HBV-related HCC development in mice is STAT3 dependent and indicates an oncogenic effect of HBx
Abstract
Background & Aims: Although most hepatocellular carcinoma (HCC) cases are driven by hepatitis and cirrhosis, a subset of patients with chronic hepatitis B develop HCC in the absence of advanced liver disease, indicating the oncogenic potential of hepatitis B virus (HBV). We investigated the role of HBV transcripts and proteins on HCC development in the absence of inflammation in HBV-transgenic mice. Methods: analyses using human cell lines were performed. Hepatocyte-specific Stat3- and Socs3-knockout was analyzed in HBV1.3 mice. Results: Approximately 38% of HBV1.3 mice developed liver tumors. Protein expression patterns, histology, and mutational landscape analyses indicated that tumors resembled human HCC. HBV1.3 mice showed no signs of active hepatitis, except STAT3 activation, up to the time point of HCC development. HBV-RNAs covering HBx sequence, 3.5-kb HBV RNA and HBx-protein were detected in HCC tissue. Interestingly, HBVxfs mice expressing all HBV proteins except a C-terminally truncated HBx (without the ability to bind DNA damage binding protein 1) showed reduced signs of DNA damage response and had a significantly reduced HCC incidence. Importantly, intercrossing HBV1.3 mice with a hepatocyte-specific STAT3-knockout abrogated HCC development. Conclusions: Expression of HBV-proteins is sufficient to cause HCC in the absence of detectable inflammation. This indicates the oncogenic potential of HBV and in particular HBx. In our model, HBV-driven HCC was STAT3 dependent. Our study highlights the immediate oncogenic potential of HBV, challenging the idea of a benign highly replicative phase of HBV infection and indicating the necessity for an HBV 'cure'. Impact and implications: Although most HCC cases in patients with chronic HBV infection occur after a sequence of liver damage and fibrosis, a subset of patients develops HCC without any signs of advanced liver damage. We demonstrate that the expression of all viral transcripts in HBV-transgenic mice suffices to induce HCC development independent of inflammation and fibrosis. These data indicate the direct oncogenic effects of HBV and emphasize the idea of early antiviral treatment in the 'immune-tolerant' phase (HBeAg-positive chronic HBV infection).
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BibTeX
@article{ringelhan2026hbvrelated,
title = {{HBV-related HCC development in mice is STAT3 dependent and indicates an oncogenic effect of HBx}},
author = {Marc Ringelhan and Svenja Schuehle and Maarten van de Klundert and Elena Kotsiliti and Marie-Laure Plissonnier and Suzanne Faure‐dupuy and Tobias Riedl and Sebastian Lange and Karin Wisskirchen and Frank Thiele and Cho-Chin Cheng and Detian Yuan and Valentina Leone and Ronny Schmidt and Juliana Hünergard and Fabian Geisler and Kristian Unger and Hana Algül and Roland Schmid and Roland Rad and Heiner Wedemeyer and Massimo Levrero and Ulrike Protzer and Mathias Heikenwalder},
journal = {JHEP Reports Innovation in Hepatology},
year = {2026},
month = sep,
doi = {10.1016/j.jhepr.2024.101128},
url = {https://hal.science/hal-05771069v1},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - HBV-related HCC development in mice is STAT3 dependent and indicates an oncogenic effect of HBx
AU - Marc Ringelhan
AU - Svenja Schuehle
AU - Maarten van de Klundert
AU - Elena Kotsiliti
AU - Marie-Laure Plissonnier
AU - Suzanne Faure‐dupuy
AU - Tobias Riedl
AU - Sebastian Lange
AU - Karin Wisskirchen
AU - Frank Thiele
AU - Cho-Chin Cheng
AU - Detian Yuan
AU - Valentina Leone
AU - Ronny Schmidt
AU - Juliana Hünergard
AU - Fabian Geisler
AU - Kristian Unger
AU - Hana Algül
AU - Roland Schmid
AU - Roland Rad
AU - Heiner Wedemeyer
AU - Massimo Levrero
AU - Ulrike Protzer
AU - Mathias Heikenwalder
PY - 2026
DA - 2026/09/30
JO - JHEP Reports Innovation in Hepatology
DO - 10.1016/j.jhepr.2024.101128
UR - https://hal.science/hal-05771069v1
AB - Background & Aims: Although most hepatocellular carcinoma (HCC) cases are driven by hepatitis and cirrhosis, a subset of patients with chronic hepatitis B develop HCC in the absence of advanced liver disease, indicating the oncogenic potential of hepatitis B virus (HBV). We investigated the role of HBV transcripts and proteins on HCC development in the absence of inflammation in HBV-transgenic mice. Methods: analyses using human cell lines were performed. Hepatocyte-specific Stat3- and Socs3-knockout was analyzed in HBV1.3 mice. Results: Approximately 38% of HBV1.3 mice developed liver tumors. Protein expression patterns, histology, and mutational landscape analyses indicated that tumors resembled human HCC. HBV1.3 mice showed no signs of active hepatitis, except STAT3 activation, up to the time point of HCC development. HBV-RNAs covering HBx sequence, 3.5-kb HBV RNA and HBx-protein were detected in HCC tissue. Interestingly, HBVxfs mice expressing all HBV proteins except a C-terminally truncated HBx (without the ability to bind DNA damage binding protein 1) showed reduced signs of DNA damage response and had a significantly reduced HCC incidence. Importantly, intercrossing HBV1.3 mice with a hepatocyte-specific STAT3-knockout abrogated HCC development. Conclusions: Expression of HBV-proteins is sufficient to cause HCC in the absence of detectable inflammation. This indicates the oncogenic potential of HBV and in particular HBx. In our model, HBV-driven HCC was STAT3 dependent. Our study highlights the immediate oncogenic potential of HBV, challenging the idea of a benign highly replicative phase of HBV infection and indicating the necessity for an HBV 'cure'. Impact and implications: Although most HCC cases in patients with chronic HBV infection occur after a sequence of liver damage and fibrosis, a subset of patients develops HCC without any signs of advanced liver damage. We demonstrate that the expression of all viral transcripts in HBV-transgenic mice suffices to induce HCC development independent of inflammation and fibrosis. These data indicate the direct oncogenic effects of HBV and emphasize the idea of early antiviral treatment in the 'immune-tolerant' phase (HBeAg-positive chronic HBV infection).
SN - 2589-5559
ER -