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NEMO Prevents Steatohepatitis and Hepatocellular Carcinoma by Inhibiting RIPK1 Kinase Activity-Mediated Hepatocyte Apoptosis.

Kondylis V, Polykratis A, Ehlken H, Ochoa-Callejero L, Straub BK, Krishna-Subramanian S, Van TM, Curth HM, Heise N, Weih F, Klein U, Schirmacher P, Kelliher M, Pasparakis M - Cancer Cell (2015)

Bottom Line: Mice lacking NEMO in liver parenchymal cells (LPC) spontaneously develop steatohepatitis and hepatocellular carcinoma (HCC) suggesting that NF-κB prevents liver disease and cancer.Here, we show that complete NF-κB inhibition by combined LPC-specific ablation of RelA, c-Rel, and RelB did not phenocopy NEMO deficiency, but constitutively active IKK2-mediated NF-κB activation prevented hepatocellular damage and HCC in NEMO(LPC-KO) mice.Knock-in expression of kinase inactive receptor-interacting protein kinase 1 (RIPK1) prevented hepatocyte apoptosis and HCC, while RIPK1 ablation induced TNFR1-associated death domain protein (TRADD)-dependent hepatocyte apoptosis and liver tumors in NEMO(LPC-KO) mice, revealing distinct kinase-dependent and scaffolding functions of RIPK1.

View Article: PubMed Central - PubMed

Affiliation: Institute for Genetics, University of Cologne, 50674 Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany; Center for Molecular Medicine (CMMC), University of Cologne, 50931, Cologne, Germany.

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Lack of RIPK1 Kinase Activity, but Not Its Scaffolding Function, Prevents HCC in NEMOLPC-KO Mice(A) Representative liver images from 52-week-old mice with the indicated genotypes. Scale bar, 1 cm.(B and C) Tumor load in mice with the indicated phenotypes as estimated by quantification of the LW/BW ratios (B), and the tumor size distribution (C). Horizontal lines indicate mean values.(D) Representative images of Masson’s trichrome stained liver sections from 52-week-old mice with the indicated genotypes. Arrows indicate anisokaryotic hepatocytes. HCC/dysplastic nodule areas are marked with an asterisk. Scale bar, 200 μm.(E) Histopathological evaluation of HCC development in 1-year-old mice with the indicated genotypes. Each color bar represents the % of livers per genotype in which the indicated stage was identified as the most advanced disease stage.
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fig6: Lack of RIPK1 Kinase Activity, but Not Its Scaffolding Function, Prevents HCC in NEMOLPC-KO Mice(A) Representative liver images from 52-week-old mice with the indicated genotypes. Scale bar, 1 cm.(B and C) Tumor load in mice with the indicated phenotypes as estimated by quantification of the LW/BW ratios (B), and the tumor size distribution (C). Horizontal lines indicate mean values.(D) Representative images of Masson’s trichrome stained liver sections from 52-week-old mice with the indicated genotypes. Arrows indicate anisokaryotic hepatocytes. HCC/dysplastic nodule areas are marked with an asterisk. Scale bar, 200 μm.(E) Histopathological evaluation of HCC development in 1-year-old mice with the indicated genotypes. Each color bar represents the % of livers per genotype in which the indicated stage was identified as the most advanced disease stage.

Mentions: In line with the reduced hepatocyte apoptosis in young mice, 1-year-old NEMOLPC-KO;Ripk1D138N/D138N or NEMOLPC-KO;RIPK1LPC-KO/D138N mice did not show macroscopic signs of liver tumor development (Figures 6A–6C). Histological examination confirmed the lack of HCC or pre-neoplastic lesions and only 23% of the livers examined exhibited areas with clear cell foci and anisokaryosis (Figures 6D and 6E). Interestingly, although the livers of NEMOLPC-KO;Ripk1D138N/D138N did not show HSC activation at 8 weeks, they exhibited mild portal fibrosis with septa formation at the age of 1 year (Figure 6D). Analysis of 1-year-old NEMOLPC-KO;RIPK1LPC-KO mice revealed the development of liver tumors with dysplastic foci, dysplastic nodules and HCC, although macroscopically ∼33% of the mice analyzed (7 out of 20) had smaller nodules compared to NEMOLPC-KO mice suggesting that RIPK1 deficiency inhibited tumor growth (Figures 6A–6E). Therefore, lack of RIPK1 kinase activity but not the absence of RIPK1 protein prevented hepatocyte apoptosis and HCC development in NEMOLPC-KO mice.


