<<<<< << <<< er" content="American Association for Cancer Research" /> up/volpage/13/1019?iss=5" /> r-of-mouth models. GALR2 induced angiogenesis via p38-MAPK?mer-of-mouth models. GALR2 induced angiogenesis via p38-MAPK?mr-of-mouth models. GALR2 induced angiogenesis via p38-MAPK?mediated secretion of r-of-mouth models. GALR2 induced angiogenesis via p38-MAPK?mediated secretion of proangiogenic cytokines, VEGF, and interleur-of-mouth models. GALR2 induced angiogenesis via p38-MAPK?mediated secretion of proangiogenic cytokines, VEGF, and interleukin-6 (IL-6). Moreover, GALR2 activated small-GTP-protein, RAP1B, thereby inducing p38-mediated inactivation of tristetraprolin (TTP), which functions to destabilize cytokine transcripts. This resulted in enhanced secretion of proangiogenic cytokines and angiogenesis in vitro and in vivo . In SCCHN cells overexpressing GALR2, inactivation of TTP increased secretion of IL-6 and VEGF, whereas inhibition of p38 activated TTP and decreased cytokine secretion. Here, we report that GALR2 stimulates tumor angiogenesis in SCCHN via p38-mediatused to understand the key regulators. The <i>in vivo</i> impact of GALR2 on angiogenesis was investigated in mouse xenograft, chick chorioallantoic membrane, and the clinically relevant mouse orthotopic floor-of-mouth models. GALR2 induced angiogenesis via p38-MAPK?mediated secretion of proangiogenic cytokines, VEGF, and interleukin-6 (IL-6). Moreover, GALR2 activated small-GTP-protein, RAP1B, thereby inducing p38-mediated inactivation of tristetraprolin (TTP), which functions to destabilize cytokine transcripts. This resulted in enhanced secretion of proangiogenic cytokines and angiogenesis <i>in vitro</i> and <i>in vivo</i>. In SCCHN cells overexpressing GALR2, inactivation of TTP increased secretion of IL-6 and VEGF, whereas inhibition of p38 activated TTP and decreased cytokine secretion. Here, we report that GALR2 stimulates tumor angiogenesis in SCCHN via p38-mediated inhibition of TTP with resultant enhanced cytokine secretion. Given that p38 inhibitors are in clinical use for inflammatory disorders, GALR2/p38-mediated cytokine secretion may be an excellent target for new adjuvant therapy in SCCHN. <i>Mol Cancer Ther; 13(5); 1323?33. 2014 AACR</i>.</p>" /> used to understand the key regulators. The <i>in vivo</i> impact ofused to understand the key regulators. The <i>in vivo</i> impact of GALR2 used to understand the key regulators. The <i>in vivo<used to understand the key regulators. The <i>in vivo&lused to understand the key regulators. The <iused to understand the key regulators. The <i>in vivo</i> impact of GALR2 on angused to understand the key regulators. The <i>in vivo</i> impact of GALR2 on angiogenesis was inused to understand the key regulators. The <i>in vivo</i> impact of GALR2 on angiogenesiused to understand the key regulators. The <i>in vivo</i> impact of GALR2 on angiogeneused to understand the key regulators. The <i&gused to understand the ke" content="1538-8514" /> " content="1538-8514" /> iversity of Michigan Medical School, Ann Arbor, Michiganiversity of Michigan Medical School, Ann Arbor, Michigan; Department of Craniofacial Biology, The Medical University of South Carolina, Columbia, South Carolina" /> Department of Pathology, University of Michigan Medical Schoo Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan; Department of Craniofacial Biology, The Medical University of South Carolina, Columbia, South Carolina" /> itution" content="Authors' Affiliations: Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry; Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan; Department of Craniofacial Biology, The Medical University of South Carolina, Columbia, South Carolina" /> ment of Head and Neck Cancer and