E6/E7 expression of human papillomavirus type 20 (HPV-20) and HPV-27 influences proliferation and differentiation of the skin in UV-irradiated SKH-hr1 transgenic mice.
The functional role of UV irradiation, in combination with the E6 and E7 proteins of the cutaneous human papillomavirus (HPV) types in the malignant conversion of benign papillomatous lesions, has not been elucidated. Transgenic SKH-hr1 hairless mice expressing HPV-20 and HPV-27 E6 and E7 proteins in the suprabasal compartment were generated and exposed to chronic UV irradiation. Histological and immunohistochemical examination of skin samples revealed enhanced proliferation of the epidermal layers and papilloma formation in both transgenic strains in comparison to what was observed with nontransgenic mice. Squamous cell carcinoma developed in the HPV-20 E6/E7 transgenic line as well as in the HPV-27 E6/E7 transgenic line. Several weeks after cessation of UV-B exposure, enhanced proliferation, as measured by BrdU incorporation, was maintained only in HPV-20 transgenic skin. Keratin 6 expression was increased in the transgenic mice throughout all cell layers. Expression of the differentiation markers involucrin and loricrin was reduced and disturbed. p63alpha expression was differentially regulated with high levels of cytoplasmic expression in clusters of cells in the granular layer of the skin in the transgenic lines 20 weeks after cessation of UV-B exposure, in contrast to uninterrupted staining in the nontransgenic lines. p53 was expressed in clusters of cells in nontransgenic and HPV-27 transgenic mice, in contrast to an even distribution in a higher number of cells in HPV-20 transgenic animals.
Michel
Angelika
A
Division for the Characterization of Tumorviruses, Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 242, 69120 Heidelberg, Germany.
Kopp-Schneider
Annette
A
Zentgraf
Hanswalter
H
Gruber
Achim D
AD
de Villiers
Ethel-Michele
EM
D052685:Alphapapillomavirus / Q000378:metabolism*; D000818:Animals; D052686:Betapapillomavirus / Q000378:metabolism*; D001973:Bromodeoxyuridine / Q000378:metabolism; D002454:Cell Differentiation; D049109:Cell Proliferation; D004817:Epidermis / Q000378:metabolism / Q000528:radiation effects / Q000821:virology; D005260:Female; D006651:Histocytochemistry; D007150:Immunohistochemistry; D053553:Keratin-6 / Q000096:biosynthesis; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis; D051379:Mice; D008822:Mice, Transgenic; D009856:Oncogene Proteins, Viral / Q000096:biosynthesis*; D010212:Papilloma / Q000473:pathology / Q000821:virology; D030361:Papillomavirus Infections / Q000821:virology; D010750:Phosphoproteins / Q000096:biosynthesis; D011498:Protein Precursors / Q000096:biosynthesis; D012867:Skin / Q000166:cytology / Q000473:pathology / Q000528:radiation effects* / Q000821:virology*; D012878:Skin Neoplasms / Q000473:pathology / Q000821:virology; D015534:Trans-Activators / Q000096:biosynthesis; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis
D053553:Keratin-6; D008565:Membrane Proteins; D009856:Oncogene Proteins, Viral; D010750:Phosphoproteins; D011498:Protein Precursors; D015534:Trans-Activators; C486419:Trp63 protein, mouse; D016159:Tumor Suppressor Protein p53; C064554:loricrin; C032253:involucrin; D001973:Bromodeoxyuridine