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 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).
Wilding
J
J
Department of Histopathology, Royal Postgraduate Medical School, London, United Kingdom.
Vousden
K H
KH
Soutter
W P
WP
McCrea
P D
PD
Del Buono
R
R
Pignatelli
M
M
D000818:Animals; D015820:Cadherins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D002454:Cell Differentiation; D002461:Cell Line, Transformed; D015536:Down-Regulation; D066246:ErbB Receptors / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism* / Q000821:virology; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009856:Oncogene Proteins, Viral / Q000378:metabolism / Q000502:physiology*; D027383:Papillomaviridae; D050725:Papillomavirus E7 Proteins; D010641:Phenotype; D011518:Proto-Oncogene Proteins / Q000378:metabolism / Q000502:physiology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism / Q000502:physiology; D012097:Repressor Proteins; D014162:Transfection; D015854:Up-Regulation
D015820:Cadherins; D066246:ErbB Receptors; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D011518:Proto-Oncogene Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D012097:Repressor Proteins; C068651:E6 protein, Human papillomavirus type 16; C059731:oncogene protein E7, Human papillomavirus type 16