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Lysyl oxidase impacts disease outcomes and correlates with global DNA hypomethylation in esophageal cancer
Abnormal function of human body enzymes and epigenetic alterations such as DNA methylation have been shown to lead to human carcinogenesis. Lysyl oxidase (LOX) enzyme has attracted attention due to its involvement in tumor progression in various cancers. The purpose of this study was to clarify the...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6890447/ https://www.ncbi.nlm.nih.gov/pubmed/31599475 http://dx.doi.org/10.1111/cas.14214 |
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author | Kalikawe, Rebecca Baba, Yoshifumi Nomoto, Daichi Okadome, Kazuo Miyake, Keisuke Eto, Kojiro Hiyoshi, Yukiharu Nagai, Youhei Iwatsuki, Masaaki Ishimoto, Takatsugu Iwagami, Shiro Miyamoto, Yuji Yoshida, Naoya Watanabe, Masayuki Baba, Hideo |
author_facet | Kalikawe, Rebecca Baba, Yoshifumi Nomoto, Daichi Okadome, Kazuo Miyake, Keisuke Eto, Kojiro Hiyoshi, Yukiharu Nagai, Youhei Iwatsuki, Masaaki Ishimoto, Takatsugu Iwagami, Shiro Miyamoto, Yuji Yoshida, Naoya Watanabe, Masayuki Baba, Hideo |
author_sort | Kalikawe, Rebecca |
collection | PubMed |
description | Abnormal function of human body enzymes and epigenetic alterations such as DNA methylation have been shown to lead to human carcinogenesis. Lysyl oxidase (LOX) enzyme has attracted attention due to its involvement in tumor progression in various cancers. The purpose of this study was to clarify the clinical importance of LOX expression and its epigenetic regulation in the pathogenesis of esophageal squamous cell carcinoma (ESCC). Using a database of 284 ESCCs, we examined LOX expression and its prognostic characteristics. The functional role of LOX was assessed by in vitro growth, migration, and invasion assays. The relationship between LOX expression, global DNA hypomethylation (ie, LINE‐1 methylation), and LOX promoter methylation was evaluated by using mRNA expression arrays and pyrosequencing technology. High LOX expression cases had a significantly shorter overall survival and cancer‐specific survival (log‐rank, P < .001). The prognostic effect of LOX expression was not significantly modified by other clinical variables. Silencing and enzymatic inhibition of LOX suppressed growth and reduced the invasion and migration ability of ESCC cell lines along with the downregulation of AKT and MMP2. An integrated gene analysis in tissues and cell lines revealed that LOX was the most highly upregulated gene in LINE‐1 hypomethylated tumors. In vitro, LOX expression was upregulated following DNA demethylation. LOX promoter methylation was not associated with LOX expression. Conclusively LOX expression was associated with poor prognosis in ESCC and was regulated epigenetically by genome‐wide hypomethylation. It could serve as a prognostic biomarker in ESCC patients, and therapeutically targeting LOX could reverse the progression of esophageal cancer. |
format | Online Article Text |
id | pubmed-6890447 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-68904472019-12-12 Lysyl oxidase impacts disease outcomes and correlates with global DNA hypomethylation in esophageal cancer Kalikawe, Rebecca Baba, Yoshifumi Nomoto, Daichi Okadome, Kazuo Miyake, Keisuke Eto, Kojiro Hiyoshi, Yukiharu Nagai, Youhei Iwatsuki, Masaaki Ishimoto, Takatsugu Iwagami, Shiro Miyamoto, Yuji Yoshida, Naoya Watanabe, Masayuki Baba, Hideo Cancer Sci Original Articles Abnormal function of human body enzymes and epigenetic alterations such as DNA methylation have been shown to lead to human carcinogenesis. Lysyl oxidase (LOX) enzyme has attracted attention due to its involvement in tumor progression in various cancers. The purpose of this study was to clarify the clinical importance of LOX expression and its epigenetic regulation in the pathogenesis of esophageal squamous cell carcinoma (ESCC). Using a database of 284 ESCCs, we examined LOX expression and its prognostic characteristics. The functional role of LOX was assessed by in vitro growth, migration, and invasion assays. The relationship between LOX expression, global DNA hypomethylation (ie, LINE‐1 methylation), and LOX promoter methylation was evaluated by using mRNA expression arrays and pyrosequencing technology. High LOX expression cases had a significantly shorter overall survival and cancer‐specific survival (log‐rank, P < .001). The prognostic effect of LOX expression was not significantly modified by other clinical variables. Silencing and enzymatic inhibition of LOX suppressed growth and reduced the invasion and migration ability of ESCC cell lines along with the downregulation of AKT and MMP2. An integrated gene analysis in tissues and cell lines revealed that LOX was the most highly upregulated gene in LINE‐1 hypomethylated tumors. In vitro, LOX expression was upregulated following DNA demethylation. LOX promoter methylation was not associated with LOX expression. Conclusively LOX expression was associated with poor prognosis in ESCC and was regulated epigenetically by genome‐wide hypomethylation. It could serve as a prognostic biomarker in ESCC patients, and therapeutically targeting LOX could reverse the progression of esophageal cancer. John Wiley and Sons Inc. 2019-11-09 2019-12 /pmc/articles/PMC6890447/ /pubmed/31599475 http://dx.doi.org/10.1111/cas.14214 Text en © 2019 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association. This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made. |
spellingShingle | Original Articles Kalikawe, Rebecca Baba, Yoshifumi Nomoto, Daichi Okadome, Kazuo Miyake, Keisuke Eto, Kojiro Hiyoshi, Yukiharu Nagai, Youhei Iwatsuki, Masaaki Ishimoto, Takatsugu Iwagami, Shiro Miyamoto, Yuji Yoshida, Naoya Watanabe, Masayuki Baba, Hideo Lysyl oxidase impacts disease outcomes and correlates with global DNA hypomethylation in esophageal cancer |
title | Lysyl oxidase impacts disease outcomes and correlates with global DNA hypomethylation in esophageal cancer |
title_full | Lysyl oxidase impacts disease outcomes and correlates with global DNA hypomethylation in esophageal cancer |
title_fullStr | Lysyl oxidase impacts disease outcomes and correlates with global DNA hypomethylation in esophageal cancer |
title_full_unstemmed | Lysyl oxidase impacts disease outcomes and correlates with global DNA hypomethylation in esophageal cancer |
title_short | Lysyl oxidase impacts disease outcomes and correlates with global DNA hypomethylation in esophageal cancer |
title_sort | lysyl oxidase impacts disease outcomes and correlates with global dna hypomethylation in esophageal cancer |
topic | Original Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6890447/ https://www.ncbi.nlm.nih.gov/pubmed/31599475 http://dx.doi.org/10.1111/cas.14214 |
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