Nrf2 Mutation/Activation Is Dispensable for the Development of Chemically Induced Mouse HCCSummary

Background & Aims: Activation of the kelch-like ECH-associated protein 1 (Keap1)–nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway has been associated with metabolic reprogramming in many tumors, including hepatocellular carcinoma (HCC). However, the contribution of Nrf2 mutations i...

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Autores principales:	Sandra Mattu, Patrizia Zavattari, Marta Anna Kowalik, Marina Serra, Pia Sulas, Rajesh Pal, Elisabetta Puliga, Salvatore Sutti, Beatrice Foglia, Maurizio Parola, Emanuele Albano, Silvia Giordano, Andrea Perra, Amedeo Columbano
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2022
Materias:	Nrf2 Ctnnb1 Gene Mutation Metabolic Reprogramming HCC Diseases of the digestive system. Gastroenterology RC799-869
Acceso en línea:	https://doaj.org/article/a287ac6f649144fb9e8b07c7fac86783
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spelling	oai:doaj.org-article:a287ac6f649144fb9e8b07c7fac867832021-11-14T04:34:14ZNrf2 Mutation/Activation Is Dispensable for the Development of Chemically Induced Mouse HCCSummary2352-345X10.1016/j.jcmgh.2021.08.011https://doaj.org/article/a287ac6f649144fb9e8b07c7fac867832022-01-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S2352345X21001788https://doaj.org/toc/2352-345XBackground & Aims: Activation of the kelch-like ECH-associated protein 1 (Keap1)–nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway has been associated with metabolic reprogramming in many tumors, including hepatocellular carcinoma (HCC). However, the contribution of Nrf2 mutations in this process remains elusive. Here, we investigated the occurrence of Nrf2 mutations in distinct models of mouse hepatocarcinogenesis. Methods: HCCs were generated by experimental protocols consisting of the following: (1) a single dose of diethylnitrosamine (DEN), followed by repeated treatments with the nuclear-receptor agonist 1,4-bis-[2-(3,5-dichloropyridyloxy)]benzene; (2) repeated treatments with 1,4-bis-[2-(3,5-dichloropyridyloxy)]benzene alone; (3) a single dose of DEN followed by exposure to a choline-deficient L-amino acid–defined diet; and (4) a single dose of DEN with no further treatment. All of these protocols led to HCC development within 28–42 weeks. Activation of the Keap1-Nrf2 pathway was investigated by analyzing the presence of Nrf2 gene mutations, and the expression of Nrf2 target genes. Metabolic reprogramming was assessed by evaluating the expression of genes involved in glycolysis, the pentose phosphate pathway, and glutaminolysis. Results: No Nrf2 mutations were found in any of the models of hepatocarcinogenesis analyzed. Intriguingly, despite the described cooperation between β-catenin and the Nrf2 pathway, we found no evidence of Nrf2 activation in both early dysplastic nodules and HCCs, characterized by the presence of up to 80%–90% β-catenin mutations. No HCC metabolic reprogramming was observed either. Conclusions: These results show that, unlike rat hepatocarcinogenesis, Nrf2 mutations do not occur in 4 distinct models of chemically induced mouse HCC. Interestingly, in the same models, metabolic reprogramming also was minimal or absent, supporting the concept that Nrf2 activation is critical for the switch from oxidative to glycolytic metabolism.Sandra MattuPatrizia ZavattariMarta Anna KowalikMarina SerraPia SulasRajesh PalElisabetta PuligaSalvatore SuttiBeatrice FogliaMaurizio ParolaEmanuele AlbanoSilvia GiordanoAndrea PerraAmedeo ColumbanoElsevierarticleNrf2Ctnnb1Gene MutationMetabolic ReprogrammingHCCDiseases of the digestive system. GastroenterologyRC799-869ENCellular and Molecular Gastroenterology and Hepatology, Vol 13, Iss 1, Pp 113-127 (2022)
institution	DOAJ
collection	DOAJ
language	EN
topic	Nrf2 Ctnnb1 Gene Mutation Metabolic Reprogramming HCC Diseases of the digestive system. Gastroenterology RC799-869
