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Cancers (Basel). 2019 Jul 17;11(7). pii: E999. doi: 10.3390/cancers11070999.

An NF-kappaB- and IKK-Independent Function of NEMO Prevents Hepatocarcinogenesis by Suppressing Compensatory Liver Regeneration.

Author information

1
Department of Medicine III, University Hospital RWTH Aachen, D-52074 Aachen, Germany.
2
Institute of Virology, Technische Universität München and Helmholtz Zentrum München, 81675 Munich, Germany.
3
Department of Hepatology and Gastroenterology, Charité University Medicine Berlin, D-13353 Berlin, Germany.
4
Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), D-69120 Heidelberg, Germany.
5
Department of Medicine III, University Hospital RWTH Aachen, D-52074 Aachen, Germany. tluedde@ukaachen.de.

Abstract

The IκBKinase (IKK) complex represents a central signaling nexus in the TNF-dependent activation of the pro-inflammatory NF-κB pathway. However, recent studies suggested that the distinct IKK subunits (IKK, IKK, and NEMO) might withhold additional NF-κB-independent functions in inflammation and cancer. Here, we generated mice lacking all three IKK subunits in liver parenchymal cells (LPC) (IKK//NEMOLPC-KO) and compared their phenotype with mice lacking both catalytic subunits (IKK/LPC-KO), allowing to functionally dissect putative I-κB-Kinase-independent functions of the regulatory subunit NEMO. We show that the additional deletion of NEMO rescues IKK/LPC-KO mice from lethal cholestasis and biliary ductopenia by triggering LPC apoptosis and inducing a strong compensatory proliferation of LPC including cholangiocytes. Beyond this beneficial effect, we show that increased hepatocyte cell-death and compensatory proliferation inhibit the activation of LPC-necroptosis but trigger spontaneous hepatocarcinogenesis in IKK//NEMOLPC-KO mice. Collectively, our data show that free NEMO molecules unbound to the catalytic IKK subunits control LPC programmed cell death pathways and proliferation, cholestasis and hepatocarcinogenesis independently of an IKK-related function. These findings support the idea of different functional levels at which NEMO controls inflammation and cancer in the liver.

KEYWORDS:

IKK complex; IKK, IKK; NEMO; NF-B; cholestasis; hepatocarcinogenesis

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