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Open AccessArticle

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

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
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Cancers 2019, 11(7), 999; https://doi.org/10.3390/cancers11070999
Received: 30 May 2019 / Revised: 5 July 2019 / Accepted: 16 July 2019 / Published: 17 July 2019
(This article belongs to the Special Issue NF-kappaB signalling pathway)
The I-κB-Kinase (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 (IKKα, IKKβ, 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) (IKKα/β/NEMOLPC-KO) and compared their phenotype with mice lacking both catalytic subunits (IKKα/βLPC-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 IKKα/βLPC-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 IKKα/β/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. View Full-Text
Keywords: hepatocarcinogenesis; cholestasis; IKK complex; NF-κB; NEMO; IKKα, IKKβ hepatocarcinogenesis; cholestasis; IKK complex; NF-κB; NEMO; IKKα, IKKβ
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Koppe, C.; Reisinger, F.; Wehr, K.; Vucur, M.; Trautwein, C.; Tacke, F.; Heikenwalder, M.; Luedde, T. An NF-kappaB- and IKK-Independent Function of NEMO Prevents Hepatocarcinogenesis by Suppressing Compensatory Liver Regeneration. Cancers 2019, 11, 999.

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