cas.15187 |
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| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_8748213</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2592317361</sourcerecordid><originalsourceid>FETCH-LOGICAL-c4677-9f1da620e9961e3fbd945a2c68f1e2094dfbca54f3f8966c94d19727b11523403</originalsourceid><addsrcrecordid>eNp1kctuEzEUhi0EoiWw4AWQJTawSOvb2OMNUhQF6E1INKytE4-ncZmMU3smIbs-AlLfsE9SpylVQcILX44_fTr2j9BbSg5oHocW0gEtaKmeoX3KhR4qQuTz-70aasLZHnqV0iUhXAotXqK9XGeClWIf_Tpz8adrsHVNg5eh2YQFrHzs0-31TesuoPMrh58yFqL1baawTxhSCtZD5yq89t0cH49Obq9_n09HUwxthc8m2-Pk-wleQjdfwwaDzcIsDe1r9KKGJrk3D-sA_fg8mY6_Dk-_fTkaj06HVkiVu69pBZIRp7WkjtezSosCmJVlTR0jWlT1zEIhal6XWkqbC1QrpmaUFowLwgfo08677GcLV1nXdhEas4x-AXFjAnjz903r5-YirEypRMkoz4IPD4IYrnqXOrPwafsV0LrQJ8MKzThVXNKMvv8HvQx9bPPzDJO05ErrPA_Qxx1lY0gpuvqxGUrMNk-T8zT3eWb23dPuH8k_AWbgcAesfeM2_zeZ8eh8p7wDF5mtXg</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2618379918</pqid></control><display><type>article</type><title>Merkel cell polyomavirus–negative Merkel cell carcinoma is associated with JAK‐STAT and MEK‐ERK pathway activation</title><source>MEDLINE</source><source>DOAJ Directory of Open Access Journals</source><source>Access via Wiley Online Library</source><source>Wiley Online Library (Open Access Collection)</source><source>PubMed Central</source><creator>Iwasaki, Takeshi ; Hayashi, Kazuhiko ; Matsushita, Michiko ; Nonaka, Daisuke ; Kohashi, Kenichi ; Kuwamoto, Satoshi ; Umekita, Yoshihisa ; Oda, Yoshinao</creator><creatorcontrib>Iwasaki, Takeshi ; Hayashi, Kazuhiko ; Matsushita, Michiko ; Nonaka, Daisuke ; Kohashi, Kenichi ; Kuwamoto, Satoshi ; Umekita, Yoshihisa ; Oda, Yoshinao</creatorcontrib><description>Merkel cell polyomavirus (MCPyV) is monoclonally integrated into the genomes of approximately 80% of Merkel cell carcinomas (MCCs). While the presence of MCPyV affects the clinicopathological features of MCC, the molecular mechanisms of MCC pathogenesis after MCPyV infection are unclear. This study investigates the association between MCPyV infection and activation of the MEK‐ERK and JAK‐STAT signaling pathways in MCC to identify new molecular targets for MCC treatment. The clinicopathological characteristics of 30 MCPyV‐positive and 20 MCPyV‐negative MCC cases were analyzed. The phosphorylation status of MEK, ERK, JAK, and STAT was determined by immunohistochemical analysis. The activation status of the MEK‐ERK and JAK‐STAT pathways and the effects of a JAK inhibitor (ruxolitinib) was analyzed in MCC cell lines. Immunohistochemically, the expression of pJAK2 (P = .038) and pERK1/2 (P = .019) was significantly higher in MCPyV‐negative than in MCPyV‐positive MCCs. Male gender (hazard ratio [HR] 2.882, P = .039), older age (HR 1.137, P < .001), negative MCPyV status (HR 0.324, P = .013), and advanced cancer stage (HR 2.672, P = .041) were identified as unfavorable prognostic factors; however, the phosphorylation states of JAK2, STAT3, MEK1/2, and ERK1/2 were unrelated to the prognosis. The inhibition of cell proliferation by ruxolitinib was greater in MCPyV‐negative MCC cell lines than in an MCPyV‐positive MCC cell line. The expression of pERK1/2 and pMEK was higher in MCPyV‐negative than in MCPyV‐positive cell lines. These results suggest that activation of the JAK2 and MEK‐ERK pathways was more prevalent in MCPyV‐negative than in MCPyV‐positive MCC and the JAK inhibitor ruxolitinib inhibited MEK‐ERK pathway activation. Consequently, the JAK‐STAT and MEK‐ERK signaling pathways may be potential targets for MCPyV‐negative MCC treatment.