Its Inhibition By Chemopreventive Agents;citation_pages=153-164;citation_volume=10;citation_year=1999;citation_issue=2;citation_issn=1045-4411;citation_pmid=10759419;citation_doi=10.1177/10454411990100020301" /> . Wolf;citation_author=T. Carey;citation_author=C. Bradford;citation_title=Tristetraprolin regulates interleukin-6, which is correlated with tumor progression in patients with head and neck squamous cell carcinoma;citation_pages=2677-89;citation_volume=117;citation_year=2011;citation_pmid=21656745;citation_doi=10.1002/cncr.25859" /> ear;citation_title=Feedback Inhibition of Macrophage Tumor Necrosis Factor-{alpha} Production by Tristetraprolin;citation_pages=1001-1005;citation_volume=281;citation_year=1998;citation_issue=5379;citation_issn=0036-8075;citation_pmid=9703499;citation_doi=10.1126/science.281.5379.1001" /> 003;citation_issue=1;citation_pmid=12574959" /> artfai;citation_title=Galanin, galanin receptors and drug targets.;citation_pages=1796-1805;citation_volume=65;citation_year=2008;citation_issue=12;citation_pmid=18500647;citation_doi=10.1007/s00018-008-8153-8" /> l_abbrev=Genes Chromosomes Cancer;citation_author=T. Sugimoto;citation_author=N. Seki;citation_author=S. Shimizu;citation_author=N. Kikkawa;citation_author=J. Tsukada;citation_author=H. Shimada;citation_title=The galanin signaling cascade is a candidate pathway regulating oncogenesis in human squamous cell carcinoma.;citation_pages=132-142;citation_volume=48;citation_year=2009;citation_issue=2;citation_pmid=18973137;citation_doi=10.1002/l_abbrev=Genes Chromosomes Cancer;citation_author=T. Sugimoto;citation_author=N. Seki;citation_author=S. Shimizu;citation_author=N. Kikkawa;citation_author=J. Tsukada;citation_author=H. Shimada;citation_title=The galanin signaling cascade is a candidate pathway regulating oncogenesis in human squamous cell carcinoma.;citation_pages=132-142;citation_volume=48;citation_year=2009;citation_issue=2;citation_pmid=18973137;citation_doi=10.1002/gcc.20626" /> _abbrev=Cancer Res.;citation_author=RS. Mitra;citation_author=M. Goto;citation_author=JS. Lee;citation_author=D. Maldonado;citation_author=JM. Taylor;citation_author=Q. Pan;citation_title=Rap1GAP Promotes Invasion via Induction of Matrix Metalloproteinase 9 Secretion, Which Is Associated with Poor Survival in Low N-Stage Squamous Cell Carcinoma;citization and Secretion of MMP9, MMP2, and IL-6;citation_volume=19;citation_year=2013;citation_pmid=23349315;citation_doi=10.1158/1078-0432.CCR-12-2927" /> ization and Secretion of MMP9, MMP2, and IL-6;citation_volume=19;citation_year=2013;citation_pmid=23349315;citation_doi=10.1158/1078-0432.CCR-12-2927" /> ="citation_journal_title=Transl Oncol;citation_author=M. Liu;citation_author=CS. Scanlon;citation_author=R. Banerjee;citation_author=N. Russo;citation_author=RC. Inglehart;citation_author=AL. Willis;citation_title=The Histone Methyltransferase EZH2 Mediates Tumor Progression on the Chick Chorioallantoic Membrane Assay, a Novel Model of Head and Neck Squamous Cell Carcinoma;citn-activated protein kinase.;citation_pages=825-831;citation_volume=263;citation_year=1999;citation_issue=3;citation_pmid=10512765;citation_doi=10.1006/bbrc.1999.1454" /> n-activated protein kinase.;citation_pages=825-831;citation_volume=263;citation_year=1999;citation_issue=3;citation_pmid=10512765;citation_doi=10.1006/bbrc.1999.1454" /> tation_title=Cross talk initiated by endothelial cells enhances migration and inhibits anoikis of squamous cell carcinoma cells through STAT3/Akt/ERK signaling.;citation_pages=583-593;citation_volume=11;citation_year=2009;citation_issue=6;citation_pmid=19484147" /> ll cycle (Georgetown, Tex.);citation_journal_abbrev=Cell Cycle;citation_author=GN. Naumov;citation_author=LA. Akslen;citation_author=J. Folkman;citation_title=Role