Integrin expression and function in HPV 16-immortalised human keratinocytes in the presence or absence of v-Ha-ras. Comparison with cervical intraepithelial neoplasia.
Keratinocytes express several receptors of the integrin family which regulate both adhesion and differentiation. We have investigated whether HPV immortalisation, which changes the growth and differentiation properties of keratinocytes, is associated with altered integrin expression or function. We compared two HPV 16-immortalised lines of human keratinocytes, up and vp, with the normal keratinocyte strains, u and v, from which they were derived and with upr, obtained by transfection of up with viral Harvey ras. Immunofluorescence, immunoprecipitation and flow cytometry demonstrated that up and vp had lower levels of integrins than u and v, the reduction in up being greater than in vp. Up and vp also had reduced levels of mRNA encoding the beta 1 integrin subunit. Reduced expression of the alpha 5 beta 1 and alpha 2 beta 1 integrins was correlated with reduced adhesion to fibronectin and collagen in up but not in vp and there were no significant differences between the normal and immortalised cells in adhesion to laminin. Reduced integrin expression was correlated with decreased motility, up showing a greater reduction in motility than vp. Introduction of activated ras into up had no effect on integrin levels, cell motility or tumorigenicity in nude mice; the only difference between up and upr was that upr showed increased adhesion to fibronectin. Examination of eight biopsies of cervical intraepithelial neoplasias with evidence of HPV infection revealed reduced or discontinuous integrin expression in the most severe lesions. We conclude that both in vivo and in culture keratinocytes the impaired differentiation that is associated with the presence of HPV is correlated with reduced integrin expression.
Hodivala
K J
KJ
Keratinocyte Laboratory, Imperial Cancer Research Fund, London.
Pei
X F
XF
Liu
Q Y
QY
Jones
P H
PH
Rytina
E R
ER
Gilbert
C
C
Singer
A
A
Watt
F M
FM
D002448:Cell Adhesion; D002465:Cell Movement; D002472:Cell Transformation, Viral; D004279:DNA, Viral / Q000032:analysis; D005260:Female; D011905:Genes, ras; D006801:Humans; D016023:Integrins / Q000096:biosynthesis* / Q000235:genetics; D015603:Keratinocytes / Q000276:immunology* / Q000382:microbiology; D027383:Papillomaviridae / Q000235:genetics; D030361:Papillomavirus Infections / Q000276:immunology / Q000382:microbiology; D014412:Tumor Virus Infections / Q000276:immunology / Q000382:microbiology; D002583:Uterine Cervical Neoplasms / Q000276:immunology / Q000382:microbiology; D002578:Uterine Cervical Dysplasia / Q000276:immunology / Q000382:microbiology
D004279:DNA, Viral; D016023:Integrins