Deletion of NEMO/IKKgamma in liver parenchymal cells causes steatohepatitis and hepatocellular carcinoma

Tom Luedde; Naiara Beraza; Vasileios Kotsikoris; Geert van Loo; Arianna Nenci; Ria De Vos; Tania Roskams; Christan Trautwein; Manolis Pasparakis

doi:10.1016/j.ccr.2006.12.016

Deletion of NEMO/IKKgamma in liver parenchymal cells causes steatohepatitis and hepatocellular carcinoma

Tom Luedde, Naiara Beraza, Vasileios Kotsikoris, Geert van Loo, Arianna Nenci, Ria De Vos, Tania Roskams, Christan Trautwein, Manolis Pasparakis

Research output: Contribution to journal › Article › Research › peer-review

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Abstract

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.

Original language	English
Pages (from-to)	119 - 132
Number of pages	14
Journal	Cancer Cell
Volume	11
Issue number	2
DOIs	https://doi.org/10.1016/j.ccr.2006.12.016
Publication status	Published - 2007
Externally published	Yes

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title = "Deletion of NEMO/IKKgamma in liver parenchymal cells causes steatohepatitis and hepatocellular carcinoma",

abstract = "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.",

author = "Tom Luedde and Naiara Beraza and Vasileios Kotsikoris and {van Loo}, Geert and Arianna Nenci and {De Vos}, Ria and Tania Roskams and Christan Trautwein and Manolis Pasparakis",

year = "2007",

doi = "10.1016/j.ccr.2006.12.016",

language = "English",

volume = "11",

pages = "119 -- 132",

journal = "Cancer Cell",

issn = "1535-6108",

publisher = "Cell Press",

number = "2",

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TY - JOUR

T1 - Deletion of NEMO/IKKgamma in liver parenchymal cells causes steatohepatitis and hepatocellular carcinoma

AU - Luedde, Tom

AU - Beraza, Naiara

AU - Kotsikoris, Vasileios

AU - van Loo, Geert

AU - Nenci, Arianna

AU - De Vos, Ria

AU - Roskams, Tania

AU - Trautwein, Christan

AU - Pasparakis, Manolis

PY - 2007

Y1 - 2007

N2 - 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.

AB - 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.

UR - http://www.sciencedirect.com/science/article/pii/S1535610807000207

U2 - 10.1016/j.ccr.2006.12.016

DO - 10.1016/j.ccr.2006.12.016

M3 - Article

SN - 1535-6108

VL - 11

SP - 119

EP - 132

JO - Cancer Cell

JF - Cancer Cell

IS - 2

ER -

Deletion of NEMO/IKKgamma in liver parenchymal cells causes steatohepatitis and hepatocellular carcinoma

Abstract

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