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AAV serotype 8-mediated liver specific GNMT expression delays progression of hepatocellular carcinoma and prevents carbon tetrachloride-induced liver damage

Glycine N-methyltransferase (GNMT) is abundantly expressed in normal livers and plays a protective role against tumor formation. GNMT depletion leads to progression of hepatocellular carcinoma (HCC). In this study, we investigated the activity of ectopic GNMT delivered using recombinant adeno-associ...

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Autores principales: Fang, Cheng-Chieh, Wu, Ching-Fen, Liao, Yi-Jen, Huang, Shiu-Feng, Chen, Marcelo, Chen, Yi-Ming Arthur
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6138656/
https://www.ncbi.nlm.nih.gov/pubmed/30217986
http://dx.doi.org/10.1038/s41598-018-30800-3
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author Fang, Cheng-Chieh
Wu, Ching-Fen
Liao, Yi-Jen
Huang, Shiu-Feng
Chen, Marcelo
Chen, Yi-Ming Arthur
author_facet Fang, Cheng-Chieh
Wu, Ching-Fen
Liao, Yi-Jen
Huang, Shiu-Feng
Chen, Marcelo
Chen, Yi-Ming Arthur
author_sort Fang, Cheng-Chieh
collection PubMed
description Glycine N-methyltransferase (GNMT) is abundantly expressed in normal livers and plays a protective role against tumor formation. GNMT depletion leads to progression of hepatocellular carcinoma (HCC). In this study, we investigated the activity of ectopic GNMT delivered using recombinant adeno-associated virus (AAV) gene therapy in mouse models of liver cirrhosis and HCC. Injection of AAV serotype 8 (AAV8) vector carrying the GNMT gene (AAV8-GNMT) in Gnmt(−/−) mice increased GNMT expression and downregulated pro-inflammatory responses, resulting in reduced liver damage and incidence of liver tumors. Moreover, AAV8-GNMT resulted in the amelioration of carbon tetrachloride (CCl(4))-induced liver fibrosis in BALB/c mice. We showed that AAV8-GNMT protected hepatocytes from CCl(4)-induced liver damage.  AAV8-GNMT significantly attenuated the levels of pro-fibrotic markers and increased efficiency of hepatocyte proliferation. These results suggest that correction of hepatic GNMT by gene therapy of AAV8-mediated gene enhancement may provide a potential strategy for preventing and delaying development of liver diseases.
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spelling pubmed-61386562018-09-15 AAV serotype 8-mediated liver specific GNMT expression delays progression of hepatocellular carcinoma and prevents carbon tetrachloride-induced liver damage Fang, Cheng-Chieh Wu, Ching-Fen Liao, Yi-Jen Huang, Shiu-Feng Chen, Marcelo Chen, Yi-Ming Arthur Sci Rep Article Glycine N-methyltransferase (GNMT) is abundantly expressed in normal livers and plays a protective role against tumor formation. GNMT depletion leads to progression of hepatocellular carcinoma (HCC). In this study, we investigated the activity of ectopic GNMT delivered using recombinant adeno-associated virus (AAV) gene therapy in mouse models of liver cirrhosis and HCC. Injection of AAV serotype 8 (AAV8) vector carrying the GNMT gene (AAV8-GNMT) in Gnmt(−/−) mice increased GNMT expression and downregulated pro-inflammatory responses, resulting in reduced liver damage and incidence of liver tumors. Moreover, AAV8-GNMT resulted in the amelioration of carbon tetrachloride (CCl(4))-induced liver fibrosis in BALB/c mice. We showed that AAV8-GNMT protected hepatocytes from CCl(4)-induced liver damage.  AAV8-GNMT significantly attenuated the levels of pro-fibrotic markers and increased efficiency of hepatocyte proliferation. These results suggest that correction of hepatic GNMT by gene therapy of AAV8-mediated gene enhancement may provide a potential strategy for preventing and delaying development of liver diseases. Nature Publishing Group UK 2018-09-14 /pmc/articles/PMC6138656/ /pubmed/30217986 http://dx.doi.org/10.1038/s41598-018-30800-3 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Fang, Cheng-Chieh
Wu, Ching-Fen
Liao, Yi-Jen
Huang, Shiu-Feng
Chen, Marcelo
Chen, Yi-Ming Arthur
AAV serotype 8-mediated liver specific GNMT expression delays progression of hepatocellular carcinoma and prevents carbon tetrachloride-induced liver damage
title AAV serotype 8-mediated liver specific GNMT expression delays progression of hepatocellular carcinoma and prevents carbon tetrachloride-induced liver damage
title_full AAV serotype 8-mediated liver specific GNMT expression delays progression of hepatocellular carcinoma and prevents carbon tetrachloride-induced liver damage
title_fullStr AAV serotype 8-mediated liver specific GNMT expression delays progression of hepatocellular carcinoma and prevents carbon tetrachloride-induced liver damage
title_full_unstemmed AAV serotype 8-mediated liver specific GNMT expression delays progression of hepatocellular carcinoma and prevents carbon tetrachloride-induced liver damage
title_short AAV serotype 8-mediated liver specific GNMT expression delays progression of hepatocellular carcinoma and prevents carbon tetrachloride-induced liver damage
title_sort aav serotype 8-mediated liver specific gnmt expression delays progression of hepatocellular carcinoma and prevents carbon tetrachloride-induced liver damage
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6138656/
https://www.ncbi.nlm.nih.gov/pubmed/30217986
http://dx.doi.org/10.1038/s41598-018-30800-3
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