NEMO Prevents Steatohepatitis and Hepatocellular Carcinoma by Inhibiting RIPK1 Kinase Activity-Mediated Hepatocyte Apoptosis.

Kondylis V, Polykratis A, Ehlken H, Ochoa-Callejero L, Straub BK, Krishna-Subramanian S, Van TM, Curth HM, Heise N, Weih F, Klein U, Schirmacher P, Kelliher M, Pasparakis M - Cancer Cell (2015)

Lack of RIPK1 Kinase Activity, but Not Its Scaffolding Function, Prevents HCC in NEMOLPC-KO Mice(A) Representative liver images from 52-week-old mice with the indicated genotypes. Scale bar, 1 cm.(B and C) Tumor load in mice with the indicated phenotypes as estimated by quantification of the LW/BW ratios (B), and the tumor size distribution (C). Horizontal lines indicate mean values.(D) Representative images of Masson’s trichrome stained liver sections from 52-week-old mice with the indicated genotypes. Arrows indicate anisokaryotic hepatocytes. HCC/dysplastic nodule areas are marked with an asterisk. Scale bar, 200 μm.(E) Histopathological evaluation of HCC development in 1-year-old mice with the indicated genotypes. Each color bar represents the % of livers per genotype in which the indicated stage was identified as the most advanced disease stage.
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4644221&req=5

fig6: Lack of RIPK1 Kinase Activity, but Not Its Scaffolding Function, Prevents HCC in NEMOLPC-KO Mice(A) Representative liver images from 52-week-old mice with the indicated genotypes. Scale bar, 1 cm.(B and C) Tumor load in mice with the indicated phenotypes as estimated by quantification of the LW/BW ratios (B), and the tumor size distribution (C). Horizontal lines indicate mean values.(D) Representative images of Masson’s trichrome stained liver sections from 52-week-old mice with the indicated genotypes. Arrows indicate anisokaryotic hepatocytes. HCC/dysplastic nodule areas are marked with an asterisk. Scale bar, 200 μm.(E) Histopathological evaluation of HCC development in 1-year-old mice with the indicated genotypes. Each color bar represents the % of livers per genotype in which the indicated stage was identified as the most advanced disease stage.
Mentions: In line with the reduced hepatocyte apoptosis in young mice, 1-year-old NEMOLPC-KO;Ripk1D138N/D138N or NEMOLPC-KO;RIPK1LPC-KO/D138N mice did not show macroscopic signs of liver tumor development (Figures 6A–6C). Histological examination confirmed the lack of HCC or pre-neoplastic lesions and only 23% of the livers examined exhibited areas with clear cell foci and anisokaryosis (Figures 6D and 6E). Interestingly, although the livers of NEMOLPC-KO;Ripk1D138N/D138N did not show HSC activation at 8 weeks, they exhibited mild portal fibrosis with septa formation at the age of 1 year (Figure 6D). Analysis of 1-year-old NEMOLPC-KO;RIPK1LPC-KO mice revealed the development of liver tumors with dysplastic foci, dysplastic nodules and HCC, although macroscopically ∼33% of the mice analyzed (7 out of 20) had smaller nodules compared to NEMOLPC-KO mice suggesting that RIPK1 deficiency inhibited tumor growth (Figures 6A–6E). Therefore, lack of RIPK1 kinase activity but not the absence of RIPK1 protein prevented hepatocyte apoptosis and HCC development in NEMOLPC-KO mice.

Bottom Line: Mice lacking NEMO in liver parenchymal cells (LPC) spontaneously develop steatohepatitis and hepatocellular carcinoma (HCC) suggesting that NF-κB prevents liver disease and cancer.Here, we show that complete NF-κB inhibition by combined LPC-specific ablation of RelA, c-Rel, and RelB did not phenocopy NEMO deficiency, but constitutively active IKK2-mediated NF-κB activation prevented hepatocellular damage and HCC in NEMO(LPC-KO) mice.Knock-in expression of kinase inactive receptor-interacting protein kinase 1 (RIPK1) prevented hepatocyte apoptosis and HCC, while RIPK1 ablation induced TNFR1-associated death domain protein (TRADD)-dependent hepatocyte apoptosis and liver tumors in NEMO(LPC-KO) mice, revealing distinct kinase-dependent and scaffolding functions of RIPK1.

View Article: PubMed Central - PubMed

Affiliation: Institute for Genetics, University of Cologne, 50674 Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany; Center for Molecular Medicine (CMMC), University of Cologne, 50931, Cologne, Germany.

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Related in: MedlinePlus