The E6 Oncoprotein from HPV16 Enhances the Canonical Wnt/β-Catenin Pathway in Skin Epidermis In Vivo

Abstract

The contribution of the Wnt signaling pathway to HPV-induced carcinogenesis is poorly understood. In high-grade dysplastic lesions that are caused by high-risk human papilloma viruses (HR-HPVs), β-catenin is often located in the cell nucleus, which suggests that Wnt pathway may be involved in the development of HPV-related carcinomas. Most of the oncogenic potential of HR-HPVs resides on the E6 protein’s PDZ-binding domain. We hypothesized that the PDZ-binding domain of the HPV16-E6 oncoprotein induces the nuclear accumulation of β-catenin due to its capacity to degrade PDZ-containing cellular targets. To test this hypothesis, we evaluated the staining pattern of β-catenin in the skin epidermis of transgenic mice expressing the full-length E6 oncoprotein (K14E6 mice) and measured LacZ gene expression in K14E6 mice that were crossed with a strain expressing LacZ that was knocked into the Axin2 locus (Axin2+/LacZ mice). Here, we show that the E6 oncoprotein enhances the nuclear accumulation of β-catenin, the accumulation of cellularβ-catenin-responsive genes and the expression of LacZ. None of these effects were observed when a truncated E6 oncoprotein that lacks the PDZ-binding domain was expressed alone (K14E6ΔPDZ mice) or in combination with Axin2+/LacZ. Conversely, co-transfection with either E6 or E6ΔPDZ similarly enhanced canonical Wnt signaling in short-term in vitro assays that utilized a luciferase Wnt/β-catenin/TCF-dependent promoter. We propose that the activation of canonical Wnt signaling could be induced by the HPV16-E6 oncoprotein; however, the participation of the E6 PDZ-binding domain seems to be important in in vivo models only.

Expression of WNT genes in cervical cancer-derived cells: Implication of WNT7A in cell proliferation and migration

“…It was also proposed that activation of canonical WNT signaling could be induced in vivo by the HPV16-E6 oncoprotein [46]. In our study, it remains to be elucidated whether HPV oncoproteins are involved in WNT7A downregulation, the goal toward which we are currently working.…”

Human papillomavirus 16 oncoprotein regulates the translocation of β‐catenin via the activation of epidermal growth factor receptor

“…Our observations are consistent with those of Wilding et al , who found that co-transfection of an immortalized keratinocyte cell line with HPV-16 E6 and E7 led to redistribution of α-, β-, and γ-catenins from the undercoat membrane to the cytoplasm 28 . Furthermore, in transgenic mice, HPV16 E6 oncoprotein enhanced the nuclear accumulation of β-catenin 29 . A study from Rampias et al .…”

Molecular and Metabolic Consequences Following E6 Transfection in an Isogenic Ovarian Cell Line (A2780) Pair

“…Although outside the scope of this study, observations in the literature suggest a likely candidate to be the Wnt pathway. Previous reports have shown that the E6 protein can activate the Wnt pathway in the epidermis of transgenic mouse expressing full-length E6 oncoprotein [24], and in HPV16-positive oropharyngeal squamous carcinoma cells [25]. The activation of the Wnt signalling pathway and of mTOR signalling has also been observed in tumour samples from the E6 variants non-European cervical cancer patients [26].…”