Snail-induced down-regulation of DeltaNp63alpha acquires invasive phenotype of human squamous cell carcinoma

Koichiro Higashikawa; Shingo Yoneda; Kei Tobiume; Masayuki Taki; Hideo Shigeishi; Nobuyuki Kamata

doi:10.1158/0008-5472.CAN-07-0932

Snail-induced down-regulation of DeltaNp63alpha acquires invasive phenotype of human squamous cell carcinoma

Cancer Res. 2007 Oct 1;67(19):9207-13. doi: 10.1158/0008-5472.CAN-07-0932.

Authors

Koichiro Higashikawa¹, Shingo Yoneda, Kei Tobiume, Masayuki Taki, Hideo Shigeishi, Nobuyuki Kamata

Affiliation

¹ Department of Oral and Maxillofacial Surgery, Division of Cervico-Gnathostomatology, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan. khigashi@hiroshima-u.ac.jp

PMID: 17909026
DOI: 10.1158/0008-5472.CAN-07-0932

Abstract

p63 is a member of the p53 family and regulates crucial events in the formation of epithelial structures, but the role of p63 in tumor is unclear. We found that Snail-induced epithelial-to-mesenchymal transition (EMT) is accompanied by down-regulation of p63 in human squamous cell carcinomas (SCC). DeltaNp63alpha is the predominantly expressed p63 isoform in SCC cells. DeltaNp63 promoter activity required a CAAT/enhancer binding protein (C/EBP) binding element and was reduced remarkably by Snail. Down-regulation of DeltaNp63alpha and reduction of C/EBPalpha were observed in EMT phenotype cells, which exhibited invasive activity in vitro. p63 knockdown in cells enhanced invasive activity in the presence of E-cadherin. Conversely, forced expression of DeltaNp63alpha blocked invasive activity of cells with the EMT phenotype. These findings indicate that Snail down-regulates DeltaNp63alpha, leading to acquisition of the invasive phenotype by SCC. The invasive activity caused by down-regulation of DeltaNp63alpha does not require down-regulation of E-cadherin.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

CCAAT-Enhancer-Binding Proteins / metabolism
Carcinoma, Squamous Cell / genetics
Carcinoma, Squamous Cell / metabolism*
Carcinoma, Squamous Cell / pathology*
Cell Line, Tumor
DNA-Binding Proteins / biosynthesis
DNA-Binding Proteins / deficiency*
DNA-Binding Proteins / genetics
Down-Regulation
Epithelial Cells / pathology
Female
Gene Expression Regulation, Neoplastic
Humans
Mesoderm / pathology
Mouth Neoplasms / genetics
Mouth Neoplasms / metabolism
Mouth Neoplasms / pathology
Neoplasm Invasiveness
Promoter Regions, Genetic
Snail Family Transcription Factors
Trans-Activators / biosynthesis
Trans-Activators / deficiency*
Trans-Activators / genetics
Transcription Factors / genetics
Transcription Factors / metabolism*
Tumor Suppressor Proteins / biosynthesis
Tumor Suppressor Proteins / deficiency*
Tumor Suppressor Proteins / genetics
Vulvar Neoplasms / genetics
Vulvar Neoplasms / metabolism
Vulvar Neoplasms / pathology

Substances

CCAAT-Enhancer-Binding Proteins
CEBPA protein, human
DNA-Binding Proteins
Snail Family Transcription Factors
TP63 protein, human
Trans-Activators
Transcription Factors
Tumor Suppressor Proteins