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Article: Attenuated transforming growth factor beta signaling promotes nuclear factor-kappaB activation in head and neck cancer

TitleAttenuated transforming growth factor beta signaling promotes nuclear factor-kappaB activation in head and neck cancer
Authors
Issue Date2009
PublisherAmerican Association for Cancer Research. The Journal's web site is located at http://cancerres.aacrjournals.org/
Citation
Cancer Research, 2009, v. 69 n. 8, p. 3415-3424 How to Cite?
AbstractAlthough constitutively activated nuclear factor-kappaB (NF-kappaB), attenuated transforming growth factor beta (TGFbeta) signaling, and TP53 mutations frequently occur in human cancers, how these pathways interact and together contribute to malignancy remains uncertain. Here, we found an association between overexpression of NF-kappaB-related genes, reduced expression of TGFbeta receptor (TbetaR) subunits and downstream targets, and TP53 genotype in head and neck squamous cell carcinoma (HNSCC). In response to recombinant TGFbeta1, both growth inhibition and TGFbeta target gene modulation were attenuated or absent in a panel of human HNSCC lines. However, in HNSCC cells that retained residual TGFbeta signaling, TGFbeta1 inhibited both constitutive and tumor necrosis factor alpha-stimulated NF-kappaB activity. Furthermore, HNSCC lines overexpressing mutant (mt) TP53 and human tumor specimens with positive TP53 nuclear staining exhibited reduced TbetaRII and knocking down mtTP53 induced TbetaRII, increasing TGFbeta downstream gene expression while inhibiting proinflammatory NF-kappaB target gene expression. Transfection of ectopic TbetaRII directly restored TGFbeta signaling while inhibiting inhibitor kappaBalpha degradation and suppressing serine-536 phosphorylation of NF-kappaB p65 and NF-kappaB transcriptional activation, linking these alterations. Finally, experiments with TbetaRII conditional knockout mice show that abrogation of TGFbeta signaling promotes the sustained induction of NF-kappaB and its proinflammatory target genes during HNSCC tumorigenesis and progression. Together, these findings elucidate a regulatory framework in which attenuated TGFbeta signaling promotes NF-kappaB activation and squamous epithelial malignancy in the setting of altered TP53 status.
Persistent Identifierhttp://hdl.handle.net/10722/210599
ISSN
2015 Impact Factor: 8.556
2015 SCImago Journal Rankings: 5.372
PubMed Central ID

 

DC FieldValueLanguage
dc.contributor.authorCohen, J-
dc.contributor.authorChen, Z-
dc.contributor.authorLu, SL-
dc.contributor.authorYang, XP-
dc.contributor.authorArun, P-
dc.contributor.authorEhsanian, R-
dc.contributor.authorBrown, MS-
dc.contributor.authorLu, H-
dc.contributor.authorYan, B-
dc.contributor.authorDiallo, O-
dc.contributor.authorWang, XJ-
dc.contributor.authorVan Waes, C-
dc.date.accessioned2015-06-19T04:23:48Z-
dc.date.available2015-06-19T04:23:48Z-
dc.date.issued2009-
dc.identifier.citationCancer Research, 2009, v. 69 n. 8, p. 3415-3424-
dc.identifier.issn0008-5472-
dc.identifier.urihttp://hdl.handle.net/10722/210599-
dc.description.abstractAlthough constitutively activated nuclear factor-kappaB (NF-kappaB), attenuated transforming growth factor beta (TGFbeta) signaling, and TP53 mutations frequently occur in human cancers, how these pathways interact and together contribute to malignancy remains uncertain. Here, we found an association between overexpression of NF-kappaB-related genes, reduced expression of TGFbeta receptor (TbetaR) subunits and downstream targets, and TP53 genotype in head and neck squamous cell carcinoma (HNSCC). In response to recombinant TGFbeta1, both growth inhibition and TGFbeta target gene modulation were attenuated or absent in a panel of human HNSCC lines. However, in HNSCC cells that retained residual TGFbeta signaling, TGFbeta1 inhibited both constitutive and tumor necrosis factor alpha-stimulated NF-kappaB activity. Furthermore, HNSCC lines overexpressing mutant (mt) TP53 and human tumor specimens with positive TP53 nuclear staining exhibited reduced TbetaRII and knocking down mtTP53 induced TbetaRII, increasing TGFbeta downstream gene expression while inhibiting proinflammatory NF-kappaB target gene expression. Transfection of ectopic TbetaRII directly restored TGFbeta signaling while inhibiting inhibitor kappaBalpha degradation and suppressing serine-536 phosphorylation of NF-kappaB p65 and NF-kappaB transcriptional activation, linking these alterations. Finally, experiments with TbetaRII conditional knockout mice show that abrogation of TGFbeta signaling promotes the sustained induction of NF-kappaB and its proinflammatory target genes during HNSCC tumorigenesis and progression. Together, these findings elucidate a regulatory framework in which attenuated TGFbeta signaling promotes NF-kappaB activation and squamous epithelial malignancy in the setting of altered TP53 status.-
dc.languageeng-
dc.publisherAmerican Association for Cancer Research. The Journal's web site is located at http://cancerres.aacrjournals.org/-
dc.relation.ispartofCancer Research-
dc.titleAttenuated transforming growth factor beta signaling promotes nuclear factor-kappaB activation in head and neck cancer-
dc.typeArticle-
dc.identifier.emailYan, B: yanbinai6017@gmail.com-
dc.identifier.authorityYan, B=rp01940-
dc.description.naturelink_to_OA_fulltext-
dc.identifier.doi10.1158/0008-5472.CAN-08-3704-
dc.identifier.pmid19351843-
dc.identifier.pmcidPMC2696277-
dc.identifier.hkuros700002296-
dc.identifier.volume69-
dc.identifier.issue8-
dc.identifier.spage3415-
dc.identifier.epage3424-
dc.publisher.placeUnited States-

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