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

Koppe Koppe,Vucur Vucur,Trautwein Trautwein,Heikenwalder Heikenwalder,Luedde Luedde,Reisinger Reisinger,Tacke Tacke,Wehr Wehr

doi:10.3390/cancers11070999

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/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.

Highlights

Hepatocellular carcinoma (HCC) develops in most cases on the basis of chronic inflammation and subsequent liver fibrosis and cirrhosis [1,2]
We further investigated whether free NEMO molecules unbound to the catalytic IKK subunits triggered cell whether death in free
We showed that additional deletion of RIPK1 in IKKα/βLPC-KO mice does not significantly influence spontaneous apoptotic liver cell death [9]

Summary

Introduction

Hepatocellular carcinoma (HCC) develops in most cases on the basis of chronic inflammation and subsequent liver fibrosis and cirrhosis [1,2]. In advanced HCC, the current treatment strategies can only extend median survival by a few months [2,3], underlining the need for a better functional understanding of key signaling pathways involved in inflammatory liver disease and hepatocarcinogenesis. The nuclear factor (NF)-κB pathway plays a prominent role in inflammatory signaling and is activated in response to cytokines like tumor necrosis factor (TNF). One prominent mediator of NF-κB signaling is the so-called I-κB-Kinase (IKK) complex, consisting of the two catalytic subunits IKKα ( called IKK1) and IKKβ (IKK2), as well as a regulatory subunit called NEMO. NEMO (IKK ) [4]. The deregulation of NF- B signaling is a major contributory factor to the pathophysiology of inflammation [5].

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Results

Discussion

Conclusion