International Agency for Research on Cancer, 150 cours Albert-Thomas, 69372 Lyon Cedex 08, France.
J Virol. 2011 Sep;85(17):9013-22. doi: 10.1128/JVI.00002-11. Epub 2011 Jun 29.
Constitutive activation of NF-κB signaling is a key event in virus- and non-virus-induced carcinogenesis. We have previously reported that cutaneous human papillomavirus type 38 (HPV38) displays transforming properties in in vitro and in vivo experimental models. However, the involvement of NF-κB signaling in HPV38-induced cell growth transformation remains to be determined. In this study, we showed that HPV38 E6 and E7 activate NF-κB and that inhibition of the pathway with the IκBα superrepressor sensitizes HPV38E6E7-immortalized human keratinocytes to tumor necrosis factor alpha (TNF-α)- and UVB radiation-mediated apoptosis. Accordingly, inhibition of NF-κB signaling resulted in the downregulation of NF-κB-regulated antiapoptotic genes, including cIAP1, cIAP2, and xIAP genes. These findings demonstrate a critical role of NF-κB activity in the survival of HPV38E6E7-immortalized human keratinocytes exposed to cytokine or UV radiation. Our data provide additional evidence for cooperation between beta HPV infection and UV irradiation in skin carcinogenesis.
NF-κB 信号的组成性激活是病毒和非病毒诱导致癌作用的关键事件。我们之前曾报道过，皮肤人乳头瘤病毒 38 型（HPV38）在体外和体内实验模型中具有转化特性。然而，NF-κB 信号在 HPV38 诱导的细胞生长转化中的参与仍有待确定。在这项研究中，我们表明 HPV38 E6 和 E7 激活 NF-κB，并且用 IκBα 超级阻遏物抑制该途径可使 HPV38E6E7 永生化的人角质形成细胞对肿瘤坏死因子-α（TNF-α）和 UVB 辐射介导的凋亡敏感。因此，抑制 NF-κB 信号导致 NF-κB 调节的抗凋亡基因（包括 cIAP1、cIAP2 和 xIAP 基因）下调。这些发现表明 NF-κB 活性在暴露于细胞因子或 UV 辐射的 HPV38E6E7 永生化人角质形成细胞的存活中起关键作用。我们的数据为 β HPV 感染和紫外线照射在皮肤致癌作用中的合作提供了额外的证据。
