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

Koppe, Christiane; Reisinger, Florian; Wehr, Karina; Vucur, Mihael; Trautwein, Christian; Tacke, Frank; Heikenwalder, Mathias; Luedde, Tom

doi:10.3390/cancers11070999

Submit to this Journal Review for this Journal Edit a Special Issue

Article Menu

...

Open AccessArticle

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

¹,

²,

¹,

¹,

¹,

^4,† and

^1,*,†

Department of Medicine III, University Hospital RWTH Aachen, D-52074 Aachen, Germany

Institute of Virology, Technische Universität München and Helmholtz Zentrum München, 81675 Munich, Germany

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)

View Full-Text Download PDF

Browse Figures

Citation Export

Abstract

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/NEMO^LPC-KO) and compared their phenotype with mice lacking both catalytic subunits (IKKα/β^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 IKKα/β^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 IKKα/β/NEMO^LPC-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

▼ Show Figures

Figure 1

This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited

Supplementary Material

Supplementary File 1:
PDF-Document (PDF, 528 KiB)

Share and Cite

MDPI and ACS Style

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. https://doi.org/10.3390/cancers11070999

AMA Style

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(7):999. https://doi.org/10.3390/cancers11070999

Chicago/Turabian Style

Koppe, Christiane, Florian Reisinger, Karina Wehr, Mihael Vucur, Christian Trautwein, Frank Tacke, Mathias Heikenwalder, and Tom Luedde. 2019. "An NF-kappaB- and IKK-Independent Function of NEMO Prevents Hepatocarcinogenesis by Suppressing Compensatory Liver Regeneration" Cancers 11, no. 7: 999. https://doi.org/10.3390/cancers11070999

Find Other Styles

Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Metrics

Abstract views Pdf views Html views

Article Menu

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

Abstract

Supplementary Material

Share and Cite

Article Metrics

Article Access Statistics

Article Access Map by Country/Region

Further Information

Guidelines

MDPI Initiatives

Follow MDPI