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Distinct Mechanisms Are Responsible for Nrf2-Keap1 Pathway Activation at Different Stages of Rat Hepatocarcinogenesis

Activation of the Nrf2-Keap1 pathway, the main intracellular defense against environmental stress, has been observed in several human cancers, including hepatocellular carcinoma (HCC). Here, we assessed whether distinct mechanisms of activation may be involved at different stages of hepatocarcinogen...

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Autores principales: Orrù, Claudia, Perra, Andrea, Kowalik, Marta Anna, Rizzolio, Sabrina, Puliga, Elisabetta, Cabras, Lavinia, Giordano, Silvia, Columbano, Amedeo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7463589/
https://www.ncbi.nlm.nih.gov/pubmed/32824383
http://dx.doi.org/10.3390/cancers12082305
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author Orrù, Claudia
Perra, Andrea
Kowalik, Marta Anna
Rizzolio, Sabrina
Puliga, Elisabetta
Cabras, Lavinia
Giordano, Silvia
Columbano, Amedeo
author_facet Orrù, Claudia
Perra, Andrea
Kowalik, Marta Anna
Rizzolio, Sabrina
Puliga, Elisabetta
Cabras, Lavinia
Giordano, Silvia
Columbano, Amedeo
author_sort Orrù, Claudia
collection PubMed
description Activation of the Nrf2-Keap1 pathway, the main intracellular defense against environmental stress, has been observed in several human cancers, including hepatocellular carcinoma (HCC). Here, we assessed whether distinct mechanisms of activation may be involved at different stages of hepatocarcinogenesis. We adopted an experimental model consisting of treatment with diethylnitrosamine (DENA) followed by a choline-devoid methionine-deficient (CMD) diet for 4 months. The CMD diet was then replaced with a basal diet, and the animals were killed at 6, 10 or 13 months after DENA injection. Nrf2 activation occurred at early steps of hepatocarcinogenesis and persisted throughout the tumorigenic process. While Nrf2 mutations were extremely frequent at early steps (90%), their incidence diminished with the progression to malignancy (25%). Conversely, while p62 was almost undetectable in early nodules, its accumulation occurred in HCCs, suggesting that Nrf2 pathway activation at late stages is mainly due to Keap1 sequestration by p62. We demonstrate that, in a model of hepatocarcinogenesis resembling human non-alcoholic fatty liver disease, Nrf2 mutations are the earliest molecular changes responsible for the activation of the Nrf2-Keap1 pathway. The progressive loss of mutations associated with a concomitant p62 accumulation implies that distinct mechanisms are responsible for Nrf2-Keap1 pathway activation at different stages of hepatocarcinogenesis.
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spelling pubmed-74635892020-09-02 Distinct Mechanisms Are Responsible for Nrf2-Keap1 Pathway Activation at Different Stages of Rat Hepatocarcinogenesis Orrù, Claudia Perra, Andrea Kowalik, Marta Anna Rizzolio, Sabrina Puliga, Elisabetta Cabras, Lavinia Giordano, Silvia Columbano, Amedeo Cancers (Basel) Article Activation of the Nrf2-Keap1 pathway, the main intracellular defense against environmental stress, has been observed in several human cancers, including hepatocellular carcinoma (HCC). Here, we assessed whether distinct mechanisms of activation may be involved at different stages of hepatocarcinogenesis. We adopted an experimental model consisting of treatment with diethylnitrosamine (DENA) followed by a choline-devoid methionine-deficient (CMD) diet for 4 months. The CMD diet was then replaced with a basal diet, and the animals were killed at 6, 10 or 13 months after DENA injection. Nrf2 activation occurred at early steps of hepatocarcinogenesis and persisted throughout the tumorigenic process. While Nrf2 mutations were extremely frequent at early steps (90%), their incidence diminished with the progression to malignancy (25%). Conversely, while p62 was almost undetectable in early nodules, its accumulation occurred in HCCs, suggesting that Nrf2 pathway activation at late stages is mainly due to Keap1 sequestration by p62. We demonstrate that, in a model of hepatocarcinogenesis resembling human non-alcoholic fatty liver disease, Nrf2 mutations are the earliest molecular changes responsible for the activation of the Nrf2-Keap1 pathway. The progressive loss of mutations associated with a concomitant p62 accumulation implies that distinct mechanisms are responsible for Nrf2-Keap1 pathway activation at different stages of hepatocarcinogenesis. MDPI 2020-08-16 /pmc/articles/PMC7463589/ /pubmed/32824383 http://dx.doi.org/10.3390/cancers12082305 Text en © 2020 by the authors. 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 (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Orrù, Claudia
Perra, Andrea
Kowalik, Marta Anna
Rizzolio, Sabrina
Puliga, Elisabetta
Cabras, Lavinia
Giordano, Silvia
Columbano, Amedeo
Distinct Mechanisms Are Responsible for Nrf2-Keap1 Pathway Activation at Different Stages of Rat Hepatocarcinogenesis
title Distinct Mechanisms Are Responsible for Nrf2-Keap1 Pathway Activation at Different Stages of Rat Hepatocarcinogenesis
title_full Distinct Mechanisms Are Responsible for Nrf2-Keap1 Pathway Activation at Different Stages of Rat Hepatocarcinogenesis
title_fullStr Distinct Mechanisms Are Responsible for Nrf2-Keap1 Pathway Activation at Different Stages of Rat Hepatocarcinogenesis
title_full_unstemmed Distinct Mechanisms Are Responsible for Nrf2-Keap1 Pathway Activation at Different Stages of Rat Hepatocarcinogenesis
title_short Distinct Mechanisms Are Responsible for Nrf2-Keap1 Pathway Activation at Different Stages of Rat Hepatocarcinogenesis
title_sort distinct mechanisms are responsible for nrf2-keap1 pathway activation at different stages of rat hepatocarcinogenesis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7463589/
https://www.ncbi.nlm.nih.gov/pubmed/32824383
http://dx.doi.org/10.3390/cancers12082305
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