This study investigates the relationship between Merkel cell polyomavirus (MCPyV) status and activation of the MEK‐ERK and JAK‐STAT signaling pathways in Merkel cell carcinoma (MCC). We observed that activation of the JAK2 and MEK‐ERK pathways was more prevalent in MCPyV‐negative than in MCPyV‐positive MCC, leading us to conclude that MCC tumorigenic pathways differ depending on MCPyV status. MEK‐ERK pathway activation was inhibited by a JAK inhibitor in vitro in MCPyV‐negative MCC. Thus, JAK‐STAT and MEK‐ERK pathway inhibition may present a promising new treatment strategy for patients with advanced MCC.</description><identifier>ISSN: 1347-9032</identifier><identifier>EISSN: 1349-7006</identifier><identifier>DOI: 10.1111/cas.15187</identifier><identifier>PMID: 34724284</identifier><language>eng</language><publisher>England: John Wiley & Sons, Inc</publisher><subject>Age Factors ; Aged ; Aged, 80 and over ; Antibodies ; Antigens ; Cancer ; Carcinoma ; Carcinoma, Merkel Cell - metabolism ; Carcinoma, Merkel Cell - virology ; Cell activation ; Cell growth ; Cell Line, Tumor ; Cell Proliferation ; Extracellular signal-regulated kinase ; Female ; Gene Expression Regulation, Neoplastic - drug effects ; Genomes ; Humans ; Infections ; JAK‐STAT pathway ; Janus kinase 2 ; Janus Kinases - metabolism ; Kinases ; Male ; MAP Kinase Signaling System - drug effects ; MEK‐ERK pathway ; Merkel cell carcinoma ; Merkel cell polyomavirus ; Merkel cell polyomavirus - pathogenicity ; Metabolic pathways ; Middle Aged ; Molecular modelling ; Nitriles - pharmacology ; Original ; Phosphorylation ; Phosphorylation - drug effects ; Prognosis ; Pyrazoles - pharmacology ; Pyrimidines - pharmacology ; Sex Characteristics ; Signal transduction ; Skin Neoplasms - metabolism ; Skin Neoplasms - virology ; Software ; STAT Transcription Factors - metabolism ; Stat3 protein ; Transcription factors ; Tumors</subject><ispartof>Cancer science, 2022-01, Vol.113 (1), p.251-260</ispartof><rights>2021 The Authors. published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.</rights><rights>2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.</rights><rights>2022. This work is published under http://creativecommons.org/licenses/by-nc-nd/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4677-9f1da620e9961e3fbd945a2c68f1e2094dfbca54f3f8966c94d19727b11523403</citedby><cites>FETCH-LOGICAL-c4677-9f1da620e9961e3fbd945a2c68f1e2094dfbca54f3f8966c94d19727b11523403</cites><orcidid>0000-0001-5277-2932 ; 0000-0001-9636-1182</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8748213/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8748213/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,315,728,781,785,865,886,1418,11566,27928,27929,45578,45579,46056,46480,53795,53797</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34724284$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Iwasaki, Takeshi</creatorcontrib><creatorcontrib>Hayashi, Kazuhiko</creatorcontrib><creatorcontrib>Matsushita, Michiko</creatorcontrib><creatorcontrib>Nonaka, Daisuke</creatorcontrib><creatorcontrib>Kohashi, Kenichi</creatorcontrib><creatorcontrib>Kuwamoto, Satoshi</creatorcontrib><creatorcontrib>Umekita, Yoshihisa</creatorcontrib><creatorcontrib>Oda, Yoshinao</creatorcontrib><title>Merkel cell polyomavirus–negative Merkel cell carcinoma is associated with