Retinoic acid inhibition of human papillomavirus type 16-mediated transformation of human keratinocytes.
We previously reported that human keratinocytes (HKc) immortalized by transfection with human papillomavirus type 16 DNA (HKc/HPV16) are more sensitive than normal HKc to growth inhibition by retinoic acid (RA), and that RA treatment of HKc/HPV16 inhibits HPV16 E6/E7 mRNA expression (L. Pirisi et al., Cancer Res., 52: 187-193, 1992). We now demonstrate that HPV16 E2 and E5 mRNAs are also decreased by RA treatment of HKc/HPV16, indicating a general inhibition by RA on the expression of HPV16 early genes. In addition, protein levels of E6 and E7, as measured by immunofluorescence, are also decreased in a dose-dependent manner following RA treatment of HKc/HPV16. Since E6 and E7 are considered the oncogenes of HPV16, we explored the possibility that RA may interfere with HPV16-mediated immortalization of HKc. RA treatment (1 nM) of normal HKc, immediately following transfection with HPV16 DNA, inhibited immortalization by about 95%. Overall, these results provide a direct biochemical basis for a role of RA in the chemo-prevention of human papillomavirus-induced cancers.
Department of Pathology, University of South Carolina School of Medicine, Columbia.
M A
MA
Khan
G R
GR
Jenkins
W H
WH
Tolleson
K E
KE
Creek
L
L
Pirisi
D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D002472:Cell Transformation, Viral / Q000187:drug effects*; D004268:DNA-Binding Proteins; D015967:Gene Expression Regulation, Viral / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009856:Oncogene Proteins, Viral / Q000187:drug effects* / Q000378:metabolism; D027383:Papillomaviridae; D050725:Papillomavirus E7 Proteins; D012333:RNA, Messenger / Q000187:drug effects* / Q000378:metabolism; D012097:Repressor Proteins; D014162:Transfection; D014212:Tretinoin / Q000494:pharmacology*
D004268:DNA-Binding Proteins; C054855:E2 protein, Human papillomavirus type 16; C068651:E6 protein, Human papillomavirus type 16; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D012333:RNA, Messenger; D012097:Repressor Proteins; C059731:oncogene protein E7, Human papillomavirus type 16; D014212:Tretinoin