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Inhibition of Bcl6b promotes gastric cancer by amplifying inflammation in mice
BACKGROUND: Chronic gastritis has been demonstrated to be a key cause of gastric cancer (GC), and control of gastric inflammation is regarded as an effective treatment for the clinical prevention of gastric carcinogenesis. However, there remains an unmet need to identify the dominant regulators of g...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6617686/ https://www.ncbi.nlm.nih.gov/pubmed/31288844 http://dx.doi.org/10.1186/s12964-019-0387-6 |
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author | Cai, Wang-Yu Lin, Ling-Yun Wang, Lin Yang, Li Ye, Guo-Dong Zeng, Qiang Cheng, Jia Xie, Yuan-Yuan Chen, Mao-Li Luo, Qi-Cong |
author_facet | Cai, Wang-Yu Lin, Ling-Yun Wang, Lin Yang, Li Ye, Guo-Dong Zeng, Qiang Cheng, Jia Xie, Yuan-Yuan Chen, Mao-Li Luo, Qi-Cong |
author_sort | Cai, Wang-Yu |
collection | PubMed |
description | BACKGROUND: Chronic gastritis has been demonstrated to be a key cause of gastric cancer (GC), and control of gastric inflammation is regarded as an effective treatment for the clinical prevention of gastric carcinogenesis. However, there remains an unmet need to identify the dominant regulators of gastric oncogenesis-associated inflammation in vivo. METHODS: The mouse model for the study of inflammation-associated GC was induced by Benzo[a]pyrene (BaP) intragastric administration in Bcl6b(−/−) and wildtype mice on a C57BL/6 background. 5-Aza-2′-deoxycytidine (5-Aza), the demethylation drug, was intraperitoneally injected to restore Bcl6b expression. Human GC tissue array was used to analyse patient survival based on BCL6B and CD3 protein expression. RESULTS: Bcl6b was gradually downregulated by its own promoter hypermethylation in parallel to an increasing inflammatory response during the progression of BaP-induced gastric carcinogenesis in mice. Moreover, knockout of Bcl6b dramatically worsened the severity of gastric cancer and aggravated the inflammatory response in the BaP-induced mice GC model. Re-activation of Bcl6b by 5-Aza impeded inflammatory amplification and BaP-induced GC development, prolonging survival time in wildtype mice, whereas no notable curative effect occurred in Bcl6b(−/−) mice with 5-Aza treatment. Finally, significant negative correlations were detected between the mRNA levels of BCL6B and inflammatory cytokines in human GC tissues; patients harbouring BCL6B-negetive and severe-inflammation GC tumours were found to exhibit the shortest survival time. CONCLUSIONS: Epigenetic inactivation of Bcl6b promotes gastric cancer through amplification of the gastric inflammatory response in vivo and offers a new approach for GC treatment and regenerative medicine. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12964-019-0387-6) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-6617686 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-66176862019-07-22 Inhibition of Bcl6b promotes gastric cancer by amplifying inflammation in mice Cai, Wang-Yu Lin, Ling-Yun Wang, Lin Yang, Li Ye, Guo-Dong Zeng, Qiang Cheng, Jia Xie, Yuan-Yuan Chen, Mao-Li Luo, Qi-Cong Cell Commun Signal Research BACKGROUND: Chronic gastritis has been demonstrated to be a key cause of gastric cancer (GC), and control of gastric inflammation is regarded as an effective treatment for the clinical prevention of gastric carcinogenesis. However, there remains an unmet need to identify the dominant regulators of gastric oncogenesis-associated inflammation in vivo. METHODS: The mouse model for the study of inflammation-associated GC was induced by Benzo[a]pyrene (BaP) intragastric administration in Bcl6b(−/−) and wildtype mice on a C57BL/6 background. 5-Aza-2′-deoxycytidine (5-Aza), the demethylation drug, was intraperitoneally injected to restore Bcl6b expression. Human GC tissue array was used to analyse patient survival based on BCL6B and CD3 protein expression. RESULTS: Bcl6b was gradually downregulated by its own promoter hypermethylation in parallel to an increasing inflammatory response during the progression of BaP-induced gastric carcinogenesis in mice. Moreover, knockout of Bcl6b dramatically worsened the severity of gastric cancer and aggravated the inflammatory response in the BaP-induced mice GC model. Re-activation of Bcl6b by 5-Aza impeded inflammatory amplification and BaP-induced GC development, prolonging survival time in wildtype mice, whereas no notable curative effect occurred in Bcl6b(−/−) mice with 5-Aza treatment. Finally, significant negative correlations were detected between the mRNA levels of BCL6B and inflammatory cytokines in human GC tissues; patients harbouring BCL6B-negetive and severe-inflammation GC tumours were found to exhibit the shortest survival time. CONCLUSIONS: Epigenetic inactivation of Bcl6b promotes gastric cancer through amplification of the gastric inflammatory response in vivo and offers a new approach for GC treatment and regenerative medicine. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12964-019-0387-6) contains supplementary material, which is available to authorized users. BioMed Central 2019-07-09 /pmc/articles/PMC6617686/ /pubmed/31288844 http://dx.doi.org/10.1186/s12964-019-0387-6 Text en © The Author(s). 2019 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided 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 Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Cai, Wang-Yu Lin, Ling-Yun Wang, Lin Yang, Li Ye, Guo-Dong Zeng, Qiang Cheng, Jia Xie, Yuan-Yuan Chen, Mao-Li Luo, Qi-Cong Inhibition of Bcl6b promotes gastric cancer by amplifying inflammation in mice |
title | Inhibition of Bcl6b promotes gastric cancer by amplifying inflammation in mice |
title_full | Inhibition of Bcl6b promotes gastric cancer by amplifying inflammation in mice |
title_fullStr | Inhibition of Bcl6b promotes gastric cancer by amplifying inflammation in mice |
title_full_unstemmed | Inhibition of Bcl6b promotes gastric cancer by amplifying inflammation in mice |
title_short | Inhibition of Bcl6b promotes gastric cancer by amplifying inflammation in mice |
title_sort | inhibition of bcl6b promotes gastric cancer by amplifying inflammation in mice |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6617686/ https://www.ncbi.nlm.nih.gov/pubmed/31288844 http://dx.doi.org/10.1186/s12964-019-0387-6 |
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