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Oral Oncol. 2015 Oct;51(10):921-8. doi: 10.1016/j.oraloncology.2015.07.006. Epub 2015 Aug 22.

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

Author information

1
Department of Head and Neck Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, United States; Division of Pulmonary and Critical Care Medicine, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, United States; Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, United States.
2
Department of Head and Neck Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, United States.
3
Division of Pulmonary and Critical Care Medicine, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, United States.
4
Division of Pulmonary and Critical Care Medicine, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, United States; Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, United States; Veterans' Affairs Greater Los Angeles Healthcare System, Los Angeles, CA 90073, United States.
5
Division of Pulmonary and Critical Care Medicine, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, United States; Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, United States; Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, United States; Veterans' Affairs Greater Los Angeles Healthcare System, Los Angeles, CA 90073, United States.
6
Department of Head and Neck Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, United States; Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, United States. Electronic address: mstjohn@mednet.ucla.edu.

Abstract

OBJECTIVES:

To investigate the role of p53 in NF-κB mediated epithelial-to-mesenchymal (EMT) in head and neck squamous cell carcinoma (HNSCC).

MATERIALS AND METHODS:

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.

RESULTS:

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.

CONCLUSION:

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.

KEYWORDS:

Epithelial-to-mesenchymal transition; Head and neck cancer; NF-κB; p53; p65

[Indexed for MEDLINE]

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