Deletion of NEMO/IKKgamma in liver parenchymal cells causes steatohepatitis and hepatocellular carcinoma.
The IkappaB kinase (IKK) subunit NEMO/IKKgamma is essential for activation of the transcription factor NF-kappaB, which regulates cellular responses to inflammation. The function of NEMO in the adult liver remains elusive. Here we show that ablation of NEMO in liver parenchymal cells caused the spontaneous development of hepatocellular carcinoma in mice. Tumor development was preceded by chronic liver disease resembling human nonalcoholic steatohepatitis (NASH). Antioxidant treatment and genetic ablation of FADD demonstrated that death receptor-mediated and oxidative stress-dependent death of NEMO-deficient hepatocytes triggered disease pathogenesis in this model. These results reveal that NEMO-mediated NF-kappaB activation in hepatocytes has an essential physiological function to prevent the spontaneous development of steatohepatitis and hepatocellular carcinoma, identifying NEMO as a tumor suppressor in the liver.
Luedde
Tom
T
Institute for Genetics, University of Cologne, Zülpicher Strasse 47, 50674 Cologne, Germany.
Beraza
Naiara
N
Kotsikoris
Vasileios
V
van Loo
Geert
G
Nenci
Arianna
A
De Vos
Rita
R
Roskams
Tania
T
Trautwein
Christian
C
Pasparakis
Manolis
M
D000818:Animals; D017209:Apoptosis; D001973:Bromodeoxyuridine; D006528:Carcinoma, Hepatocellular / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D024202:Electrophoretic Mobility Shift Assay; D053200:Fas-Associated Death Domain Protein / Q000235:genetics / Q000502:physiology; D005234:Fatty Liver / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D015870:Gene Expression; D022781:Hepatocytes / Q000378:metabolism; D051550:I-kappa B Kinase / Q000502:physiology*; D015151:Immunoblotting; D020287:In Situ Nick-End Labeling; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D016350:Leucine Zippers; D008099:Liver / Q000293:injuries / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D025801:Ubiquitin / Q000378:metabolism
D053200:Fas-Associated Death Domain Protein; D047908:Intracellular Signaling Peptides and Proteins; C514981:NEMO protein, mouse; D016328:NF-kappa B; D012333:RNA, Messenger; D025801:Ubiquitin; D051550:I-kappa B Kinase; C496562:Ikbkb protein, mouse; D001973:Bromodeoxyuridine