JAK‐STAT and MEK‐ERK pathway activation</title><title>Cancer science</title><addtitle>Cancer Sci</addtitle><description>Merkel cell polyomavirus (MCPyV) is monoclonally integrated into the genomes of approximately 80% of Merkel cell carcinomas (MCCs). While the presence of MCPyV affects the clinicopathological features of MCC, the molecular mechanisms of MCC pathogenesis after MCPyV infection are unclear. This study investigates the association between MCPyV infection and activation of the MEK‐ERK and JAK‐STAT signaling pathways in MCC to identify new molecular targets for MCC treatment. The clinicopathological characteristics of 30 MCPyV‐positive and 20 MCPyV‐negative MCC cases were analyzed. The phosphorylation status of MEK, ERK, JAK, and STAT was determined by immunohistochemical analysis. The activation status of the MEK‐ERK and JAK‐STAT pathways and the effects of a JAK inhibitor (ruxolitinib) was analyzed in MCC cell lines. Immunohistochemically, the expression of pJAK2 (P = .038) and pERK1/2 (P = .019) was significantly higher in MCPyV‐negative than in MCPyV‐positive MCCs. Male gender (hazard ratio [HR] 2.882, P = .039), older age (HR 1.137, P < .001), negative MCPyV status (HR 0.324, P = .013), and advanced cancer stage (HR 2.672, P = .041) were identified as unfavorable prognostic factors; however, the phosphorylation states of JAK2, STAT3, MEK1/2, and ERK1/2 were unrelated to the prognosis. The inhibition of cell proliferation by ruxolitinib was greater in MCPyV‐negative MCC cell lines than in an MCPyV‐positive MCC cell line. The expression of pERK1/2 and pMEK was higher in MCPyV‐negative than in MCPyV‐positive cell lines. These results suggest that activation of the JAK2 and MEK‐ERK pathways was more prevalent in MCPyV‐negative than in MCPyV‐positive MCC and the JAK inhibitor ruxolitinib inhibited MEK‐ERK pathway activation. Consequently, the JAK‐STAT and MEK‐ERK signaling pathways may be potential targets for MCPyV‐negative MCC treatment.
This study investigates the relationship between Merkel cell polyomavirus (MCPyV) status and activation of the MEK‐ERK and JAK‐STAT signaling pathways in Merkel cell carcinoma (MCC). We observed that activation of the JAK2 and MEK‐ERK pathways was more prevalent in MCPyV‐negative than in MCPyV‐positive MCC, leading us to conclude that MCC tumorigenic pathways differ depending on MCPyV status. MEK‐ERK pathway activation was inhibited by a JAK inhibitor in vitro in MCPyV‐negative MCC. Thus, JAK‐STAT and MEK‐ERK pathway inhibition may present a promising new treatment strategy for patients with advanced MCC.</description><subject>Age Factors</subject><subject>Aged</subject><subject>Aged, 80 and over</subject><subject>Antibodies</subject><subject>Antigens</subject><subject>Cancer</subject><subject>Carcinoma</subject><subject>Carcinoma, Merkel Cell - metabolism</subject><subject>Carcinoma, Merkel Cell - virology</subject><subject>Cell activation</subject><subject>Cell growth</subject><subject>Cell Line, Tumor</subject><subject>Cell Proliferation</subject><subject>Extracellular signal-regulated kinase</subject><subject>Female</subject><subject>Gene Expression Regulation, Neoplastic - drug effects</subject><subject>Genomes</subject><subject>Humans</subject><subject>Infections</subject><subject>JAK‐STAT pathway</subject><subject>Janus kinase 2</subject><subject>Janus