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iPLA2β-Null Mice Show HCC Protection by an Induction of Cell-Cycle Arrest after Diethylnitrosamine Treatment

Group VIA phospholipase A2 (iPLA2β) play diverse biological functions in epithelial cells and macrophages. Global deletion in iPLA2β-null (KO) mice leads to protection against hepatic steatosis in non-alcoholic fatty liver disease, in part, due to the replenishment of the loss of hepatocellular phos...

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Autores principales: Andrade, Adriana, Poth, Tanja, Brobeil, Alexander, Merle, Uta, Chamulitrat, Walee
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9697657/
https://www.ncbi.nlm.nih.gov/pubmed/36430237
http://dx.doi.org/10.3390/ijms232213760
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author Andrade, Adriana
Poth, Tanja
Brobeil, Alexander
Merle, Uta
Chamulitrat, Walee
author_facet Andrade, Adriana
Poth, Tanja
Brobeil, Alexander
Merle, Uta
Chamulitrat, Walee
author_sort Andrade, Adriana
collection PubMed
description Group VIA phospholipase A2 (iPLA2β) play diverse biological functions in epithelial cells and macrophages. Global deletion in iPLA2β-null (KO) mice leads to protection against hepatic steatosis in non-alcoholic fatty liver disease, in part, due to the replenishment of the loss of hepatocellular phospholipids. As the loss of phospholipids also occurs in hepatocellular carcinoma (HCC), we hypothesized that global deletion in KO mice may lead to protection against HCC. Here, HCC induced by diethylnitrosamine (DEN) was chosen because DEN causes direct injury to the hepatocytes. Male wild-type (WT) and KO mice at 3–5 weeks of age (12–13 mice/group) were subjected to a single intraperitoneal treatment with 10 mg/kg DEN, and mice were killed 12 months later. Analyses of histology, plasma cytokines, and gene expression were performed. Due to the low-dose DEN used, we observed a liver nodule in 3 of 13 WT and 2 of 12 KO mice. Only one DEN-treated WT mouse was confirmed to have HCC. DEN-treated KO mice did not show any HCC but showed suppressed hepatic expression of cell-cycle cyclinD2 and BCL2 as well as inflammatory markers IL-1β, IL-10, and VCAM-1. Notably, DEN-treated KO mice showed increased hepatic necrosis and elevated levels of plasma lactate dehydrogenase suggesting an exacerbation of liver injury. Thus, global iPLA2β deficiency in DEN-treated mice rendered HCC protection by an induction of cell-cycle arrest. Our results suggest the role of iPLA2β inhibition in HCC treatment.
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spelling pubmed-96976572022-11-26 iPLA2β-Null Mice Show HCC Protection by an Induction of Cell-Cycle Arrest after Diethylnitrosamine Treatment Andrade, Adriana Poth, Tanja Brobeil, Alexander Merle, Uta Chamulitrat, Walee Int J Mol Sci Article Group VIA phospholipase A2 (iPLA2β) play diverse biological functions in epithelial cells and macrophages. Global deletion in iPLA2β-null (KO) mice leads to protection against hepatic steatosis in non-alcoholic fatty liver disease, in part, due to the replenishment of the loss of hepatocellular phospholipids. As the loss of phospholipids also occurs in hepatocellular carcinoma (HCC), we hypothesized that global deletion in KO mice may lead to protection against HCC. Here, HCC induced by diethylnitrosamine (DEN) was chosen because DEN causes direct injury to the hepatocytes. Male wild-type (WT) and KO mice at 3–5 weeks of age (12–13 mice/group) were subjected to a single intraperitoneal treatment with 10 mg/kg DEN, and mice were killed 12 months later. Analyses of histology, plasma cytokines, and gene expression were performed. Due to the low-dose DEN used, we observed a liver nodule in 3 of 13 WT and 2 of 12 KO mice. Only one DEN-treated WT mouse was confirmed to have HCC. DEN-treated KO mice did not show any HCC but showed suppressed hepatic expression of cell-cycle cyclinD2 and BCL2 as well as inflammatory markers IL-1β, IL-10, and VCAM-1. Notably, DEN-treated KO mice showed increased hepatic necrosis and elevated levels of plasma lactate dehydrogenase suggesting an exacerbation of liver injury. Thus, global iPLA2β deficiency in DEN-treated mice rendered HCC protection by an induction of cell-cycle arrest. Our results suggest the role of iPLA2β inhibition in HCC treatment. MDPI 2022-11-09 /pmc/articles/PMC9697657/ /pubmed/36430237 http://dx.doi.org/10.3390/ijms232213760 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Andrade, Adriana
Poth, Tanja
Brobeil, Alexander
Merle, Uta
Chamulitrat, Walee
iPLA2β-Null Mice Show HCC Protection by an Induction of Cell-Cycle Arrest after Diethylnitrosamine Treatment
title iPLA2β-Null Mice Show HCC Protection by an Induction of Cell-Cycle Arrest after Diethylnitrosamine Treatment
title_full iPLA2β-Null Mice Show HCC Protection by an Induction of Cell-Cycle Arrest after Diethylnitrosamine Treatment
title_fullStr iPLA2β-Null Mice Show HCC Protection by an Induction of Cell-Cycle Arrest after Diethylnitrosamine Treatment
title_full_unstemmed iPLA2β-Null Mice Show HCC Protection by an Induction of Cell-Cycle Arrest after Diethylnitrosamine Treatment
title_short iPLA2β-Null Mice Show HCC Protection by an Induction of Cell-Cycle Arrest after Diethylnitrosamine Treatment
title_sort ipla2β-null mice show hcc protection by an induction of cell-cycle arrest after diethylnitrosamine treatment
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9697657/
https://www.ncbi.nlm.nih.gov/pubmed/36430237
http://dx.doi.org/10.3390/ijms232213760
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