Abstract
The Wnt/β-catenin signaling pathway regulates cell proliferation and differentiation and its aberrant activation in cervical cancer has been described. Persistent infection with high risk human papillomavirus (HR-HPV) is the most important factor for the development of this neoplasia, since E6 and E7 viral oncoproteins alter cellular processes, promoting cervical cancer development. A role of HPV-16 E6 in Wnt/β-catenin signaling has been proposed, although the participation of HPV-18 E6 has not been previously studied. The aim of this work was to investigate the participation of HPV-18 E6 and E6*I, in the regulation of the Wnt/β-catenin signaling pathway. Here, we show that E6 proteins up-regulate TCF-4 transcriptional activity and promote overexpression of Wnt target genes. In addition, it was demonstrated that E6 and E6*I bind to the TCF-4 (T cell factor 4) and β-catenin, impacting TCF-4 stabilization. We found that both E6 and E6*I proteins interact with the promoter of Sp5, in vitro and in vivo. Moreover, although differences in TCF-4 transcriptional activation were found among E6 intratype variants, no changes were observed in the levels of regulated genes. Furthermore, our data support that E6 proteins cooperate with β-catenin to promote cell proliferation.
Highlights
The Wnt signaling pathway regulates a variety of processes, including cell proliferation and differentiation [1]
We demonstrate that E6 and E6*I from HPV-18 interact with TCF-4, but are able to induce the TCF-4 stabilization
Our findings revealed that both E6 and E6*I increased nuclear TCF-4 protein levels, which may directly impact in TCF-4 transcriptional activation
Summary
The Wnt signaling pathway regulates a variety of processes, including cell proliferation and differentiation [1]. In vitro assays have demonstrated that HPV-16 E6 induces TCF-4 transcriptional activation, whereas β-catenin is not stabilized. No interactions of HPV-18 E6 protein with members of the Wnt activation complex (TCF-4, β-catenin) have been identified so far, and the mechanisms by which E6 induces TCF transcriptional activation are poorly understood. Through a TCF-4-dependent luciferase reporter plasmid, we show that E6 and E6*I up-regulate TCF-4 transcriptional activity, which is enhanced with the expression of exogenous β-catenin. HPV-18 E6 and E6*I Proteins Enhance β-Catenin/TCF-4 Transcription an A233G mutation in the donor splicing site that promotes a decrease in the expression of E6*I. Overexpression of E6 proteins stimulate native promoters containing TCF-4 responsive elements, as evidenced by the expression of the Wnt target genes, Axin and Cyclin D1, evaluated by Int. J. 0.001 and *** p < 0.0001 vs. empty vector values
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