Kinases - metabolism</subject><subject>Kinases</subject><subject>Male</subject><subject>MAP Kinase Signaling System - drug effects</subject><subject>MEK‐ERK pathway</subject><subject>Merkel cell carcinoma</subject><subject>Merkel cell polyomavirus</subject><subject>Merkel cell polyomavirus - pathogenicity</subject><subject>Metabolic pathways</subject><subject>Middle Aged</subject><subject>Molecular modelling</subject><subject>Nitriles - pharmacology</subject><subject>Original</subject><subject>Phosphorylation</subject><subject>Phosphorylation - drug effects</subject><subject>Prognosis</subject><subject>Pyrazoles - pharmacology</subject><subject>Pyrimidines - pharmacology</subject><subject>Sex Characteristics</subject><subject>Signal transduction</subject><subject>Skin Neoplasms - metabolism</subject><subject>Skin Neoplasms - virology</subject><subject>Software</subject><subject>STAT Transcription Factors - metabolism</subject><subject>Stat3 protein</subject><subject>Transcription factors</subject><subject>Tumors</subject><issn>1347-9032</issn><issn>1349-7006</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>24P</sourceid><sourceid>WIN</sourceid><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNp1kctuEzEUhi0EoiWw4AWQJTawSOvb2OMNUhQF6E1INKytE4-ncZmMU3smIbs-AlLfsE9SpylVQcILX44_fTr2j9BbSg5oHocW0gEtaKmeoX3KhR4qQuTz-70aasLZHnqV0iUhXAotXqK9XGeClWIf_Tpz8adrsHVNg5eh2YQFrHzs0-31TesuoPMrh58yFqL1baawTxhSCtZD5yq89t0cH49Obq9_n09HUwxthc8m2-Pk-wleQjdfwwaDzcIsDe1r9KKGJrk3D-sA_fg8mY6_Dk-_fTkaj06HVkiVu69pBZIRp7WkjtezSosCmJVlTR0jWlT1zEIhal6XWkqbC1QrpmaUFowLwgfo08677GcLV1nXdhEas4x-AXFjAnjz903r5-YirEypRMkoz4IPD4IYrnqXOrPwafsV0LrQJ8MKzThVXNKMvv8HvQx9bPPzDJO05ErrPA_Qxx1lY0gpuvqxGUrMNk-T8zT3eWb23dPuH8k_AWbgcAesfeM2_zeZ8eh8p7wDF5mtXg</recordid><startdate>202201</startdate><enddate>202201</enddate><creator>Iwasaki, Takeshi</creator><creator>Hayashi, Kazuhiko</creator><creator>Matsushita, Michiko</creator><creator>Nonaka, Daisuke</creator><creator>Kohashi, Kenichi</creator><creator>Kuwamoto, Satoshi</creator><creator>Umekita, Yoshihisa</creator><creator>Oda, Yoshinao</creator><general>John Wiley & Sons, Inc</general><general>John Wiley and Sons Inc</general><scope>24P</scope><scope>WIN</scope><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>8FE</scope><scope>8FH</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>LK8</scope><scope>M7P</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-5277-2932</orcidid><orcidid>https://orcid.org/0000-0001-9636-1182</orcidid></search><sort><creationdate>202201</creationdate><title>Merkel cell polyomavirus–negative Merkel cell carcinoma is associated with JAK‐STAT and MEK‐ERK pathway activation</title><author>Iwasaki, Takeshi ; Hayashi, Kazuhiko ; Matsushita, Michiko ; Nonaka, Daisuke ; Kohashi, Kenichi ; Kuwamoto, Satoshi ; Umekita, Yoshihisa ; Oda, Yoshinao</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4677-9f1da620e9961e3fbd945a2c68f1e2094dfbca54f3f8966c94d19727b11523403</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Age Factors</topic><topic>Aged</topic><topic>Aged, 80 and over</topic><topic>Antibodies</topic><topic>Antigens</topic><topic>Cancer</topic><topic>Carcinoma</topic><topic>Carcinoma, Merkel Cell - metabolism</topic><topic>Carcinoma, Merkel Cell - virology</topic><topic>Cell activation</topic><topic>Cell growth</topic><topic>Cell