p38α and p38δ mitogen-activated protein kinase isoforms regulate invasion and growth of head and neck squamous carcinoma cells
Recent studies indicate that the specificity of p38 mitogen-activated protein kinase (MAPK)-mediated cellular stress responses is determined by the expression pattern of the distinct p38 isoforms. Here, we have analysed the function of distinct p38 isoforms in the growth and invasion of head and nec...
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| Veröffentlicht in: | Oncogene 2007-08, Vol.26 (36), p.5267-5279 |
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| creator | Junttila, M R Ala-aho, R Jokilehto, T Peltonen, J Kallajoki, M Grenman, R Jaakkola, P Westermarck, J Kähäri, V-M |
| description | Recent studies indicate that the specificity of p38 mitogen-activated protein kinase (MAPK)-mediated cellular stress responses is determined by the expression pattern of the distinct p38 isoforms. Here, we have analysed the function of distinct p38 isoforms in the growth and invasion of head and neck squamous cell carcinomas (HNSCCs). Activation of p38 MAPK by arsenite resulted in inactivation of the ERK1,2 signaling pathway by dephosphorylation of MEK1,2 in primary human epidermal keratinocytes (HEKs), whereas in HNSCC cells this p38-mediated inhibition of the ERK1,2 pathway was absent. Quantitation of p38 pathway component mRNA expression in HNSCC cell lines (
n
=42) compared to HEKs (
n
=8) revealed that p38
α
and p38
δ
isoforms are predominantly expressed in both cell types and that MKK3 is the primary upstream activator expressed. Inhibition of endogenous p38
α
or p38
δ
activity by adenoviral delivery of corresponding dominant-negative p38 isoforms potently reduced MMP-13 and MMP-1 expressions, and suppressed the invasion of HNSCC cells through collagen. Dominant-negative p38
α
and p38
δ
inhibited squamous cell carcinoma (SCC) cell proliferation and inhibition of p38
α
activity also compromised survival of SCC cells. p38
α
and p38
δ
were predominantly expressed in HNSCCs (
n
=24) and nonneoplastic epithelium
in vivo
(
n
=6), with MKK3 being the primary upstream activator. Activation and expression of p38
α
and p38
δ
by tumor cells was detected in HNSCCs
in vivo
(
n
=16). Adenoviral expression of dominant-negative p38
α
or p38
δ
in cutaneous SCC cells potently inhibited their implantation in skin of severe combined immunodeficiency mice and growth of xenografts
in vivo
. Our results indicate that p38
α
and p38
δ
specifically promote the malignant phenotype of SCC cells by regulating cell survival, proliferation and invasion, suggesting these p38 MAPK isoforms as potential therapeutic targets in HNSCCs. |
| doi_str_mv | 10.1038/sj.onc.1210332 |
| format | Article |
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n
=42) compared to HEKs (
n
=8) revealed that p38
α
and p38
δ
isoforms are predominantly expressed in both cell types and that MKK3 is the primary upstream activator expressed. Inhibition of endogenous p38
α
or p38
δ
activity by adenoviral delivery of corresponding dominant-negative p38 isoforms potently reduced MMP-13 and MMP-1 expressions, and suppressed the invasion of HNSCC cells through collagen. Dominant-negative p38
α
and p38
δ
inhibited squamous cell carcinoma (SCC) cell proliferation and inhibition of p38
α
activity also compromised survival of SCC cells. p38
α
and p38
δ
were predominantly expressed in HNSCCs (
n
=24) and nonneoplastic epithelium
in vivo
(
n
=6), with MKK3 being the primary upstream activator. Activation and expression of p38
α
and p38
δ
by tumor cells was detected in HNSCCs
in vivo
(
n
=16). Adenoviral expression of dominant-negative p38
α
or p38
δ
in cutaneous SCC cells potently inhibited their implantation in skin of severe combined immunodeficiency mice and growth of xenografts
in vivo
