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Absence of Either Ripk3 or Mlkl Reduces Incidence of Hepatocellular Carcinoma Independent of Liver Fibrosis

Nonalcoholic fatty liver disease (NAFLD) is one of the etiologies that contribute to hepatocellular carcinoma (HCC), and chronic inflammation is one of the proposed mediators of HCC. Because necroptosis is a cell death pathway that induces inflammation, we tested whether necroptosis-induced inflamma...

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Autores principales: Mohammed, Sabira, Thadathil, Nidheesh, Ohene-Marfo, Phoebe, Tran, Albert L., Van Der Veldt, Michael, Georgescu, Constantin, Oh, Sangphil, Nicklas, Evan H., Wang, Dawei, Haritha, Nair Hariprasad, Luo, Wenyi, Janknecht, Ralf, Miller, Benjamin F., Wren, Jonathan D., Freeman, Willard M., Deepa, Sathyaseelan S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for Cancer Research 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10472095/
https://www.ncbi.nlm.nih.gov/pubmed/37204757
http://dx.doi.org/10.1158/1541-7786.MCR-22-0820
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author Mohammed, Sabira
Thadathil, Nidheesh
Ohene-Marfo, Phoebe
Tran, Albert L.
Van Der Veldt, Michael
Georgescu, Constantin
Oh, Sangphil
Nicklas, Evan H.
Wang, Dawei
Haritha, Nair Hariprasad
Luo, Wenyi
Janknecht, Ralf
Miller, Benjamin F.
Wren, Jonathan D.
Freeman, Willard M.
Deepa, Sathyaseelan S.
author_facet Mohammed, Sabira
Thadathil, Nidheesh
Ohene-Marfo, Phoebe
Tran, Albert L.
Van Der Veldt, Michael
Georgescu, Constantin
Oh, Sangphil
Nicklas, Evan H.
Wang, Dawei
Haritha, Nair Hariprasad
Luo, Wenyi
Janknecht, Ralf
Miller, Benjamin F.
Wren, Jonathan D.
Freeman, Willard M.
Deepa, Sathyaseelan S.
author_sort Mohammed, Sabira
collection PubMed
description Nonalcoholic fatty liver disease (NAFLD) is one of the etiologies that contribute to hepatocellular carcinoma (HCC), and chronic inflammation is one of the proposed mediators of HCC. Because necroptosis is a cell death pathway that induces inflammation, we tested whether necroptosis-induced inflammation contributes to the progression of NAFLD to HCC in a mouse model of diet-induced HCC. Male and female wild-type (WT) mice and mouse models where necroptosis is blocked (Ripk3(−/−) or Mlkl(−/−) mice) were fed either a control diet, choline-deficient low-fat diet or choline-deficient high-fat diet. Blocking necroptosis reduced markers of inflammation [proinflammatory cytokines (TNFα, IL6, and IL1β), F4/80(+ve) macrophages, CCR2(+ve) infiltrating monocytes], inflammation-associated oncogenic pathways (JNK, PD-L1/PD-1, β-catenin), and HCC in male mice. We demonstrate that hepatic necroptosis promotes recruitment and activation of liver macrophages leading to chronic inflammation, which in turn trigger oncogenic pathways leading to the progression of NAFLD to HCC in male mice. Whereas in female mice, blocking necroptosis reduced HCC independent of inflammation. Our data show a sex-specific difference in the development of inflammation, fibrosis, and HCC in WT mice. However, blocking necroptosis reduced HCC in both males and females without altering liver fibrosis. Thus, our study suggests that necroptosis is a valid therapeutic target for NAFLD-mediated HCC. IMPLICATIONS: Necroptosis is a major contributor to hepatic inflammation that drives the progression of NAFLD to HCC and therefore represents a valid target for NAFLD-mediated HCC.
