Hepatocellular carcinoma (HCC) is the third leading cause of cancer mortality worldwide. In the US, HCC rates and HCC-related deaths have increased significantly in the past three decades, whereas incidence and mortality for most other solid tumors have declined. HCC develops almost exclusively in the setting of chronic liver disease (CLD), and is a direct and the clinically most devastating consequence of chronic hepatocellular death. The link between cell death and HCC is highlighted by a 7-10 fold increase in HCC risk in patients with ALT >45 U/l in comparison to those with normal ALT. In mice, chronic hepatocellular injury is sufficient to trigger HCC development in the absence of additional genetic hits. Hence, HCC is a prototypical example for the hypothesis that cancer is a wound that does not heal. However, molecular mechanisms that link hepatocellular injury to carcinogenesis remain elusive. Knowledge about mediators involved in this process may allow pharmacologic blockade of the cancer-promoting effects of hepatocellular injury, and hence may provide a basis for developing cancer prevention therapies for patients with chronic liver injury. Here we seek to test the hypothesis that damage-associated molecular patterns (DAMPs) from injured hepatocytes provide a molecular link between cell death and hepatocarcinogenesis. Based on abundant preliminary data demonstrating a central role for HMGB1 in hepatic cell death responses in the injured liver - including the recruitment of neutrophils and the expansion of progenitors - we seek to prove the hypothesis that the DAMP high-mobility group box 1 (HMGB1), links hepatocellular death to carcinogenesis by driving maladaptive and tumor-promoting wound healing. Using conditional ablation of HMBG1 in mice, we will determine the role of HMGB1 in injury-driven and purely genotoxic HCC models, and determine whether pharmacologic HMGB1 inhibition prevents HCC development (Aim 1). Based on our findings that (i) HMGB1 has a key role in recruiting neutrophils towards injured hepatocytes via neutrophil-expressed RAGE and (ii) that recruited neutrophils functionally contribute to hepatocarcinogenesis and directly trigger DNA damage in hepatocytes, we will determine the role of the HMGB1-RAGE axis in the recruitment of neutrophils and their functional contribution to hepatocarcinogenesis via specific effector pathways including neutrophil elastase and neutrophil extracellular traps (Aim 2). Finally, we will determine whether the HMGB1-RAGE axis provides a signal to the epithelial compartment to trigger the expansion of progenitors and/or the acquisition of a progenitor phenotype within tumors, which are both known to increase cancer risk and worsen prognosis (Aim 3). Together, the proposed experiments will not only provide a mechanistic explanation for the link between hepatocellular death and HCC development, but may also provide novel targets for HCC prevention and treatment.

Public Health Relevance

Cell death is the main driver of disease development and progression in chronic liver disease, which often progresses to liver cancer. However, it is not well understood how cell death of hepatocytes promotes the development of many of the complications of chronic liver disease. Here, we study the hypothesis that the molecule high-mobility group box 1 (HMGB1), which is released from dead hepatocytes and acts as a damage- associated molecular pattern (DAMP), links cell death to the development of liver cancer.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Johnson, Ronald L
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Columbia University (N.Y.)
Internal Medicine/Medicine
Schools of Medicine
New York
United States
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Caviglia, Jorge Matias; Yan, Jun; Jang, Myoung-Kuk et al. (2018) MicroRNA-21 and Dicer are dispensable for hepatic stellate cell activation and the development of liver fibrosis. Hepatology 67:2414-2429
Hernandez, Celine; Huebener, Peter; Pradere, Jean-Philippe et al. (2018) HMGB1 links chronic liver injury to progenitor responses and hepatocarcinogenesis. J Clin Invest 128:2436-2451
Affo, Silvia; Yu, Le-Xing; Schwabe, Robert F (2017) The Role of Cancer-Associated Fibroblasts and Fibrosis in Liver Cancer. Annu Rev Pathol 12:153-186
Hernandez, C; Huebener, P; Schwabe, R F (2016) Damage-associated molecular patterns in cancer: a double-edged sword. Oncogene 35:5931-5941