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Clock gene Per2 as a controller of liver carcinogenesis

Environmental disruption of molecular clocks promoted liver carcinogenesis and accelerated cancer progression in rodents. We investigated the specific role of clock gene Period 2 (Per2) for liver carcinogenesis and clock-controlled cellular proliferation, genomic instability and inflammation. We ass...

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Autores principales: Mteyrek, Ali, Filipski, Elisabeth, Guettier, Catherine, Okyar, Alper, Lévi, Francis
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5349878/
https://www.ncbi.nlm.nih.gov/pubmed/27494874
http://dx.doi.org/10.18632/oncotarget.11037
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author Mteyrek, Ali
Filipski, Elisabeth
Guettier, Catherine
Okyar, Alper
Lévi, Francis
author_facet Mteyrek, Ali
Filipski, Elisabeth
Guettier, Catherine
Okyar, Alper
Lévi, Francis
author_sort Mteyrek, Ali
collection PubMed
description Environmental disruption of molecular clocks promoted liver carcinogenesis and accelerated cancer progression in rodents. We investigated the specific role of clock gene Period 2 (Per2) for liver carcinogenesis and clock-controlled cellular proliferation, genomic instability and inflammation. We assessed liver histopathology, and determined molecular and physiology circadian patterns in mice on chronic diethylnitrosamine (DEN) exposure according to constitutive Per2 mutation. First, we found that Per2(m/m) liver displayed profound alterations in proliferation gene expression, including c-Myc derepression, phase-advanced Wee1, and arrhythmic Ccnb1 and K-ras mRNA expressions, as well as deregulated inflammation, through arrhythmic liver IL-6 protein concentration, in the absence of any DEN exposure. These changes could then make Per2(m/m) mice more prone to subsequently develop liver cancers on DEN. Indeed, primary liver cancers were nearly fourfold as frequent in Per2(m/m) mice as compared to wild-type (WT), 4 months after DEN exposure. The liver molecular clock was severely disrupted throughout the whole carcinogenesis process, including the initiation stage, i.e. within the initial 17 days on DEN. Per2(m/m) further exhibited increased c-Myc and Ccnb1 mean 24h expressions, lack of P53 response, and arrhythmic ATM, Wee1 and Ccnb1 expressions. DEN-induced tumor related inflammation was further promoted through increased protein concentrations of liver IL-6 and TNF-α as compared to WT during carcinogenesis initiation. Per2 mutation severely deregulated liver gene or protein expressions related to three cancer hallmarks, including uncontrolled proliferation, genomic instability, and tumor promoting inflammation, and accelerated liver carcinogenesis several-fold. Clock gene Per2 acted here as a liver tumor suppressor from initiation to progression.
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spelling pubmed-53498782017-04-06 Clock gene Per2 as a controller of liver carcinogenesis Mteyrek, Ali Filipski, Elisabeth Guettier, Catherine Okyar, Alper Lévi, Francis Oncotarget Research Paper Environmental disruption of molecular clocks promoted liver carcinogenesis and accelerated cancer progression in rodents. We investigated the specific role of clock gene Period 2 (Per2) for liver carcinogenesis and clock-controlled cellular proliferation, genomic instability and inflammation. We assessed liver histopathology, and determined molecular and physiology circadian patterns in mice on chronic diethylnitrosamine (DEN) exposure according to constitutive Per2 mutation. First, we found that Per2(m/m) liver displayed profound alterations in proliferation gene expression, including c-Myc derepression, phase-advanced Wee1, and arrhythmic Ccnb1 and K-ras mRNA expressions, as well as deregulated inflammation, through arrhythmic liver IL-6 protein concentration, in the absence of any DEN exposure. These changes could then make Per2(m/m) mice more prone to subsequently develop liver cancers on DEN. Indeed, primary liver cancers were nearly fourfold as frequent in Per2(m/m) mice as compared to wild-type (WT), 4 months after DEN exposure. The liver molecular clock was severely disrupted throughout the whole carcinogenesis process, including the initiation stage, i.e. within the initial 17 days on DEN. Per2(m/m) further exhibited increased c-Myc and Ccnb1 mean 24h expressions, lack of P53 response, and arrhythmic ATM, Wee1 and Ccnb1 expressions. DEN-induced tumor related inflammation was further promoted through increased protein concentrations of liver IL-6 and TNF-α as compared to WT during carcinogenesis initiation. Per2 mutation severely deregulated liver gene or protein expressions related to three cancer hallmarks, including uncontrolled proliferation, genomic instability, and tumor promoting inflammation, and accelerated liver carcinogenesis several-fold. Clock gene Per2 acted here as a liver tumor suppressor from initiation to progression. Impact Journals LLC 2016-08-03 /pmc/articles/PMC5349878/ /pubmed/27494874 http://dx.doi.org/10.18632/oncotarget.11037 Text en Copyright: © 2016 Mteyrek et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Mteyrek, Ali
Filipski, Elisabeth
Guettier, Catherine
Okyar, Alper
Lévi, Francis
Clock gene Per2 as a controller of liver carcinogenesis
title Clock gene Per2 as a controller of liver carcinogenesis
title_full Clock gene Per2 as a controller of liver carcinogenesis
title_fullStr Clock gene Per2 as a controller of liver carcinogenesis
title_full_unstemmed Clock gene Per2 as a controller of liver carcinogenesis
title_short Clock gene Per2 as a controller of liver carcinogenesis
title_sort clock gene per2 as a controller of liver carcinogenesis
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5349878/
https://www.ncbi.nlm.nih.gov/pubmed/27494874
http://dx.doi.org/10.18632/oncotarget.11037
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