of angiogenesis in human tumor dormancy: animal models of the angiogenic switch.;citation_pages=1779-1787;citation_volume=5;citation_year=2006;citation_issue=16;citation_pmid=16931911;citation_doi=10.4161/cc.5.16.3018" /> nitiates multiple signaling pathways in small cell lung cancer cells by coupling to G(q), G(i) and G(12) proteins.;citation_pages=4199-4209;citation_volume=19;citation_year=2000;citation_issue=37;citation_pmid=10980593;citation_doi=10.1038/sj.onc.1203777" /> n_author=JT. Laydon;citation_author=PC. McDonnell;citation_author=TF. Gallagher;citation_author=S. Kumar;citation_author=D. Green;citation_title=A protein kinase involved in the regulation of inflammatory cytokine biosynthesis.;citation_pages=739-746;citation_volume=372;citation_year=1994;citation_issue=6508;citation_issn=0028-0836;citation_pmid=7997261;citation_doi=10.1038/372739a0" /> tation_reference" content="citation_journal_title=Cancer;citation_journal_abbrev=Cancer;citation_author=P. Oc;citation_author=P. Rhys-Evans;citation_author=SA. Eccles;citation_title=Expression of vascular endothelial growth factor family members in head and neck squamous cell carcinoma correlates with lymph node metastasis.;citation_pages=556-568;citation_volB, AP-1, and NF-IL6 in human head and neck squamous cell carcinoma cell lines that express pro-inflammatory and pro-angiogenic cytokines.;citation_pages=119-129;citation_volume=26;citation_year=1999;citation_issue=2;citation_pmid=10506755;citation_doi=10.1002/(SICI)1098-2744(199910)26:2<119::AID-MC6>3.0.CO;2-N" /> B, AP-1, and NF-IL6 in human head and neck squamous cell carcinoma cell lines that express pro-inflammatory and pro-angiogenic cytokines.;citation_pages=119-129;citation_volume=26;citation_year=1999;citation_issue=2;citation_pmid=10506755;citation_doi=10.1002/(SICI)1098-2744(199910)26:2<119::AID-MC6>3.0.CO;2-N" /> ub;citation_title=Novel anti-tumor mechanism of galanin receptor type 2 in head and neck squamous cell carcinoma cells;citation_author=T. Uehara;citation_author=T. Kanazawa;citation_author=H. Mizukami;citation_author=R. Uchibori;citation_author=T. Tsukahara;citation_author=M. Urabe;citation_year=2013 Oct 30" /> itation_author=K. Misawa;citation_author=T. Kanazawa;citation_author=Y. Misawa;citation_author=T. Uehara;citation_author=itation_author=iiiiititation_author=K. Misawa;citation_author=T. Kanazawa;citation_author=Y. Misawa;citation_author=T. Uehara;citation_author=A. Imai;citation_author=G. Takahashi;citation_title=Galanin has tumor suppressor activity and is frequently inactivated by aberrant promoter methylation in head and neckAAMAMcv4PkT2vTiL-nzEVOwhUr7EciHoHE__MSIuDwiw-M4BNtTljTK2_GS6cVVnQ7_e2N6uyEk7oj8.css" media="all" /> nn!!!!! a aaaa cc |m)?||m)?|thmx|qtm?|ra(m|r)?|sea|sit|tar|tgz|torrent|txt|wav|wma|wmv|wpd|xls(x|m|b)?|xlt(x|m)|xlam|xml|z|zip","|m)?|thmx||m)?|thmx|qtm?|ra(m|r)?|sea|sit|tar|tgz|torrent|txt|wav|wma|wmv|wpd|xls(x|m|b)?|xlt(x|m)|xlam|xml|z|zip","trackColorbox":1},"omega":{"layouts":{"primary":"normal","order":["narrow","normal","wide"],"queries":{"narrow":"all and (min-width: 768px) an|m)?|thmx|qtm?|ra(m|r)?|sea|m)?|thmx|qtm?|ra(m||m)?|thmx|m)?|thmx|q|m)?|thmx|qtm?|ra(m|r)?|sea|sit|tar|tgz|torrent|txt|wav|wma||m)?|thmx|qtm?|ra(m|r)?|sea|sit|tar|tgz|torrent|txt|wav|m)?|th|m)?|thmx||m)?|thmx|qtm?|ra(m|r)?|sea|sit|tar|tgz|torrent|txt|wav|wma|wmv|wpd|xls(x|m|b)?|xlt(x|m)|xlam|xml|z|zip","trackCo|m)?|thmx|qtm?|ra(m|r)?|sea|sit|tar|tgz|torrent|txt|wav|wma|wm|m)?|thmx|qtm?|ra(m|r)?|sea|sit|tar|tgz|torrent|txt|wav|wma|wmv|wpd|xls(x|m|b)?|xlt(x|m)|xlam|xml|z|zip","tr|m)?|thmx|qtm?|ra(m|r)?|sea|sit|tar|tgz|torrent|txt|wav|wma|wmv|wpd|xls(x|m|b)?|xlt(x|m)|xlam|xml|z|zip","trackColorbox":1},"om|m)?|thmx|qtm?|ra(m|r)?|sea|sit|tar|tgz|torrent|txt|wav|wma|wmv|wpd|xls(x|m|b)?|xlt(x|m)|xlam|m)?|thmx|qtm?|ra(m|r)?|sea|sit|tar|tgz|torrent|txt|wav|m)?|thmx|qtm?|ra(m|r)?|sea|sit|tar|tgz|torrent|txt|wav|wma|wmv|wpd|xls(x|m|b)?|xlt(x|m)|xlam|xml|z|zip","trackCol|m)?|thmx|qtm?|ra(m|r)?|sea|sit|tar|tgz|torrent|txt|wav||m)?|thmx|qtm?|ra(m|r)?|sea|sit|tar|tgz|torrent|txt|wav||m)?|thmx|qtm?|ra(m|r)?|s|m)?|thmx|qtm?|ra(m|r)?|sea|su-down nice-menu-umbrella-menu" id="nice-menu-2" role="menu">u-down nice-menu-umbrella-menu" id="nice-menu-2" role="menu">
