p53 modulates NF-κB mediated epithelial-to-mesenchymal transition in head and neck squamous cell carcinoma.

To investigate the role of p53 in NF-κB mediated epithelial-to-mesenchymal (EMT) in head and neck squamous cell carcinoma (HNSCC). We utilized HNSCC and normal oral epithelial cell lines as our model system. We used a lentiviral shRNA system to silence the expression of p65 and p53 in these cell lines. Mutant and wild-type (WT) p53 background genotypes were analyzed. The expression of epithelial and mesenchymal markers was determined using western blotting and quantitative PCR assays. Cell morphology, growth, and invasion were determined using a 3-dimensional spheroid culture and anchorage independent growth (AIG) assays. In HNSCC cells with mutant p53 we found that silencing p65 expression promoted EMT. In contrast, in the context of WT p53, ectopic p65 over-expression promoted EMT. Ablation of WT p53 in normal oral epithelial cells blocked EMT induced by p65 over-expression. We demonstrate that AIG and apoptosis induced by NF-κB activation is regulated by p53. Our data demonstrates that p53 mutational status is critical in determining the outcome of NF-κB activation in HNSCC. In the presence of WT p53, excess p65 signal can promote EMT. Conversely, ablation of p65 in the context of mutant p53 drives EMT. These results demonstrate that p53 mutational status alters the outcome of NF-κB signaling. These results, though preliminary, demonstrate the critical role of p53 mutational status in determining the outcome of NF-κB signaling and suggest that monitoring p53 status may inform the utility of NF-κB inhibitor treatment in HNSCC.

Lin Y ，Mallen-St Clair J ，Luo J ，Sharma S ，Dubinett S ，St John M ... -  《-》

A signal network involving coactivated NF-kappaB and STAT3 and altered p53 modulates BAX/BCL-XL expression and promotes cell survival of head and neck squamous cell carcinomas.

Lee TL ，Yeh J ，Friedman J ，Yan B ，Yang X ，Yeh NT ，Van Waes C ，Chen Z ... -  《-》

Stabilization of Slug by NF-κB is Essential for TNF-α -Induced Migration and Epithelial-Mesenchymal Transition in Head and Neck Squamous Cell Carcinoma Cells.

Slug protein, a transcription factor for the induction of epithelial-mesenchymal transition (EMT) and cancer cell invasion and metastasis, is frequently upregulated in human epithelial cancers. However, mutation of this gene in cancer is rare, and the mechanism of its dysregulation remains unknown, especially in head and neck squamous cell carcinoma (HNSCC). We examined the role of TNF-α in the stabilization of Slug by immunoprecipitation-westernblot analysis. Migration of HNSCC cells with or without knockdown of Slug gene expression was assayed by a wound healing assay. Immunohistochemical staining analysis was used to measurement Slug levels in both normal and HNSCC tumor tissues. The inflammatory cytokine TNF-α stabilized Slug protein by inhibiting its ubiquitination through the NF-κB pathway. Inhibition of NF-κB or knockdown of p65 abrogated the TNF-α-induced stabilization of Slug. Knockdown of Slug expression inhibited cancer cell migration and EMT characteristics induced by TNF-α. Moreover, increased levels of Slug were found to correlate with lymph node metastasis and predict poor prognosis in patients with HNSCC. NF-κB-mediated stabilization of Slug underlies the inflammation-induced EMT and metastasis in HNSCC, which may serve as a therapeutic target for metastatic HNSCC.

Liu S ，Shi L ，Wang Y ，Ye D ，Ju H ，Ma H ，Yang W ，Wang Y ，Hu J ，Deng J ，Zhang Z ... -  《-》

A novel nuclear factor-kappaB gene signature is differentially expressed in head and neck squamous cell carcinomas in association with TP53 status.

Lee TL ，Yang XP ，Yan B ，Friedman J ，Duggal P ，Bagain L ，Dong G ，Yeh NT ，Wang J ，Zhou J ，Elkahloun A ，Van Waes C ，Chen Z ... -  《-》

Evidence that TNF-TNFR1-TRADD-TRAF2-RIP-TAK1-IKK pathway mediates constitutive NF-kappaB activation and proliferation in human head and neck squamous cell carcinoma.

Jackson-Bernitsas DG ，Ichikawa H ，Takada Y ，Myers JN ，Lin XL ，Darnay BG ，Chaturvedi MM ，Aggarwal BB ... -  《ONCOGENE》