{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T05:01:02Z","timestamp":1782882062158,"version":"3.54.5"},"reference-count":52,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2018,11,28]],"date-time":"2018-11-28T00:00:00Z","timestamp":1543363200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molecular Carcinogenesis"],"published-print":{"date-parts":[[2019,3]]},"abstract":"<jats:sec><jats:label\/><jats:p>Head and neck squamous cell carcinomas (HNSCC) preferentially spread to regional cervical tissues and lymph nodes. Here, we hypothesized that lymphotoxin\u2010\u03b2 (LT\u03b2), receptor LT\u03b2R, and NF\u2010\u03baB\u2010inducing kinase (NIK), promote the aberrant activation of alternative NF\u2010\u03baB2\/RELB pathway and genes, that enhance migration and invasion of HNSCC. Genomic and expression alterations of the alternative NF\u2010kB pathway were examined in 279 HNSCC tumors from The Cancer Genome Atlas (TCGA) and a panel of HNSCC lines. LT\u03b2R is amplified or overexpressed in HNSCC of the larynx or oral cavity, while LT\u03b2, NIK, and RELB are overexpressed in cancers arising within lymphoid oropharyngeal and tonsillar sites. Similarly, subsets of HNSCC lines displayed overexpression of LT\u03b2R, NIK, and RELB proteins. Recombinant LT\u03b2, and siRNA depletion of endogenous LT\u03b2R and NIK, modulated expression of LT\u03b2R, NIK, and nuclear translocation of NF\u2010\u03baB2(p52)\/RELB as well as functional NF\u2010\u03baB promoter reporter activity. Treatment with a NIK inhibitor (1,3[2H,4H]\u2010Iso\u2010Quinoline Dione) reduced the protein expression of NIK and NF\u2010\u03baB2(p52)\/RELB, and blocked LT\u03b2 induced nuclear translocation of RELB. NIK and RELB siRNA knockdown or NIK inhibitor slowed HNSCC migration or invation in vitro. LT\u03b2\u2010induces expression of migration and metastasis related genes, including hepatocyte growth\/scatter factor receptor MET. Knockdown of NIK or MET similarly inhibited the migration of HNSCC cell lines. This may help explain why HNSCC preferentially migrate to local lymph nodes, where LT\u03b2 is expressed. Our findings show that LT\u03b2\/LT\u03b2R promotes activation of the alternative NIK\u2010NF\u2010\u03baB2\/RELB pathway to enhance MET\u2010mediated cell migration in HNSCC, which could be potential therapeutic targets in HNSCC.<\/jats:p><\/jats:sec>","DOI":"10.1002\/mc.22938","type":"journal-article","created":{"date-parts":[[2018,11,29]],"date-time":"2018-11-29T04:20:24Z","timestamp":1543465224000},"page":"411-425","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Lymphotoxin\u2010\u03b2 receptor\u2010NIK signaling induces alternative RELB\/NF\u2010\u03baB2 activation to promote metastatic gene expression and cell migration in head and neck cancer"],"prefix":"10.1002","volume":"58","author":[{"given":"Rita","family":"Das","sequence":"first","affiliation":[{"name":"Tumor Biology Section, Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders National Institutes of Health Bethesda Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jamie","family":"Coupar","sequence":"additional","affiliation":[{"name":"Tumor Biology Section, Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders National Institutes of Health Bethesda Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul E.","family":"Clavijo","sequence":"additional","affiliation":[{"name":"Tumor Biology Section, Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders National Institutes of Health Bethesda Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony","family":"Saleh","sequence":"additional","affiliation":[{"name":"Tumor Biology Section, Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders National Institutes of Health Bethesda Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tsu\u2010Fan","family":"Cheng","sequence":"additional","affiliation":[{"name":"Tumor Biology Section, Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders National Institutes of Health Bethesda Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinping","family":"Yang","sequence":"additional","affiliation":[{"name":"Tumor Biology Section, Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders National Institutes of Health Bethesda Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianhong","family":"Chen","sequence":"additional","affiliation":[{"name":"Tumor Biology Section, Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders National Institutes of Health Bethesda Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carter","family":"Van Waes","sequence":"additional","affiliation":[{"name":"Tumor Biology Section, Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders National Institutes of Health Bethesda Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5322-5110","authenticated-orcid":false,"given":"Zhong","family":"Chen","sequence":"additional","affiliation":[{"name":"Tumor Biology Section, Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders National Institutes of Health