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spelling pubmed-104720952023-09-02 Absence of Either Ripk3 or Mlkl Reduces Incidence of Hepatocellular Carcinoma Independent of Liver Fibrosis Mohammed, Sabira Thadathil, Nidheesh Ohene-Marfo, Phoebe Tran, Albert L. Van Der Veldt, Michael Georgescu, Constantin Oh, Sangphil Nicklas, Evan H. Wang, Dawei Haritha, Nair Hariprasad Luo, Wenyi Janknecht, Ralf Miller, Benjamin F. Wren, Jonathan D. Freeman, Willard M. Deepa, Sathyaseelan S. Mol Cancer Res Cell Fate Decisions Nonalcoholic fatty liver disease (NAFLD) is one of the etiologies that contribute to hepatocellular carcinoma (HCC), and chronic inflammation is one of the proposed mediators of HCC. Because necroptosis is a cell death pathway that induces inflammation, we tested whether necroptosis-induced inflammation contributes to the progression of NAFLD to HCC in a mouse model of diet-induced HCC. Male and female wild-type (WT) mice and mouse models where necroptosis is blocked (Ripk3(−/−) or Mlkl(−/−) mice) were fed either a control diet, choline-deficient low-fat diet or choline-deficient high-fat diet. Blocking necroptosis reduced markers of inflammation [proinflammatory cytokines (TNFα, IL6, and IL1β), F4/80(+ve) macrophages, CCR2(+ve) infiltrating monocytes], inflammation-associated oncogenic pathways (JNK, PD-L1/PD-1, β-catenin), and HCC in male mice. We demonstrate that hepatic necroptosis promotes recruitment and activation of liver macrophages leading to chronic inflammation, which in turn trigger oncogenic pathways leading to the progression of NAFLD to HCC in male mice. Whereas in female mice, blocking necroptosis reduced HCC independent of inflammation. Our data show a sex-specific difference in the development of inflammation, fibrosis, and HCC in WT mice. However, blocking necroptosis reduced HCC in both males and females without altering liver fibrosis. Thus, our study suggests that necroptosis is a valid therapeutic target for NAFLD-mediated HCC. IMPLICATIONS: Necroptosis is a major contributor to hepatic inflammation that drives the progression of NAFLD to HCC and therefore represents a valid target for NAFLD-mediated HCC. American Association for Cancer Research 2023-09-01 2023-05-19 /pmc/articles/PMC10472095/ /pubmed/37204757 http://dx.doi.org/10.1158/1541-7786.MCR-22-0820 Text en ©2023 The Authors; Published by the American Association for Cancer Research https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) license.
spellingShingle Cell Fate Decisions
Mohammed, Sabira
Thadathil, Nidheesh
Ohene-Marfo, Phoebe
Tran, Albert L.
Van Der Veldt, Michael
Georgescu, Constantin
Oh, Sangphil
Nicklas, Evan H.
Wang, Dawei
Haritha, Nair Hariprasad
Luo, Wenyi
Janknecht, Ralf
Miller, Benjamin F.
Wren, Jonathan D.
Freeman, Willard M.
Deepa, Sathyaseelan S.
Absence of Either Ripk3 or Mlkl Reduces Incidence of Hepatocellular Carcinoma Independent of Liver Fibrosis
title Absence of Either Ripk3 or Mlkl Reduces Incidence of Hepatocellular Carcinoma Independent of Liver Fibrosis
title_full Absence of Either Ripk3 or Mlkl Reduces Incidence of Hepatocellular Carcinoma Independent of Liver Fibrosis
title_fullStr Absence of Either Ripk3 or Mlkl Reduces Incidence of Hepatocellular Carcinoma Independent of Liver Fibrosis
title_full_unstemmed Absence of Either Ripk3 or Mlkl Reduces Incidence of Hepatocellular Carcinoma Independent of Liver Fibrosis
title_short Absence of Either Ripk3 or Mlkl Reduces Incidence of Hepatocellular Carcinoma Independent of Liver Fibrosis
title_sort absence of either ripk3 or mlkl reduces incidence of hepatocellular carcinoma independent of liver fibrosis
topic Cell Fate Decisions
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10472095/
https://www.ncbi.nlm.nih.gov/pubmed/37204757
http://dx.doi.org/10.1158/1541-7786.MCR-22-0820
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