E-cadherin transfection down-regulates the epidermal growth factor receptor and reverses the invasive phenotype of human papilloma virus-transfected keratinocytes

• Published in: Cancer research (Chicago, Ill.) Ill.), 1996-11, Vol.56 (22), p.5285-5292
• Main Authors: WILDING, J, VOUSDEN, K. H, SOUTTER, W. P, MCCREA, P. D, BUONO, R. D, PIGNATELLI, M
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Cadherins - genetics; Cadherins - metabolism; Cadherins - physiology; Cell Differentiation; Cell Line, Transformed; Dissemination; Down-Regulation; Humans; Keratinocytes - metabolism; Keratinocytes - virology; Medical sciences; Mice; Mice, Nude; Neoplasm Invasiveness; Oncogene Proteins, Viral - metabolism; Oncogene Proteins, Viral - physiology; Papillomaviridae; Papillomavirus E7 Proteins; Phenotype; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins - physiology; Receptor, Epidermal Growth Factor - metabolism; Receptor, Epidermal Growth Factor - physiology; Receptor, ErbB-2 - metabolism; Receptor, ErbB-2 - physiology; Repressor Proteins; Transfection; Tumor cell; Tumors; Up-Regulation
• ISSN: 0008-5472; 1538-7445

The human papillomavirus type 16 (HPV-16), the type most often associated with cervical cancer, immortalizes primary keratinocytes and inhibits serum/calcium-stimulated differentiation in culture. In this study, we have used a model of keratinocyte immortalization based upon HPV-16 to analyze perturbation of function and expression of E-cadherin, a Ca(2+)-dependent cell-cell adhesion molecule expressed by normal keratinocytes, and its associated proteins. An immortalized keratinocyte cell line generated by cotransfection with HPV-16 E6 and E7 showed decreased membrane E-cadherin expression and redistribution of alpha-, beta-, and gamma-catenin from the undercoat membrane to the cytoplasm. No changes in the level of expression were seen. Selection of the immortalized keratinocyte cell line for resistance to differentiation generated a more transformed cell line with an invasive phenotype, down-regulated E-cadherin and alpha-catenin, and up-regulated the epidermal growth factor receptor (EGFr). Transfection of an E-cadherin expression construct into the differentiation-resistant cell line restored membrane-bound E-cadherin and catenin expression, down-regulated the EGFr, and reversed the invasive phenotype. These results indicate that overexpression of the EGFr correlates with perturbation of the E-cadherin/catenin complex seen in the HPV-16 E6- and E7-transfected keratinocytes and may underlie a functional interaction between growth-regulatory factors and adhesion molecules (E-cadherin/catenin).