Abstract
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.
Highlights
Liver cancer is the second most common cause of cancer deaths worldwide and is projected to increase by ~40% by 2030 [1]
Concomitant regulation of Wnt signaling at multiple levels of the signaling cascade via various mechanisms to achieve the “just right” level of Wnt signaling for a particular process is a common theme emerging for Wnt-addicted cancers [14,15,16] and here, we demonstrate that hepatitis B virus (HBV) p22 might contribute to our understanding of this fine tuning in cancer
Our data identifies HBV p22 as a novel regulator of Wnt signaling in the context of cancer and provides insight into the mechanisms of ‘just right’ Wnt signaling in cancer
Summary
Liver cancer is the second most common cause of cancer deaths worldwide and is projected to increase by ~40% by 2030 [1]. The Wnt signal transduction pathway is aberrantly activated in most cases of HCC and mutations to the catenin beta 1 (CTNNB1) gene, the gene that codes for β-catenin, occurs in up to. Β-Catenin is the main effector of the canonical Wnt signaling pathway [5] and these mutations to CTNNB1 lead to constitutive activation of. Upon activation of Wnt-FZD signaling, GSK3 enzyme activity is inhibited and β-catenin escapes phosphorylation and subsequent degradation, accumulates in the cytoplasm and translocates into the nucleus where it complexes with the enhanceosome to initiate the TCF/β-catenin target gene transcription [9]. The phosphorylation sites of β-catenin are absent due to mutations to the CTNNB1 gene, leading to the constitutive activation of Wnt/β-catenin signaling [3,4,10]
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