Bethesda Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2018,11,28]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI59889"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21332"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc2982"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0116517"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1159\/000341690"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.coi.2013.01.001"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/nri3406"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.05033-11"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2006.08.007"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1074-7613(00)80588-9"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cytogfr.2011.11.007"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.179.12.8069"},{"key":"e_1_2_7_14_1","first-page":"318","article-title":"Chemotactic activity of lymphotoxin and tumour necrosis factor alpha for human neutrophils","volume":"66","author":"Newman I","year":"1989","journal-title":"Immunology"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.imbio.2012.06.010"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2010.260"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.165.2.804"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/cr.2010.177"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-06-2221"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-07-1287"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.7.3792"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-065X.2011.01088.x"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2013.49"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-07-4470"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-065X.2012.01099.x"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1209942"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1207851"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.1002\/hed.21198"},{"key":"e_1_2_7_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep14068"},{"key":"e_1_2_7_30_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2012-01-405951"},{"key":"e_1_2_7_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2010.06.027"},{"key":"e_1_2_7_32_1","doi-asserted-by":"publisher","DOI":"10.2144\/04365BM03"},{"key":"e_1_2_7_33_1","doi-asserted-by":"publisher","DOI":"10.1177\/108705719900400206"},{"key":"e_1_2_7_34_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.2089"},{"key":"e_1_2_7_35_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature14129"},{"key":"e_1_2_7_36_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-15-3317"},{"key":"e_1_2_7_37_1","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2016.112"},{"key":"e_1_2_7_38_1","first-page":"5911","article-title":"Hepatocyte growth factor\/scatter factor\u2010induced activation of MEK and P13 K signal pathways contributes to expression of proangiogenic cytokines interleukin\u20108 and vascular endothelial growth factor in Head and Neck squamous cell carcinoma","volume":"61","author":"Dong G","year":"2001","journal-title":"Cancer res"},{"key":"e_1_2_7_39_1","unstructured":"Xinping YangHC WangR ChenJ et al. Genomic RNAi Screening and Functional Validation Reveals Cross Activation of Classical and Alternative NF\u2010kB Pathways in Head and Neck Squamous Cell Carcinoma of Different HPV Status AACR 2017 meeting Washington DC 2017.2017."},{"key":"e_1_2_7_40_1","doi-asserted-by":"publisher","DOI":"10.1177\/1534735408327250"},{"key":"e_1_2_7_41_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M401372200"},{"key":"e_1_2_7_42_1","doi-asserted-by":"publisher","DOI":"10.1002\/hed.20833"},{"key":"e_1_2_7_43_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-10-3445"},{"key":"e_1_2_7_44_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-17-0642"},{"key":"e_1_2_7_45_1","doi-asserted-by":"publisher","DOI":"10.1002\/hed.20246"},{"key":"e_1_2_7_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neo.2014.08.014"},{"key":"e_1_2_7_47_1","doi-asserted-by":"publisher","DOI":"10.1054\/bjoc.2000.1423"},{"key":"e_1_2_7_48_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M403286200"},{"key":"e_1_2_7_49_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0088347"},{"key":"e_1_2_7_50_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.str.2012.09.012"},{"key":"e_1_2_7_51_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M112.366658"},{"key":"e_1_2_7_52_1","first-page":"200","article-title":"BIRC3cIAP2 providing the anti\u2010apoptosis signaling downstream of TNFR through TRAF1 and TRAF2","volume":"34","author":"de Almagro MCDV","year":"2012","journal-title":"Exp Oncol"},{"key":"e_1_2_7_53_1","doi-asserted-by":"publisher","DOI":"10.1089\/wound.2013.0512"}],"container-title":["Molecular Carcinogenesis"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fmc.22938","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/mc.22938","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,14]],"date-time":"2023-09-14T12:34:18Z","timestamp":1694694858000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/mc.22938"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,11,28]]},"references-count":52,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2019,3]]}},"alternative-id":["10.1002\/mc.22938"],"URL":"https:\/\/doi.org\/10.1002\/mc.22938","archive":["Portico"],"relation":{},"ISSN":["0899-1987","1098-2744"],"issn-type":[{"value":"0899-1987","type":"print"},{"value":"1098-2744","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,11,28]]},"assertion":[{"value":"2018-10-03","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-10-29","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-11-28","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}