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Prostaglandin E(2) induces DNA hypermethylation in gastric cancer in vitro and in vivo

Rationale: Prostaglandin E(2) (PGE(2)) is a pro-inflammatory eicosanoid up-regulated in gastric cancer (GC). However, its impact on epigenetic dysfunction in the process of gastric carcinogenesis is unknown. In this study, we investigate the role of PGE(2) in DNA methylation in gastric epithelium in...

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Autores principales: Wong, Chi Chun, Kang, Wei, Xu, Jiaying, Qian, Yun, Luk, Simson Tsz Yat, Chen, Huarong, Li, Weilin, Zhao, Liuyang, Zhang, Xiaoming, Chiu, Phlip WY, Ng, Enders KW, Yu, Jun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Ivyspring International Publisher 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6735505/
https://www.ncbi.nlm.nih.gov/pubmed/31534549
http://dx.doi.org/10.7150/thno.35766
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author Wong, Chi Chun
Kang, Wei
Xu, Jiaying
Qian, Yun
Luk, Simson Tsz Yat
Chen, Huarong
Li, Weilin
Zhao, Liuyang
Zhang, Xiaoming
Chiu, Phlip WY
Ng, Enders KW
Yu, Jun
author_facet Wong, Chi Chun
Kang, Wei
Xu, Jiaying
Qian, Yun
Luk, Simson Tsz Yat
Chen, Huarong
Li, Weilin
Zhao, Liuyang
Zhang, Xiaoming
Chiu, Phlip WY
Ng, Enders KW
Yu, Jun
author_sort Wong, Chi Chun
collection PubMed
description Rationale: Prostaglandin E(2) (PGE(2)) is a pro-inflammatory eicosanoid up-regulated in gastric cancer (GC). However, its impact on epigenetic dysfunction in the process of gastric carcinogenesis is unknown. In this study, we investigate the role of PGE(2) in DNA methylation in gastric epithelium in vitro, in mice, and humans. Methods: PGE(2)-induced DNMT3B and DNA methylation was determined in gastric cell lines and COX-2 transgenic mice. Effect of COX-2 inhibition on DNA methylation was evaluated in a randomized controlled trial. Efficacy of combined COX-2/PGE(2) and DNMT inhibition on GC growth was examined in cell lines and mice models. Results: PCR array analysis of PGE(2)-treated GC cells revealed the up-regulation of DNMT3B, a de novo DNA methyltransferase. In GC cells, PGE(2) induced DNMT3B expression and activity, leading to increased methylated cytosine (5mC) and promoter methylation of tumor suppressive genes (MGMT and CNR1). Consistently, Cox-2 (rate-limiting enzyme for PGE(2) biosynthesis) transgenic expression in mice significantly induced Dnmt3b expression, increased 5mC content, and promoted Mgmt promoter methylation. We retrospectively analyzed the 5mC content of 42 patients with intestinal metaplasia (a precancerous lesion of GC) treated with a COX-2 specific inhibitor Rofecoxib or placebo for 2 years, revealing that the COX-2 inhibitor significantly down-regulated 5mC levels (N=42, P=0.009). Collectively, these data indicate that PGE(2) is closely related to DNA hypermethylation in vitro and in vivo. Using genome-wide 450K methylation array, we identified chromosomal genes (POT1, ATM and HIST1H2AA) were preferentially methylated by PGE(2). Biofunctional work revealed that POT1 functions as a tumor suppressor. Finally, we demonstrated that combinatorial inhibition of COX-2 and DNMT using Celecoxib and Decitabine synergistically inhibited GC growth in vitro and in vivo. Conclusion: This study suggested that PGE(2) promotes DNA methylation in GC, and that co-targeting of PGE(2) and DNMT inhibits GC.
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spelling pubmed-67355052019-09-18 Prostaglandin E(2) induces DNA hypermethylation in gastric cancer in vitro and in vivo Wong, Chi Chun Kang, Wei Xu, Jiaying Qian, Yun Luk, Simson Tsz Yat Chen, Huarong Li, Weilin Zhao, Liuyang Zhang, Xiaoming Chiu, Phlip WY Ng, Enders KW Yu, Jun Theranostics Research Paper Rationale: Prostaglandin E(2) (PGE(2)) is a pro-inflammatory eicosanoid up-regulated in gastric cancer (GC). However, its impact on epigenetic dysfunction in the process of gastric carcinogenesis is unknown. In this study, we investigate the role of PGE(2) in DNA methylation in gastric epithelium in vitro, in mice, and humans. Methods: PGE(2)-induced DNMT3B and DNA methylation was determined in gastric cell lines and COX-2 transgenic mice. Effect of COX-2 inhibition on DNA methylation was evaluated in a randomized controlled trial. Efficacy of combined COX-2/PGE(2) and DNMT inhibition on GC growth was examined in cell lines and mice models. Results: PCR array analysis of PGE(2)-treated GC cells revealed the up-regulation of DNMT3B, a de novo DNA methyltransferase. In GC cells, PGE(2) induced DNMT3B expression and activity, leading to increased methylated cytosine (5mC) and promoter methylation of tumor suppressive genes (MGMT and CNR1). Consistently, Cox-2 (rate-limiting enzyme for PGE(2) biosynthesis) transgenic expression in mice significantly induced Dnmt3b expression, increased 5mC content, and promoted Mgmt promoter methylation. We retrospectively analyzed the 5mC content of 42 patients with intestinal metaplasia (a precancerous lesion of GC) treated with a COX-2 specific inhibitor Rofecoxib or placebo for 2 years, revealing that the COX-2 inhibitor significantly down-regulated 5mC levels (N=42, P=0.009). Collectively, these data indicate that PGE(2) is closely related to DNA hypermethylation in vitro and in vivo. Using genome-wide 450K methylation array, we identified chromosomal genes (POT1, ATM and HIST1H2AA) were preferentially methylated by PGE(2). Biofunctional work revealed that POT1 functions as a tumor suppressor. Finally, we demonstrated that combinatorial inhibition of COX-2 and DNMT using Celecoxib and Decitabine synergistically inhibited GC growth in vitro and in vivo. Conclusion: This study suggested that PGE(2) promotes DNA methylation in GC, and that co-targeting of PGE(2) and DNMT inhibits GC. Ivyspring International Publisher 2019-08-14 /pmc/articles/PMC6735505/ /pubmed/31534549 http://dx.doi.org/10.7150/thno.35766 Text en © The author(s) This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
spellingShingle Research Paper
Wong, Chi Chun
Kang, Wei
Xu, Jiaying
Qian, Yun
Luk, Simson Tsz Yat
Chen, Huarong
Li, Weilin
Zhao, Liuyang
Zhang, Xiaoming
Chiu, Phlip WY
Ng, Enders KW
Yu, Jun
Prostaglandin E(2) induces DNA hypermethylation in gastric cancer in vitro and in vivo
title Prostaglandin E(2) induces DNA hypermethylation in gastric cancer in vitro and in vivo
title_full Prostaglandin E(2) induces DNA hypermethylation in gastric cancer in vitro and in vivo
title_fullStr Prostaglandin E(2) induces DNA hypermethylation in gastric cancer in vitro and in vivo
title_full_unstemmed Prostaglandin E(2) induces DNA hypermethylation in gastric cancer in vitro and in vivo
title_short Prostaglandin E(2) induces DNA hypermethylation in gastric cancer in vitro and in vivo
title_sort prostaglandin e(2) induces dna hypermethylation in gastric cancer in vitro and in vivo
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6735505/
https://www.ncbi.nlm.nih.gov/pubmed/31534549
http://dx.doi.org/10.7150/thno.35766
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