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Attenuated Transforming Growth Factor β Signaling Promotes Nuclear Factor-B Activation in Head and Neck Cancer

¹ Howard Hughes Medical Institute-NIH Research Scholars Program, ² Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, Maryland; and ³ Department of Otolaryngology, Oregon Health and Science University, Portland, Oregon

Requests for reprints: Carter Van Waes, National Institute on Deafness and Other Communication Disorders, NIH, Building 10, CRC Room 4-2732, 10 Center Drive, Rockville, MD 20892. Phone: 301-402-4216; Fax: 301-402-1140; E-mail: vanwaesc{at}nidcd.nih.gov and Zhong Chen, Phone: 301-435-2073; Fax: 301-402-1140; E-mail: chenz{at}nidcd.nih.gov.

Key Words: TGFβ • NF-B • TP53 • head and neck cancer

Although constitutively activated nuclear factor-B (NF-B), attenuated transforming growth factor β (TGFβ) 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-B–related genes, reduced expression of TGFβ receptor (TβR) subunits and downstream targets, and TP53 genotype in head and neck squamous cell carcinoma (HNSCC). In response to recombinant TGFβ1, both growth inhibition and TGFβ target gene modulation were attenuated or absent in a panel of human HNSCC lines. However, in HNSCC cells that retained residual TGFβ signaling, TGFβ1 inhibited both constitutive and tumor necrosis factor –stimulated NF-B activity. Furthermore, HNSCC lines overexpressing mutant (mt) TP53 and human tumor specimens with positive TP53 nuclear staining exhibited reduced TβRII and knocking down mtTP53 induced TβRII, increasing TGFβ downstream gene expression while inhibiting proinflammatory NF-B target gene expression. Transfection of ectopic TβRII directly restored TGFβ signaling while inhibiting inhibitor B degradation and suppressing serine-536 phosphorylation of NF-B p65 and NF-B transcriptional activation, linking these alterations. Finally, experiments with TβRII conditional knockout mice show that abrogation of TGFβ signaling promotes the sustained induction of NF-B and its proinflammatory target genes during HNSCC tumorigenesis and progression. Together, these findings elucidate a regulatory framework in which attenuated TGFβ signaling promotes NF-B activation and squamous epithelial malignancy in the setting of altered TP53 status. [Cancer Res 2009;69(8):3415–24]