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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 11:999 (2019)
Verlagsversion Forschungsdaten DOI
Open Access Gold
Creative Commons Lizenzvertrag
The I-kappa B-Kinase (IKK) complex represents a central signaling nexus in the TNF-dependent activation of the pro-inflammatory NF-kappa B pathway. However, recent studies suggested that the distinct IKK subunits (IKK alpha, IKK beta, and NEMO) might withhold additional NF-kappa B-independent functions in inflammation and cancer. Here, we generated mice lacking all three IKK subunits in liver parenchymal cells (LPC) (IKK alpha/beta/NEMOLPC-KO) and compared their phenotype with mice lacking both catalytic subunits (IKK alpha/beta(LPC-KO)), allowing to functionally dissect putative I-kappa B-Kinase-independent functions of the regulatory subunit NEMO. We show that the additional deletion of NEMO rescues IKK alpha/beta(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 alpha/beta/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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Hepatocarcinogenesis ; Cholestasis ; Ikk Complex ; Nf-kappa B ; Nemo ; Ikk Alpha ; Ikk Beta; Hepatocellular-carcinoma; Cell-death; Steatohepatitis; Homeostasis; Expression; Deletion; Pathway; Alpha; Beta
ISSN (print) / ISBN 2072-6694
Zeitschrift Cancers
Quellenangaben Band: 11, Heft: 7, Seiten: , Artikelnummer: 999 Supplement: ,
Verlag MDPI
Verlagsort St Alban-anlage 66, Ch-4052 Basel, Switzerland
Begutachtungsstatus Peer reviewed