Line, Tumor</topic><topic>Cell Proliferation</topic><topic>Extracellular signal-regulated kinase</topic><topic>Female</topic><topic>Gene Expression Regulation, Neoplastic - drug effects</topic><topic>Genomes</topic><topic>Humans</topic><topic>Infections</topic><topic>JAK‐STAT pathway</topic><topic>Janus kinase 2</topic><topic>Janus Kinases - metabolism</topic><topic>Kinases</topic><topic>Male</topic><topic>MAP Kinase Signaling System - drug effects</topic><topic>MEK‐ERK pathway</topic><topic>Merkel cell carcinoma</topic><topic>Merkel cell polyomavirus</topic><topic>Merkel cell polyomavirus - pathogenicity</topic><topic>Metabolic pathways</topic><topic>Middle Aged</topic><topic>Molecular modelling</topic><topic>Nitriles - pharmacology</topic><topic>Original</topic><topic>Phosphorylation</topic><topic>Phosphorylation - drug effects</topic><topic>Prognosis</topic><topic>Pyrazoles - pharmacology</topic><topic>Pyrimidines - pharmacology</topic><topic>Sex Characteristics</topic><topic>Signal transduction</topic><topic>Skin Neoplasms - metabolism</topic><topic>Skin Neoplasms - virology</topic><topic>Software</topic><topic>STAT Transcription Factors - metabolism</topic><topic>Stat3 protein</topic><topic>Transcription factors</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Iwasaki, Takeshi</creatorcontrib><creatorcontrib>Hayashi, Kazuhiko</creatorcontrib><creatorcontrib>Matsushita, Michiko</creatorcontrib><creatorcontrib>Nonaka, Daisuke</creatorcontrib><creatorcontrib>Kohashi, Kenichi</creatorcontrib><creatorcontrib>Kuwamoto, Satoshi</creatorcontrib><creatorcontrib>Umekita, Yoshihisa</creatorcontrib><creatorcontrib>Oda, Yoshinao</creatorcontrib><collection>Wiley Online Library (Open Access Collection)</collection><collection>Wiley Online Library (Open Access Collection)</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>Biological Science Database</collection><collection>Access via ProQuest (Open Access)</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><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cancer science</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Iwasaki, Takeshi</au><au>Hayashi, Kazuhiko</au><au>Matsushita, Michiko</au><au>Nonaka, Daisuke</au><au>Kohashi, Kenichi</au><au>Kuwamoto, Satoshi</au><au>Umekita, Yoshihisa</au><au>Oda, Yoshinao</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Merkel cell polyomavirus–negative Merkel cell carcinoma is associated with JAK‐STAT and MEK‐ERK pathway activation</atitle><jtitle>Cancer science</jtitle><addtitle>Cancer Sci</addtitle><date>2022-01</date><risdate>2022</risdate><volume>113</volume><issue>1</issue><spage>251</spage><epage>260</epage><pages>251-260</pages><issn>1347-9032</issn><eissn>1349-7006</eissn><abstract>Merkel cell polyomavirus (MCPyV) is monoclonally integrated into the genomes of approximately 80% of Merkel cell carcinomas (MCCs). While the presence of MCPyV affects the clinicopathological features of MCC, the molecular mechanisms of MCC pathogenesis after MCPyV infection are unclear. This study investigates the association between MCPyV infection and activation of the MEK‐ERK and JAK‐STAT signaling pathways in MCC to identify new molecular targets for MCC treatment. The clinicopathological characteristics of 30 MCPyV‐positive and 20 MCPyV‐negative MCC cases were analyzed. The phosphorylation status of MEK, ERK, JAK, and