. Our results indicate that p38
α
and p38
δ
specifically promote the malignant phenotype of SCC cells by regulating cell survival, proliferation and invasion, suggesting these p38 MAPK isoforms as potential therapeutic targets in HNSCCs.</description><identifier>ISSN: 0950-9232</identifier><identifier>EISSN: 1476-5594</identifier><identifier>DOI: 10.1038/sj.onc.1210332</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>Apoptosis ; Arsenite ; Biological and medical sciences ; Cell activation ; Cell Biology ; Cell physiology ; Cell proliferation ; Cell survival ; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes ; Collagen ; Collagenase 3 ; Dephosphorylation ; Development and progression ; Epithelium ; Extracellular signal-regulated kinase ; Fundamental and applied biological sciences. Psychology ; Gene expression ; Genetic aspects ; Genetic regulation ; Head & neck cancer ; Head and neck cancer ; Head and neck carcinoma ; Human Genetics ; Internal Medicine ; Interstitial collagenase ; Isoforms ; Keratinocytes ; Kinases ; MAP kinase ; Matrix metalloproteinase ; Medical sciences ; Medicine ; Medicine & Public Health ; MKK3 protein ; Molecular and cellular biology ; Oncology ; original-article ; Otorhinolaryngology (head neck, general aspects and miscellaneous) ; Otorhinolaryngology. Stomatology ; Phenotypes ; Protein kinase ; Quantitation ; Severe combined immunodeficiency ; Signal transduction ; Squamous cell carcinoma ; Tumor cells ; Tumor suppressor genes ; Tumors ; Xenografts</subject><ispartof>Oncogene, 2007-08, Vol.26 (36), p.5267-5279</ispartof><rights>Springer Nature Limited 2007</rights><rights>2007 INIST-CNRS</rights><rights>COPYRIGHT 2007 Nature Publishing Group</rights><rights>Nature Publishing Group 2007.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c404t-e89e65f24304ccc035cb780f073af76fa1029348fdf7ef7cf42fbfbb2f65f6213</citedby><cites>FETCH-LOGICAL-c404t-e89e65f24304ccc035cb780f073af76fa1029348fdf7ef7cf42fbfbb2f65f6213</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=18991246$$DView record in Pascal Francis$$Hfree_for_read</backlink></links><search><creatorcontrib>Junttila, M R</creatorcontrib><creatorcontrib>Ala-aho, R</creatorcontrib><creatorcontrib>Jokilehto, T</creatorcontrib><creatorcontrib>Peltonen, J</creatorcontrib><creatorcontrib>Kallajoki, M</creatorcontrib><creatorcontrib>Grenman, R</creatorcontrib><creatorcontrib>Jaakkola, P</creatorcontrib><creatorcontrib>Westermarck, J</creatorcontrib><creatorcontrib>Kähäri, V-M</creatorcontrib><title>p38α and p38δ mitogen-activated protein kinase isoforms regulate invasion and growth of head and neck squamous carcinoma cells</title><title>Oncogene</title><addtitle>Oncogene</addtitle><description>Recent studies indicate that the specificity of p38 mitogen-activated protein kinase (MAPK)-mediated cellular stress responses is determined by the expression pattern of the distinct p38 isoforms. Here, we have analysed the function of distinct p38 isoforms in the growth and invasion of head and neck squamous cell carcinomas (HNSCCs). Activation of p38 MAPK by arsenite resulted in inactivation of the ERK1,2 signaling pathway by dephosphorylation of MEK1,2 in primary human epidermal keratinocytes (HEKs), whereas in HNSCC cells this p38-mediated inhibition of the ERK1,2 pathway was absent. Quantitation of p38 pathway component mRNA expression in HNSCC cell lines (
n
=42) compared to HEKs (
n
=8) revealed that p38
α
and p38
δ
isoforms are predominantly expressed in both cell types and that MKK3 is the primary upstream activator expressed. Inhibition of endogenous p38
α
or p38
δ
activity by adenoviral delivery of corresponding dominant-negative p38 isoforms potently reduced MMP-13 and MMP-1 expressions, and suppressed the invasion of HNSCC cells through collagen. Dominant-negative p38
α
and p38
δ