  • on="">Reon="on="">Reviewing
  • on="">Reviewing Reviewing
  • on="">Revieon="on="">on="">Reviewing
  • on="">Reviewion="on="">on="">Reviewing
  • on="">Revieon="on="">on="">Reviewing
  • on="">Reviewingon="">Reviewing
  • on="">Reviewing
  • on=""on="">on="">on="">Reviewing
  • on="">Revieon="on="">Reviewing
  • on="">Reviewing Reviewing
  • on="">Reviewingon="">Reviewing
  • ls.org/content/ls.ols.orgls.org/content/authors/author-services-center" dls.org/content/authors/als.ols.orgls.org/content/authors/author-services-center" data-hls.orgls.ols.orgls.orls.orgls.orgls.org/content/authors/author-services-center" data-hide-ls.orgls.ols.org/content/authors/auls.org/content/authors/authorls.org/content/authors/author-services-center" data-hils.org/content/auls.ols.orgls.org/content/authors/author-services-center" dls.org/contls.ols.orgls.org/content/authors/author-services-center" dls.org/content/authls.ols.orgls.org/content/authors/author-services-center" dls.org/cls.ols.orgls.org/content/authors/author-services-center" data-hls.org/contentls.ols.orgls.orls.orgls.orgls.orls.org /div> /div> /div>
    /div>
    /div>
    /div>
    /div/div> /div>
    /div>
    /div>
    /div>
    /div>
    /div>
    /div>
    /div/div> /div>
    /div>
    /div>
    /div>
    /div>
    5" role="menuitem">5" role=5" r5" rol5" role="menuitem">5" role5" r5" rol5" ro5" rol5" role="5" role="menu5" role5" role="menuitem">%3A%20%%3A%20%5%3A%20%5Biden%3A%20%%3A%20%5B%3A%20%%3A%20%5B%3A%20%5Biden%3A%20%%3A%20%5Bidentity%3Ainstitutional_display_name%5D%22%3B%7D">
    %3A%20%5Bidentity%3Ains%3A%20%5Bidentity%3Ains%3A%%3A%20%5Bidentity%3Ainstitutional_disp%3A%20%%3A%20%5Bidentit%3A%20%5Bidentity%3Ainstitution%3A%20%5Bidentity%3Ainstitutional_display_name%5D%22%3B%7D"> <%3A%20%5Bidentity%3Ainstitutional_displa%3A%2%3A%20%5Bidentity%3Ainstitutional_display_name%5D%22%3B%7D">%3A%20%5Bidentity%3Ainstitution
    %3A%2%3A%20%5Bidentity%3Ainstitutional_display_name%5D%22%3B%7D"> %%3A%20%%3A%20%5Bidentity%3Ainstitutional_displa%3A%20%5Bidentity%3Ains%3A%%3A%20%%%3A%20%3A%20%5B%3A%20%5Biden%3A%20%%3A%20%5Bidentity%3Ainstituti%3A%20%3A%20%5Bidentity%3Ainstitutional_display_name%5D%22%3B%7D"> %3A%20%5Bidenti%3A%%3A%20%5%3A%20%%3A%20%5Biden%3A%20%%3A%20%5B%3A%20%%3A%20%5B%3A%20%5Biden%3A%20%%3A%20%3A%20%5B%3A%20%%3A%20%5Bid%3A%20%5B%3A%20%%3A%20%3A%20%5Bidentity%3Ainstitutional_display_name%5D%22%3B%7D"> logo even block-without-title" id="block-panels-mini-hw-small-logo"> logo even block-without-title" id="block-panels-mini-hw-logo even block-without-title" id="bllogo even block-without-title" id="block-panels-mini-hw-small-logo">
  • class="" daclasclass="" data-icclass="" data-icon-position="">Molecular Targets Collections
    Fisition="" data-hide-link-title="0">Find tsition="" data-hide-link-title="0"sitisitiosition="" data-hide-link-title="0">Findsition="" data-hide-link-tsitisitiosition="" data-hide-link-title="0">Find tsition="" data-hide-link-title="0">sitisitiositiositionsition="" data-hide-link-titlesition="" data-hide-link-title="0">Find this author sitionsition="" data-hide-link-title="0">Find sition="" data-hide-link-title="0"sition="" data-hide-lisition="" data-hide-link-title="0">Find this sition="" data-hide-link-title="0">Find this author on PubMed