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Article

The Hepatitis B Virus Pre-Core Protein p22 Activates Wnt Signaling

1
The Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne 3000, Australia
2
Cancer Research UK Beatson Institute, Glasgow G61 1BD, UK
3
The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia
4
Department of Medical Biology, The University of Melbourne, Melbourne 3010, Australia
5
Victorian Infectious Diseases Reference Laboratory, The Peter Doherty Institute for Infection and Immunity, Melbourne 3000, Australia
6
Department of Surgery, Austin Health, The University of Melbourne, Melbourne 3010, Australia
7
Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne 3000, Australia
8
European Cancer Stem Cell Research Institute, Cardiff University, Cardiff CF24 4HQ, UK
9
School of Pharmacy and Biomedical Sciences, Curtin University, Perth, WA 6102, Australia
*
Authors to whom correspondence should be addressed.
Cancers 2020, 12(6), 1435; https://doi.org/10.3390/cancers12061435
Received: 21 April 2020 / Revised: 24 May 2020 / Accepted: 27 May 2020 / Published: 31 May 2020
An emerging theme for Wnt-addicted cancers is that the pathway is regulated at multiple steps via various mechanisms. Infection with hepatitis B virus (HBV) is a major risk factor for liver cancer, as is deregulated Wnt signaling, however, the interaction between these two causes is poorly understood. To investigate this interaction, we screened the effect of the various HBV proteins for their effect on Wnt/β-catenin signaling and identified the pre-core protein p22 as a novel and potent activator of TCF/β-catenin transcription. The effect of p22 on TCF/β-catenin transcription was dose dependent and inhibited by dominant-negative TCF4. HBV p22 activated synthetic and native Wnt target gene promoter reporters, and TCF/β-catenin target gene expression in vivo. Importantly, HBV p22 activated Wnt signaling on its own and in addition to Wnt or β-catenin induced Wnt signaling. Furthermore, HBV p22 elevated TCF/β-catenin transcription above constitutive activation in colon cancer cells due to mutations in downstream genes of the Wnt pathway, namely APC and CTNNB1. Collectively, our data identifies a previously unappreciated role for the HBV pre-core protein p22 in elevating Wnt signaling. Understanding the molecular mechanisms of p22 activity will provide insight into how Wnt signaling is fine-tuned in cancer. View Full-Text
Keywords: Wnt signaling; hepatitis B virus; HBV; cancer; liver cancer; β-catenin; TCF/LEF Wnt signaling; hepatitis B virus; HBV; cancer; liver cancer; β-catenin; TCF/LEF
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MDPI and ACS Style

Tran, B.M.; Flanagan, D.J.; Ebert, G.; Warner, N.; Tran, H.; Fifis, T.; Kastrappis, G.; Christophi, C.; Pellegrini, M.; Torresi, J.; Phesse, T.J.; Vincan, E. The Hepatitis B Virus Pre-Core Protein p22 Activates Wnt Signaling. Cancers 2020, 12, 1435. https://doi.org/10.3390/cancers12061435

AMA Style

Tran BM, Flanagan DJ, Ebert G, Warner N, Tran H, Fifis T, Kastrappis G, Christophi C, Pellegrini M, Torresi J, Phesse TJ, Vincan E. The Hepatitis B Virus Pre-Core Protein p22 Activates Wnt Signaling. Cancers. 2020; 12(6):1435. https://doi.org/10.3390/cancers12061435

Chicago/Turabian Style

Tran, Bang M., Dustin J. Flanagan, Gregor Ebert, Nadia Warner, Hoanh Tran, Theodora Fifis, Georgios Kastrappis, Christopher Christophi, Marc Pellegrini, Joseph Torresi, Toby J. Phesse, and Elizabeth Vincan. 2020. "The Hepatitis B Virus Pre-Core Protein p22 Activates Wnt Signaling" Cancers 12, no. 6: 1435. https://doi.org/10.3390/cancers12061435

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