inhibited squamous cell carcinoma (SCC) cell proliferation and inhibition of p38
α
activity also compromised survival of SCC cells. p38
α
and p38
δ
were predominantly expressed in HNSCCs (
n
=24) and nonneoplastic epithelium
in vivo
(
n
=6), with MKK3 being the primary upstream activator. Activation and expression of p38
α
and p38
δ
by tumor cells was detected in HNSCCs
in vivo
(
n
=16). Adenoviral expression of dominant-negative p38
α
or p38
δ
in cutaneous SCC cells potently inhibited their implantation in skin of severe combined immunodeficiency mice and growth of xenografts
in vivo
. Our results indicate that p38
α
and p38
δ
specifically promote the malignant phenotype of SCC cells by regulating cell survival, proliferation and invasion, suggesting these p38 MAPK isoforms as potential therapeutic targets in HNSCCs.</description><subject>Apoptosis</subject><subject>Arsenite</subject><subject>Biological and medical sciences</subject><subject>Cell activation</subject><subject>Cell Biology</subject><subject>Cell physiology</subject><subject>Cell proliferation</subject><subject>Cell survival</subject><subject>Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes</subject><subject>Collagen</subject><subject>Collagenase 3</subject><subject>Dephosphorylation</subject><subject>Development and progression</subject><subject>Epithelium</subject><subject>Extracellular signal-regulated kinase</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Gene expression</subject><subject>Genetic aspects</subject><subject>Genetic regulation</subject><subject>Head & neck cancer</subject><subject>Head and neck cancer</subject><subject>Head and neck carcinoma</subject><subject>Human Genetics</subject><subject>Internal Medicine</subject><subject>Interstitial collagenase</subject><subject>Isoforms</subject><subject>Keratinocytes</subject><subject>Kinases</subject><subject>MAP kinase</subject><subject>Matrix metalloproteinase</subject><subject>Medical sciences</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>MKK3 protein</subject><subject>Molecular and cellular biology</subject><subject>Oncology</subject><subject>original-article</subject><subject>Otorhinolaryngology (head neck, general aspects and miscellaneous)</subject><subject>Otorhinolaryngology. Stomatology</subject><subject>Phenotypes</subject><subject>Protein kinase</subject><subject>Quantitation</subject><subject>Severe combined immunodeficiency</subject><subject>Signal transduction</subject><subject>Squamous cell carcinoma</subject><subject>Tumor cells</subject><subject>Tumor suppressor genes</subject><subject>Tumors</subject><subject>Xenografts</subject><issn>0950-9232</issn><issn>1476-5594</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2007</creationdate><recordtype>article</recordtype><sourceid>8G5</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNp1UctuFDEQtBBILCHXnC0hjrPxa17HKIKAFIkLnK1er3vizYyduGeCuPFLSPkOvglns9Jegnxod3VV2a1i7EyKtRS6O6fdOkW3lqp0Wr1iK2napqrr3rxmK9HXouqVVm_ZO6KdEKLthVqx33e6-_uHQ9zyp9sjn8KcBh8rcHN4gNkXPKfZh8hvQwTyPFDClCfi2Q_LWBg8xAegkOLeZcjp53zDE_IbD9s9FL275XS_wJQW4g6yCzFNwJ0fR3rP3iCM5E8P9YT9-Pzp--WX6vrb1dfLi-vKGWHmyne9b2pURgvjnBO6dpu2EyhaDdg2CFKoXpsOt9h6bB0ahRvcbBQWVaOkPmEfnn3LOveLp9nu0pJjedKqxkjdatGpI2uA0dsQMc0Z3BTI2QvZNVKq3jSFtX6BVc7WT8Gl6DEU_CWBy4koe7R3OUyQf1kp7FN4lna2hGcP4RXBx8NvgRyMmCG6QEdV1_dS7Y3Pn3lURnHw-bjVf5z_Ac3FrEI</recordid><startdate>20070809</startdate><enddate>20070809</enddate><creator>Junttila, M R</creator><creator>Ala-aho, R</creator><creator>Jokilehto, T</creator><creator>Peltonen, J</creator><creator>Kallajoki, M</creator><creator>Grenman, R</creator><creator>Jaakkola, P</creator><creator>Westermarck, J</creator><creator>Kähäri, V-M</creator><general>Nature Publishing Group UK</general><general>Nature Publishing</general><general>Nature Publishing