Increased migration of Langerhans cells in response to HPV16 E6 and E7 oncogene silencing: role of CCL20.
Human papillomavirus (HPV) infection, particularly type 16, is causally associated with cancer of the uterine cervix. The persistence or progression of cervical lesions suggests that viral antigens are not adequately presented to the immune system. This hypothesis is reinforced by the observation that most squamous intraepithelial lesions (SILs) show quantitative and functional alterations of Langerhans cells (LC). The infiltration of immature LC in the squamous epithelium is mainly controlled by Macrophage Inflammatory Protein 3alpha/CCL20. After having shown that CCL20 production is altered in HPV-transformed keratinocytes (KC), the possible role of HPV16 E6 and E7 viral oncoproteins in the reduced CCL20 levels observed in SILs was investigated by silencing HPV16 E6 and E7 oncogenes by RNA interference (siRNA). This treatment not only increased CCL20 secretion but also resulted in the modulation of NF-kappaB p50, p52 and p65 precursor localization. Moreover, silencing of E6 and E7 oncogenes in HPV16-transformed KC induced a significantly higher migratory capacity of LC in a Boyden chamber assay and in an in vitro formed (pre)neoplastic epithelium reminiscent of high-grade SILs. Anti-CCL20 neutralizing antibody experiments showed that the increased migration of LC is due to the re-expression of CCL20 in E6 and E7 siRNA transfected KC. These data suggest that HPV16 E6/E7-induced down-regulation of CCL20 observed during the cervical carcinogenesis may contribute to a diminished capacity of the immune system to control HPV infection.
Caberg
Jean-Hubert
JH
Department of Pathology, GIGA-Cancer, B35, University of Liege, CHU Sart Tilman, Liege, Belgium. jhcaberg@student.ulg.ac.be
Hubert
Pascale
P
Herman
Ludivine
L
Herfs
Michael
M
Roncarati
Patrick
P
Boniver
Jacques
J
Delvenne
Philippe
P
D015153:Blotting, Western; D045744:Cell Line, Tumor; D002465:Cell Movement; D054418:Chemokine CCL20 / Q000235:genetics / Q000502:physiology*; D015536:Down-Regulation; D005260:Female; D005434:Flow Cytometry; D020868:Gene Silencing; D006801:Humans; D007801:Langerhans Cells / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D009856:Oncogene Proteins, Viral / Q000235:genetics; D030361:Papillomavirus Infections / Q000235:genetics / Q000378:metabolism / Q000821:virology; D012097:Repressor Proteins / Q000235:genetics; D015398:Signal Transduction; D002583:Uterine Cervical Neoplasms / Q000276:immunology / Q000503:physiopathology*
C108355:CCL20 protein, human; D054418:Chemokine CCL20; C068651:E6 protein, Human papillomavirus type 16; D009856:Oncogene Proteins, Viral; D012097:Repressor Proteins