spellingShingle	Nrf2 Ctnnb1 Gene Mutation Metabolic Reprogramming HCC Diseases of the digestive system. Gastroenterology RC799-869 Sandra Mattu Patrizia Zavattari Marta Anna Kowalik Marina Serra Pia Sulas Rajesh Pal Elisabetta Puliga Salvatore Sutti Beatrice Foglia Maurizio Parola Emanuele Albano Silvia Giordano Andrea Perra Amedeo Columbano Nrf2 Mutation/Activation Is Dispensable for the Development of Chemically Induced Mouse HCCSummary
description	Background & Aims: Activation of the kelch-like ECH-associated protein 1 (Keap1)–nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway has been associated with metabolic reprogramming in many tumors, including hepatocellular carcinoma (HCC). However, the contribution of Nrf2 mutations in this process remains elusive. Here, we investigated the occurrence of Nrf2 mutations in distinct models of mouse hepatocarcinogenesis. Methods: HCCs were generated by experimental protocols consisting of the following: (1) a single dose of diethylnitrosamine (DEN), followed by repeated treatments with the nuclear-receptor agonist 1,4-bis-[2-(3,5-dichloropyridyloxy)]benzene; (2) repeated treatments with 1,4-bis-[2-(3,5-dichloropyridyloxy)]benzene alone; (3) a single dose of DEN followed by exposure to a choline-deficient L-amino acid–defined diet; and (4) a single dose of DEN with no further treatment. All of these protocols led to HCC development within 28–42 weeks. Activation of the Keap1-Nrf2 pathway was investigated by analyzing the presence of Nrf2 gene mutations, and the expression of Nrf2 target genes. Metabolic reprogramming was assessed by evaluating the expression of genes involved in glycolysis, the pentose phosphate pathway, and glutaminolysis. Results: No Nrf2 mutations were found in any of the models of hepatocarcinogenesis analyzed. Intriguingly, despite the described cooperation between β-catenin and the Nrf2 pathway, we found no evidence of Nrf2 activation in both early dysplastic nodules and HCCs, characterized by the presence of up to 80%–90% β-catenin mutations. No HCC metabolic reprogramming was observed either. Conclusions: These results show that, unlike rat hepatocarcinogenesis, Nrf2 mutations do not occur in 4 distinct models of chemically induced mouse HCC. Interestingly, in the same models, metabolic reprogramming also was minimal or absent, supporting the concept that Nrf2 activation is critical for the switch from oxidative to glycolytic metabolism.
format	article
author	Sandra Mattu Patrizia Zavattari Marta Anna Kowalik Marina Serra Pia Sulas Rajesh Pal Elisabetta Puliga Salvatore Sutti Beatrice Foglia Maurizio Parola Emanuele Albano Silvia Giordano Andrea Perra Amedeo Columbano
author_facet	Sandra Mattu Patrizia Zavattari Marta Anna Kowalik Marina Serra Pia Sulas Rajesh Pal Elisabetta Puliga Salvatore Sutti Beatrice Foglia Maurizio Parola Emanuele Albano Silvia Giordano Andrea Perra Amedeo Columbano
author_sort	Sandra Mattu
title	Nrf2 Mutation/Activation Is Dispensable for the Development of Chemically Induced Mouse HCCSummary
title_short	Nrf2 Mutation/Activation Is Dispensable for the Development of Chemically Induced Mouse HCCSummary
title_full	Nrf2 Mutation/Activation Is Dispensable for the Development of Chemically Induced Mouse HCCSummary
title_fullStr	Nrf2 Mutation/Activation Is Dispensable for the Development of Chemically Induced Mouse HCCSummary
title_full_unstemmed	Nrf2 Mutation/Activation Is Dispensable for the Development of Chemically Induced Mouse HCCSummary
title_sort	nrf2 mutation/activation is dispensable for the development of chemically induced mouse hccsummary
publisher	Elsevier
publishDate	2022
url	https://doaj.org/article/a287ac6f649144fb9e8b07c7fac86783
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Nrf2 Mutation/Activation Is Dispensable for the Development of Chemically Induced Mouse HCCSummary

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