Group</general><scope>IQODW</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</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>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M2O</scope><scope>M7P</scope><scope>MBDVC</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>RC3</scope></search><sort><creationdate>20070809</creationdate><title>p38α and p38δ mitogen-activated protein kinase isoforms regulate invasion and growth of head and neck squamous carcinoma cells</title><author>Junttila, M R ; Ala-aho, R ; Jokilehto, T ; Peltonen, J ; Kallajoki, M ; Grenman, R ; Jaakkola, P ; Westermarck, J ; Kähäri, V-M</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c404t-e89e65f24304ccc035cb780f073af76fa1029348fdf7ef7cf42fbfbb2f65f6213</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2007</creationdate><topic>Apoptosis</topic><topic>Arsenite</topic><topic>Biological and medical sciences</topic><topic>Cell activation</topic><topic>Cell Biology</topic><topic>Cell physiology</topic><topic>Cell proliferation</topic><topic>Cell survival</topic><topic>Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes</topic><topic>Collagen</topic><topic>Collagenase 3</topic><topic>Dephosphorylation</topic><topic>Development and progression</topic><topic>Epithelium</topic><topic>Extracellular signal-regulated kinase</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>Gene expression</topic><topic>Genetic aspects</topic><topic>Genetic regulation</topic><topic>Head & neck cancer</topic><topic>Head and neck cancer</topic><topic>Head and neck carcinoma</topic><topic>Human Genetics</topic><topic>Internal Medicine</topic><topic>Interstitial collagenase</topic><topic>Isoforms</topic><topic>Keratinocytes</topic><topic>Kinases</topic><topic>MAP kinase</topic><topic>Matrix metalloproteinase</topic><topic>Medical sciences</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>MKK3 protein</topic><topic>Molecular and cellular biology</topic><topic>Oncology</topic><topic>original-article</topic><topic>Otorhinolaryngology (head neck, general aspects and miscellaneous)</topic><topic>Otorhinolaryngology. Stomatology</topic><topic>Phenotypes</topic><topic>Protein kinase</topic><topic>Quantitation</topic><topic>Severe combined immunodeficiency</topic><topic>Signal transduction</topic><topic>Squamous cell carcinoma</topic><topic>Tumor cells</topic><topic>Tumor suppressor genes</topic><topic>Tumors</topic><topic>Xenografts</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Junttila, M R</creatorcontrib><creatorcontrib>Ala-aho, R</creatorcontrib><creatorcontrib>Jokilehto, T</creatorcontrib><creatorcontrib>Peltonen, J</creatorcontrib><creatorcontrib>Kallajoki, M</creatorcontrib><creatorcontrib>Grenman, R</creatorcontrib><creatorcontrib>Jaakkola, P</creatorcontrib><creatorcontrib>Westermarck, J</creatorcontrib><creatorcontrib>Kähäri, V-M</creatorcontrib><collection>Pascal-Francis</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Research Library (Alumni Edition)</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>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>Research Library Prep</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Research Library</collection><collection>Biological Science Database</collection><collection>Research Library (Corporate)</collection><collection>Biotechnology and BioEngineering Abstracts</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>ProQuest Central Basic</collection><collection>Genetics Abstracts</collection><jtitle>Oncogene</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Junttila, M R</au><au>Ala-aho, R</au><au>Jokilehto, T</au><au>Peltonen, J</au><au>Kallajoki, M</au><au>Grenman, R</au><au>Jaakkola, P</au><au>Westermarck, J</au><au>Kähäri, V-M</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>p38α and p38δ mitogen-activated protein kinase isoforms regulate invasion and growth of head and neck squamous