E-CADHERIN TRANSFECTION DOWN-REGULATES THE EPIDERMAL GROWTH-FACTOR RECEPTOR AND REVERSES THE INVASIVE PHENOTYPE OF HUMAN PAPILLOMA VIRUS-TRANSFECTED KERATINOCYTES

The human papillomavirus type 16 (HPV-16), the type most often associa ted with cervical cancer, immortalizes primary keratinocytes and inhib its 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 Ca2+-dependent cell-cell adhesion molecule expressed by normal kerati nocytes, and its associated proteins. An immortalized keratinocyte cel l line generated by cotransfection with HPV-16 E6 and E7 showed decrea sed membrane E-cadherin expression and redistribution of alpha-, beta- , and gamma-catenin from the undercoat membrane to the cytoplasm. No c hanges in the level of expression were seen. Selection of the immortal ized keratinocyte cell line for resistance to differentiation generate d a more transformed cell line with an invasive phenotype, down-regula ted e-cadherin and alpha-catenin, and up-regulated the epidermal growt h factor receptor (EGFr). Transfection of an E-cadherin expression con struct 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 overexpre ssion of the EGFr correlates with perturbation of the E-cadherin/caten in complex seen in the HPV-16 E6- and E7-transfected keratinocytes and map underlie a functional interaction between growth-regulatory facto rs and adhesion molecules (E-cadherin/catenin).