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. 2009 Jan;58(1):39-47.
doi: 10.1007/s00262-008-0522-5. Epub 2008 Apr 26.

"VSports注册入口" Increased migration of Langerhans cells in response to HPV16 E6 and E7 oncogene silencing: role of CCL20

Jean-Hubert Caberg  1 , Pascale Hubert, Ludivine Herman, Michael Herfs, Patrick Roncarati, Jacques Boniver, Philippe Delvenne
Affiliations

Increased migration of Langerhans cells in response to HPV16 E6 and E7 oncogene silencing: role of CCL20 (V体育2025版)

Jean-Hubert Caberg et al. Cancer Immunol Immunother. 2009 Jan.

Abstract

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 VSports手机版. .

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Figures

Fig. 1
Fig. 1
CCL20 immunostaining in cervical biopsy specimens. Normal exocervical squamous epithelium (a) or high-grade SIL (b) stained with an antibody against CCL20. Semi-quantitative evaluation of CCL20 expression in cervical biopsy specimens (c)
Fig. 2
Fig. 2
Western blot detection of E7 and p53 protein in total cell extracts from E6 (siE6) and E7 (siE7) siRNA treated SiHa cells at 48 h. SiHa cells treated with control siRNA (siC) were used as control. β-actin served as loading control
Fig. 3
Fig. 3
CCL20 secretion in cultures of E6 and E7 siRNA treated SiHa cells measured by ELISA. SiHa cells treated with control siRNA (siC) served as control. Values are expressed as increased CCL20 secretion in supernatants from E6 and E7 siRNA treated cells relative to supernatants from cells treated with siC
Fig. 4
Fig. 4
Cytoplasmic and nuclear protein levels of p50 (NF-κB1), p52 (NF-κB2) and p65 detected by Western blot. KU-70 and PLCγ1 were used, respectively as total and cytoplasmic loading controls. The figure shows the modulation of subcellular localization of p50, p52 and p65 according to the inhibition of E6 (siE6), E7 (siE7), E6 and E7 (siE6/E7) in SiHa cells. SiHa cells treated with control siRNA (siC) and normal keratinocytes (KN) served as controls. The densitometric values represent ratios of protein band density in cells treated with E6 and/or E7 siRNAs compared to control siRNA
Fig. 5
Fig. 5
a–c Phenotypical analysis of LC generated in vivo. The two-parameter contour plots show CD1a fluorescein isothiocyanate (FITC) on the x-axis and CD14 (a), CCR6 (b) and CD207 (c) phycoerythrin (PE) on the y-axis. The values correspond to the percentages of positive cells in the entire population. d Migration of LC in a Boyden chamber assay with culture supernatants from E6 (siE6), E7 (siE7) or both (siE6/E7) siRNA treated SiHa cells. Culture supernatants from SiHa cells treated with control siRNA (siC) served as controls. Supernatants were treated (greyscale) or not (white) with a CCL20 blocking antibody. Results are expressed as the means ± SD of three experiments. Asterisks indicate statistically significant differences ***P < 0.001
Fig. 6
Fig. 6
CD1a immunostaining of HPV16 positive SiHa cell-derived organotypic cultures infiltrated by LC (arrows). Epithelial sheets of control (a), E6 (b), E7 (c) and E6/E7 (d) siRNA-treated SiHa keratinocytes after immunoperoxydase with an anti-CD1a antibody for the detection of LC
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