carcinoma cells</atitle><jtitle>Oncogene</jtitle><stitle>Oncogene</stitle><date>2007-08-09</date><risdate>2007</risdate><volume>26</volume><issue>36</issue><spage>5267</spage><epage>5279</epage><pages>5267-5279</pages><issn>0950-9232</issn><eissn>1476-5594</eissn><abstract>Recent studies indicate that the specificity of p38 mitogen-activated protein kinase (MAPK)-mediated cellular stress responses is determined by the expression pattern of the distinct p38 isoforms. Here, we have analysed the function of distinct p38 isoforms in the growth and invasion of head and neck squamous cell carcinomas (HNSCCs). Activation of p38 MAPK by arsenite resulted in inactivation of the ERK1,2 signaling pathway by dephosphorylation of MEK1,2 in primary human epidermal keratinocytes (HEKs), whereas in HNSCC cells this p38-mediated inhibition of the ERK1,2 pathway was absent. Quantitation of p38 pathway component mRNA expression in HNSCC cell lines (
n
=42) compared to HEKs (
n
=8) revealed that p38
α
and p38
δ
isoforms are predominantly expressed in both cell types and that MKK3 is the primary upstream activator expressed. Inhibition of endogenous p38
α
or p38
δ
activity by adenoviral delivery of corresponding dominant-negative p38 isoforms potently reduced MMP-13 and MMP-1 expressions, and suppressed the invasion of HNSCC cells through collagen. Dominant-negative p38
α
and p38
δ
inhibited squamous cell carcinoma (SCC) cell proliferation and inhibition of p38
α
activity also compromised survival of SCC cells. p38
α
and p38
δ
were predominantly expressed in HNSCCs (
n
=24) and nonneoplastic epithelium
in vivo
(
n
=6), with MKK3 being the primary upstream activator. Activation and expression of p38
α
and p38
δ
by tumor cells was detected in HNSCCs
in vivo
(
n
=16). Adenoviral expression of dominant-negative p38
α
or p38
δ
in cutaneous SCC cells potently inhibited their implantation in skin of severe combined immunodeficiency mice and growth of xenografts
in vivo
. Our results indicate that p38
α
and p38
δ
specifically promote the malignant phenotype of SCC cells by regulating cell survival, proliferation and invasion, suggesting these p38 MAPK isoforms as potential therapeutic targets in HNSCCs.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><doi>10.1038/sj.onc.1210332</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
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| ispartof | Oncogene, 2007-08, Vol.26 (36), p.5267-5279 |
| issn | 0950-9232 1476-5594 |
| language | eng |
| recordid | cdi_proquest_journals_2641373082 |
| source | Nature; EZB-FREE-00999 freely available EZB journals; Alma/SFX Local Collection |
| subjects | Apoptosis Arsenite Biological and medical sciences Cell activation Cell Biology Cell physiology Cell proliferation Cell survival Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes Collagen Collagenase 3 Dephosphorylation Development and progression Epithelium Extracellular signal-regulated kinase Fundamental and applied biological sciences. Psychology Gene expression Genetic aspects Genetic regulation Head & neck cancer Head and neck cancer Head and neck carcinoma Human Genetics Internal Medicine Interstitial collagenase Isoforms Keratinocytes Kinases MAP kinase Matrix metalloproteinase Medical sciences Medicine Medicine & Public Health MKK3 protein Molecular and cellular biology Oncology original-article Otorhinolaryngology (head neck, general aspects and miscellaneous) Otorhinolaryngology. Stomatology Phenotypes Protein kinase Quantitation Severe combined immunodeficiency Signal transduction Squamous cell carcinoma Tumor cells Tumor suppressor genes Tumors Xenografts |
| title | p38α and p38δ mitogen-activated protein kinase isoforms regulate invasion and growth of head and neck squamous carcinoma cells |
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