STAT was determined by immunohistochemical analysis. The activation status of the MEK‐ERK and JAK‐STAT pathways and the effects of a JAK inhibitor (ruxolitinib) was analyzed in MCC cell lines. Immunohistochemically, the expression of pJAK2 (P = .038) and pERK1/2 (P = .019) was significantly higher in MCPyV‐negative than in MCPyV‐positive MCCs. Male gender (hazard ratio [HR] 2.882, P = .039), older age (HR 1.137, P < .001), negative MCPyV status (HR 0.324, P = .013), and advanced cancer stage (HR 2.672, P = .041) were identified as unfavorable prognostic factors; however, the phosphorylation states of JAK2, STAT3, MEK1/2, and ERK1/2 were unrelated to the prognosis. The inhibition of cell proliferation by ruxolitinib was greater in MCPyV‐negative MCC cell lines than in an MCPyV‐positive MCC cell line. The expression of pERK1/2 and pMEK was higher in MCPyV‐negative than in MCPyV‐positive cell lines. These results suggest that activation of the JAK2 and MEK‐ERK pathways was more prevalent in MCPyV‐negative than in MCPyV‐positive MCC and the JAK inhibitor ruxolitinib inhibited MEK‐ERK pathway activation. Consequently, the JAK‐STAT and MEK‐ERK signaling pathways may be potential targets for MCPyV‐negative MCC treatment.
This study investigates the relationship between Merkel cell polyomavirus (MCPyV) status and activation of the MEK‐ERK and JAK‐STAT signaling pathways in Merkel cell carcinoma (MCC). We observed that activation of the JAK2 and MEK‐ERK pathways was more prevalent in MCPyV‐negative than in MCPyV‐positive MCC, leading us to conclude that MCC tumorigenic pathways differ depending on MCPyV status. MEK‐ERK pathway activation was inhibited by a JAK inhibitor in vitro in MCPyV‐negative MCC. Thus, JAK‐STAT and MEK‐ERK pathway inhibition may present a promising new treatment strategy for patients with advanced MCC.</abstract><cop>England</cop><pub>John Wiley & Sons, Inc</pub><pmid>34724284</pmid><doi>10.1111/cas.15187</doi><tpages>10</tpages><orcidid>https://orcid.org/0000-0001-5277-2932</orcidid><orcidid>https://orcid.org/0000-0001-9636-1182</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | Cancer science, 2022-01, Vol.113 (1), p.251-260 |
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| subjects | Age Factors Aged Aged, 80 and over Antibodies Antigens Cancer Carcinoma Carcinoma, Merkel Cell - metabolism Carcinoma, Merkel Cell - virology Cell activation Cell growth Cell Line, Tumor Cell Proliferation Extracellular signal-regulated kinase Female Gene Expression Regulation, Neoplastic - drug effects Genomes Humans Infections JAK‐STAT pathway Janus kinase 2 Janus Kinases - metabolism Kinases Male MAP Kinase Signaling System - drug effects MEK‐ERK pathway Merkel cell carcinoma Merkel cell polyomavirus Merkel cell polyomavirus - pathogenicity Metabolic pathways Middle Aged Molecular modelling Nitriles - pharmacology Original Phosphorylation Phosphorylation - drug effects Prognosis Pyrazoles - pharmacology Pyrimidines - pharmacology Sex Characteristics Signal transduction Skin Neoplasms - metabolism Skin Neoplasms - virology Software STAT Transcription Factors - metabolism Stat3 protein Transcription factors Tumors |
| title | Merkel cell polyomavirus–negative Merkel cell carcinoma is associated with JAK‐STAT and MEK‐ERK pathway activation |
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