First published April 1, 2019 - More info
Cell death is a key driver of disease progression and carcinogenesis in chronic liver disease (CLD), highlighted by the well-established clinical correlation between hepatocellular death and risk for the development of cirrhosis and hepatocellular carcinoma (HCC). Moreover, hepatocellular death is sufficient to trigger fibrosis and HCC in mice. However, the pathways through which cell death drives CLD progression remain elusive. Here, we tested the hypothesis that high-mobility group box 1 (HMGB1), a damage-associated molecular pattern (DAMP) with key roles in acute liver injury, may link cell death to injury responses and hepatocarcinogenesis in CLD. While liver-specific HMGB1 deficiency did not significantly affect chronic injury responses such as fibrosis, regeneration, and inflammation, it inhibited ductular/progenitor cell expansion and hepatocyte metaplasia. HMGB1 promoted ductular expansion independently of active secretion in a nonautonomous fashion, consistent with its role as a DAMP. Liver-specific HMGB1 deficiency reduced HCC development in 3 mouse models of chronic injury but not in a model lacking chronic liver injury. As with CLD, HMGB1 ablation reduced the expression of progenitor and oncofetal markers, a key determinant of HCC aggressiveness, in tumors. In summary, HMGB1 links hepatocyte death to ductular reaction, progenitor signature, and hepatocarcinogenesis in CLD.
Celine Hernandez, Peter Huebener, Jean-Philippe Pradere, Richard A. Friedman, Robert F. Schwabe
Original citation: J Clin Invest. 2018;128(6):2436–2451. https://doi.org/10.1172/JCI91786
Citation for this expression of concern: J Clin Invest. 2019;129(4):1803. https://doi.org/10.1172/JCI128261
An investigative committee at the University of Liverpool recently identified evidence of data fabrication relating to the mass spectrometry data contributed by Daniel J. Antoine, shown in Figures 3B and 5A of this paper. The Editorial Board is issuing this Expression of Concern to alert readers to this problem. No issues have been raised in regard to any of the other data in this manuscript.
See the related article at HMGB1 links chronic liver injury to progenitor responses and hepatocarcinogenesis.