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Hypermethylation Leads to Bone Morphogenetic Protein 6 Downregulation in Hepatocellular Carcinoma

BACKGROUND: In the liver, bone morphogenetic protein 6 (BMP-6) maintains balanced iron metabolism. However, the mechanism that underlies greater BMP-6 expression in hepatocellular carcinoma (HCC) tissue than adjacent non-cancerous tissue is unclear. This study sought to investigate the epigenetic me...

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Autores principales: He, Yinghua, Cui, Ying, Xu, Baiying, Gu, Jun, Wang, Wei, Luo, Xiaoying
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3907571/
https://www.ncbi.nlm.nih.gov/pubmed/24498236
http://dx.doi.org/10.1371/journal.pone.0087994
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author He, Yinghua
Cui, Ying
Xu, Baiying
Gu, Jun
Wang, Wei
Luo, Xiaoying
author_facet He, Yinghua
Cui, Ying
Xu, Baiying
Gu, Jun
Wang, Wei
Luo, Xiaoying
author_sort He, Yinghua
collection PubMed
description BACKGROUND: In the liver, bone morphogenetic protein 6 (BMP-6) maintains balanced iron metabolism. However, the mechanism that underlies greater BMP-6 expression in hepatocellular carcinoma (HCC) tissue than adjacent non-cancerous tissue is unclear. This study sought to investigate the epigenetic mechanisms of BMP-6 expression by analysing the relationship between the DNA methylation status of BMP-6 and the expression of BMP-6. METHODS: Methylation-specific polymerase chain reaction (PCR), bisulphite sequencing PCR, the MethyLight assay, and quantitative real-time PCR were performed to examine BMP-6 methylation and mRNA expression levels. Immunohistochemistry (IHC) was performed on tissue arrays to evaluate the BMP-6 protein level. RESULTS: BMP-6 mRNA expression was approximately 84.09% lower in HCC tissues than in adjacent non-cancerous tissues, and this low level of expression was associated with a poor prognosis. Moreover, the hypermethylation observed in HCC cell lines and HCC tissues was correlated with the BMP-6 mRNA expression level, and this correlation was validated following treatment with 5-aza-CdR, a demethylation agent. In addition, BMP-6 DNA methylation was upregulated by 68.42% in 114 clinical HCC tissue samples compared to adjacent normal tissues, whereas the BMP-6 staining intensity was downregulated by 77.03% in 75 clinical HCC tissue samples in comparison to adjacent normal tissues. Furthermore, elevated expression of BMP-6 in HCC cell lines inhibited cell colony formation. CONCLUSIONS: Our results suggest that BMP-6 CpG island hypermethylation leads to decreased BMP-6 expression in HCC tissues.
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spelling pubmed-39075712014-02-04 Hypermethylation Leads to Bone Morphogenetic Protein 6 Downregulation in Hepatocellular Carcinoma He, Yinghua Cui, Ying Xu, Baiying Gu, Jun Wang, Wei Luo, Xiaoying PLoS One Research Article BACKGROUND: In the liver, bone morphogenetic protein 6 (BMP-6) maintains balanced iron metabolism. However, the mechanism that underlies greater BMP-6 expression in hepatocellular carcinoma (HCC) tissue than adjacent non-cancerous tissue is unclear. This study sought to investigate the epigenetic mechanisms of BMP-6 expression by analysing the relationship between the DNA methylation status of BMP-6 and the expression of BMP-6. METHODS: Methylation-specific polymerase chain reaction (PCR), bisulphite sequencing PCR, the MethyLight assay, and quantitative real-time PCR were performed to examine BMP-6 methylation and mRNA expression levels. Immunohistochemistry (IHC) was performed on tissue arrays to evaluate the BMP-6 protein level. RESULTS: BMP-6 mRNA expression was approximately 84.09% lower in HCC tissues than in adjacent non-cancerous tissues, and this low level of expression was associated with a poor prognosis. Moreover, the hypermethylation observed in HCC cell lines and HCC tissues was correlated with the BMP-6 mRNA expression level, and this correlation was validated following treatment with 5-aza-CdR, a demethylation agent. In addition, BMP-6 DNA methylation was upregulated by 68.42% in 114 clinical HCC tissue samples compared to adjacent normal tissues, whereas the BMP-6 staining intensity was downregulated by 77.03% in 75 clinical HCC tissue samples in comparison to adjacent normal tissues. Furthermore, elevated expression of BMP-6 in HCC cell lines inhibited cell colony formation. CONCLUSIONS: Our results suggest that BMP-6 CpG island hypermethylation leads to decreased BMP-6 expression in HCC tissues. Public Library of Science 2014-01-30 /pmc/articles/PMC3907571/ /pubmed/24498236 http://dx.doi.org/10.1371/journal.pone.0087994 Text en © 2014 He et al http://creativecommons.org/licenses/by/4.0/ 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 properly credited.
spellingShingle Research Article
He, Yinghua
Cui, Ying
Xu, Baiying
Gu, Jun
Wang, Wei
Luo, Xiaoying
Hypermethylation Leads to Bone Morphogenetic Protein 6 Downregulation in Hepatocellular Carcinoma
title Hypermethylation Leads to Bone Morphogenetic Protein 6 Downregulation in Hepatocellular Carcinoma
title_full Hypermethylation Leads to Bone Morphogenetic Protein 6 Downregulation in Hepatocellular Carcinoma
title_fullStr Hypermethylation Leads to Bone Morphogenetic Protein 6 Downregulation in Hepatocellular Carcinoma
title_full_unstemmed Hypermethylation Leads to Bone Morphogenetic Protein 6 Downregulation in Hepatocellular Carcinoma
title_short Hypermethylation Leads to Bone Morphogenetic Protein 6 Downregulation in Hepatocellular Carcinoma
title_sort hypermethylation leads to bone morphogenetic protein 6 downregulation in hepatocellular carcinoma
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3907571/
https://www.ncbi.nlm.nih.gov/pubmed/24498236
http://dx.doi.org/10.1371/journal.pone.0087994
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