Selective suppression of monocyte chemoattractant protein‐1 expression by human papillomavirus E6 and E7 oncoproteins in human cervical epithelial and epidermal cells

Abstract

Infection of cervical keratinocytes by high-risk HPV is in-HPVs are etiologically involved in carcinoma of the uterine cervix. Among the nearly 90 HPV serotypes isolated to date, a subset of high-risk viruses has been found in over 90% of human cervical cancers. 1 These include HPV16 (detected in 50% of tumors), HPV18, HPV31 and HPV33. The products of the viral oncogenes E6 and E7 from high-risk viruses have been implicated in carcinogenesis because their expression is sufficient for the immortalization of primary human keratinocytes in vitro. 2-4 E6 targets p53 for ubiquitin-mediated degradation, while E7 binds and inactivates the product of the tumor-suppressor gene Rb. 5,6 Despite this efficient program for inactivating tumor-suppressor proteins, development of cervical carcinoma is a multistep process for which E6 and E7 are necessary but not sufficient. Other genetic changes are required, which may be a consequence, in part, of the chromosomal instability produced by expression of these oncogenes. 7 In addition, however, the host can mount an immune response against HPV, which keeps the infection in a clinically latent state, and this latency must be overcome for cervical cancer to appear. 1,8 -10 Very little is known about the regulation of the immune response directed against HPV-infected epithelial cells. Although epithelial cells can present antigen and release proinflammatory cytokines when activated, [11][12][13][14] there is little or no inflammation at the site of primary HPV infection, 8 and the few inflammatory cells that are present appear not to be activated. 15 In addition, as epithelial dysplasia worsens during progression toward cervical carcinoma, the cervical mucosa is gradually depleted of macrophages, T cells and Langerhans cells. 16 These observations suggest that HPV is capable of suppressing the host's immune and inflammatory responses to viral infection and transformation.One of the earliest cellular responses to injury or infection is the release of chemokines, which are low m.w. chemoattractant proteins that elicit local infiltration of inflammatory and immune cells. 17 The chemokine MCP-1 is particularly relevant in the setting of viral infection because of its ability to attract monocytes, memory T cells and NK cells in vivo. 18 However, even though MCP-1 expression is induced after infection by a variety of RNA and DNA viruses, MCP-1 expression is suppressed after epithelial cell infection by HPV in vitro. 19 This parallels the situation in vivo, where advancing cervical intraepithelial neoplasia is associated with loss of MCP-1 expression. 20 The mechanisms responsible for HPV-mediated suppression of MCP-1 expression are unclear. The present study was undertaken to examine the effects of HPV E6 and E7 on chemokine expression by primary epithelial cells of the reproductive tract. Surprisingly, we found that viral oncogenes selectively render MCP-1 unresponsive to induction by proinflammatory cytokines and that this refractoriness is also seen in most cervical carcinoma cell li...

Molecular Pathobiology of Human Cervical High-Grade Lesions: Paracrine STAT3 Activation in Tumor-Instructed Myeloid Cells Drives Local MMP-9 Expression

“…The involvement of myeloid CCL2 in our experiments corresponded very well to in vivo studies showing that CCL2 expression is localized predominantly to the inflammatory infiltrate in neoplastic cervical lesions (9,38). One may speculate that myeloid CCL2 induction may compensate for the failure of HPV-positive keratinocytes to express CCL2 (39).…”

TGF-β Mediates Proinflammatory Seminal Fluid Signaling in Human Cervical Epithelial Cells

“…Additionally, primary cells show considerably higher IL-8 and CCL2 output, consistent with reports that immortalizing cervical keratinocytes with human papilloma virus DNAs can suppress cytokine secretion (61). In particular, reduced CCL2 expression in Ect1 cells has been attributed to active suppression by viral oncogenes E6 and E7 (62). Thus, in the in vivo setting, cervical epithelial cells may respond to seminal fluid TGF-b stimulation with a wider range of cytokine response than observed in this study in Ect1 cells.…”

The countercurrent principle in invasion and metastasis of cancer cells. Recent insights on the roles of chemokines

“…Furthermore, 4 of 6 cervical carcinoma cell lines that scored positive for human papilloma virus transformation, did not express MCP-1/CCL2. Suppression of MCP-1/CCL2 expression Kunz et al, 1999 seems to coincide with the program of E6/E7-induced transformation of primary epithelial cells (Kleine-Lowinski et al, 2003).…”