Oncotarget

Research Papers:

Hepatic B cell leukemia-3 suppresses chemically-induced hepatocarcinogenesis in mice through altered MAPK and NF-κB activation

Nadine Gehrke, Marcus A. Wörns, Amrit Mann, Yvonne Huber, Nadine Hoevelmeyer, Thomas Longerich, Ari Waisman, Peter R. Galle and Jörn M. Schattenberg _

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Oncotarget. 2017; 8:56095-56109. https://doi.org/10.18632/oncotarget.10893

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Abstract

Nadine Gehrke1,*, Marcus A. Wörns1,*, Amrit Mann1, Yvonne Huber1, Nadine Hoevelmeyer2, Thomas Longerich3, Ari Waisman2, Peter R. Galle1 and Jörn M. Schattenberg1

1Department of Medicine and University Medical Center of the Johannes Gutenberg University, Mainz, Germany

2Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg University, Mainz, Germany

3Institute of Pathology, University Hospital RWTH Aachen, Aachen, Germany

*These authors contributed equally to this work

Correspondence to:

Jörn M. Schattenberg, email: [email protected]

Keywords: B cell leukemia-3 (Bcl-3), hepatocellular carcinoma (HCC), mitogen-activated protein kinase (MAPK), apoptosis, nuclear factor kappa B (NF-kB)

Received: January 16, 2016     Accepted: July 18, 2016     Published: July 28, 2016

ABSTRACT

The transcriptional nuclear factor kappa B (NF-κB)-coactivator B cell leukemia-3 (Bcl-3) is a molecular regulator of cell death and proliferation. Bcl-3 has been shown to be widely expressed in different cancer types including hepatocellular carcinoma (HCC). Its influence on hepatocarcinogenesis is still undetermined. To examine the role of Bcl-3 in hepatocarcinogenesis mice with hepatocyte-specific overexpression of Bcl-3 (Bcl-3Hep) were exposed to diethylnitrosamine (DEN) and phenobarbital (PB). Hepatic Bcl-3 overexpression attenuated DEN/PB-induced hepatocarcinogenesis. Bcl-3Hep mice exhibited a lower number and smaller tumor nodules in response to DEN/PB at 40 weeks of age. Reduced HCC formation was accompanied by a lower rate of cell proliferation and a distinct expression pattern of growth and differentiation-related genes. Activation of c-Jun N-terminal kinase (JNK) and especially extracellular-signal regulated kinase (ERK) was reduced in tumor and tumor-surrounding liver tissue of Bcl-3Hep mice, while p38 and NF-κB p65 were phosphorylated to a higher extent compared to the wild type. In parallel, the absolute number of intrahepatic macrophages, CD8+ T cells and activated B cells was reduced in DEN/PB-treated Bcl-3Hep mice mirroring a reduction of tumor-associated inflammation. Interestingly, at the early time point of 7 weeks following tumor initiation, a higher rate of apoptotic cell death was observed in Bcl-3Hep mice. In summary, hepatocyte-restricted Bcl-3 overexpression reduced hepatocarcinogenesis related to prolonged liver injury early after tumor initiation likely due to decreased survival of DEN/PB-damaged, premalignant cells. Therefore, Bcl-3 could become a novel player in the development of therapeutic and diagnostic tools for HCC.


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