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

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

^* To whom correspondence should be addressed. E-mail: vanwaesc{at}nidcd.nih.gov.

	Abstract

Although constitutively activated nuclear factor-B (NF-B), attenuated transforming growth factor (TGF) 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 TGF receptor (TR) subunits and downstream targets, and TP53 genotype in head and neck squamous cell carcinoma (HNSCC). In response to recombinant TGF1, both growth inhibition and TGF target gene modulation were attenuated or absent in a panel of human HNSCC lines. However, in HNSCC cells that retained residual TGF signaling, TGF1 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 TRII and knocking down mtTP53 induced TRII, increasing TGF downstream gene expression while inhibiting proinflammatory NF-B target gene expression. Transfection of ectopic TRII directly restored TGF 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 TRII conditional knockout mice show that abrogation of TGF 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 TGF signaling promotes NF-B activation and squamous epithelial malignancy in the setting of altered TP53 status. [Cancer Res 2009;69(8):3415–24]

Key Words: TGF, NF-B, TP53, head and neck cancer