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RERG suppresses cell proliferation, migration and angiogenesis through ERK/NF-κB signaling pathway in nasopharyngeal carcinoma

BACKGROUND: Nasopharyngeal carcinoma (NPC) is a malignancy of the head and neck that is prevalent in Southeast Asia and southern China. Recent studies in epigenetics suggest that DNA methylation plays a pivotal role in the onset and progression of cancer. Combining the methyl-DNA binding domain capt...

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Autores principales: Zhao, Weilin, Ma, Ning, Wang, Shumin, Mo, Yingxi, Zhang, Zhe, Huang, Guangwu, Midorikawa, Kaoru, Hiraku, Yusuke, Oikawa, Shinji, Murata, Mariko, Takeuchi, Kazuhiko
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5490152/
https://www.ncbi.nlm.nih.gov/pubmed/28659184
http://dx.doi.org/10.1186/s13046-017-0554-9
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author Zhao, Weilin
Ma, Ning
Wang, Shumin
Mo, Yingxi
Zhang, Zhe
Huang, Guangwu
Midorikawa, Kaoru
Hiraku, Yusuke
Oikawa, Shinji
Murata, Mariko
Takeuchi, Kazuhiko
author_facet Zhao, Weilin
Ma, Ning
Wang, Shumin
Mo, Yingxi
Zhang, Zhe
Huang, Guangwu
Midorikawa, Kaoru
Hiraku, Yusuke
Oikawa, Shinji
Murata, Mariko
Takeuchi, Kazuhiko
author_sort Zhao, Weilin
collection PubMed
description BACKGROUND: Nasopharyngeal carcinoma (NPC) is a malignancy of the head and neck that is prevalent in Southeast Asia and southern China. Recent studies in epigenetics suggest that DNA methylation plays a pivotal role in the onset and progression of cancer. Combining the methyl-DNA binding domain capture technique and cDNA microarray analysis, we identified a unique hypermethylated gene, RERG (Ras-like estrogen-regulated growth inhibitor), that was down-regulated in NPC tissues. RERG is a tumor suppressor gene that was first reported in breast cancer. However, the functions of RERG are largely unknown in other tumor types. METHODS: RERG expression was assessed in human subjects (NPC primary tissues and non-cancer tissues) and cell lines (NPC cell lines and an immortalized epithelial cell line NP460). Further, we investigated the methylation rate of RERG in both human subject and cell lines. 5-Aza-2’-deoxycytidine (Aza) or combined with trichostatin A (TSA) were treated to three NPC cell lines (HK1, C666-1 and HK1_EBV). In addition, the role of RERG in NPC cells and its underlying mechanisms were explored by overexpression of RERG in NPC cell lines. RESULTS: RERG was significantly down-regulated in NPC cancer nests compared to normal nasopharyngeal epithelium cells. Furthermore, the RERG promoter was frequently methylated in NPC tissues and cell lines. The RERG methylation rate yielded an area under the curve (AUC) of receiver operating characteristic (ROC) curve was 0.897 (95%CI: 0.818–0.976). The down-regulation of RERG was restored in NPC cells treated with Aza and TSA. In addition, ectopic expression of RERG in NPC cell lines resulted in a significant suppression of cell proliferation, clonogenicity, migration and invasion. RERG-overexpressing cells showed significantly slower growth and less angiogenesis in tumor xenografts in nude mice. RERG suppressed the ERK/NF-κB signaling pathway and inhibited tumor growth and angiogenesis with down-regulation of MMPs and IL8 in tumors of nude mouse xenografts. CONCLUSIONS: Our results suggest that RERG is frequently silenced by promoter CpG methylation in NPC, and acts as a functional tumor suppressor by suppressing the ERK/NF-κB signaling pathway. These findings support the potential use of RERG as a novel molecular target in NPC therapy. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13046-017-0554-9) contains supplementary material, which is available to authorized users.
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spelling pubmed-54901522017-06-30 RERG suppresses cell proliferation, migration and angiogenesis through ERK/NF-κB signaling pathway in nasopharyngeal carcinoma Zhao, Weilin Ma, Ning Wang, Shumin Mo, Yingxi Zhang, Zhe Huang, Guangwu Midorikawa, Kaoru Hiraku, Yusuke Oikawa, Shinji Murata, Mariko Takeuchi, Kazuhiko J Exp Clin Cancer Res Research BACKGROUND: Nasopharyngeal carcinoma (NPC) is a malignancy of the head and neck that is prevalent in Southeast Asia and southern China. Recent studies in epigenetics suggest that DNA methylation plays a pivotal role in the onset and progression of cancer. Combining the methyl-DNA binding domain capture technique and cDNA microarray analysis, we identified a unique hypermethylated gene, RERG (Ras-like estrogen-regulated growth inhibitor), that was down-regulated in NPC tissues. RERG is a tumor suppressor gene that was first reported in breast cancer. However, the functions of RERG are largely unknown in other tumor types. METHODS: RERG expression was assessed in human subjects (NPC primary tissues and non-cancer tissues) and cell lines (NPC cell lines and an immortalized epithelial cell line NP460). Further, we investigated the methylation rate of RERG in both human subject and cell lines. 5-Aza-2’-deoxycytidine (Aza) or combined with trichostatin A (TSA) were treated to three NPC cell lines (HK1, C666-1 and HK1_EBV). In addition, the role of RERG in NPC cells and its underlying mechanisms were explored by overexpression of RERG in NPC cell lines. RESULTS: RERG was significantly down-regulated in NPC cancer nests compared to normal nasopharyngeal epithelium cells. Furthermore, the RERG promoter was frequently methylated in NPC tissues and cell lines. The RERG methylation rate yielded an area under the curve (AUC) of receiver operating characteristic (ROC) curve was 0.897 (95%CI: 0.818–0.976). The down-regulation of RERG was restored in NPC cells treated with Aza and TSA. In addition, ectopic expression of RERG in NPC cell lines resulted in a significant suppression of cell proliferation, clonogenicity, migration and invasion. RERG-overexpressing cells showed significantly slower growth and less angiogenesis in tumor xenografts in nude mice. RERG suppressed the ERK/NF-κB signaling pathway and inhibited tumor growth and angiogenesis with down-regulation of MMPs and IL8 in tumors of nude mouse xenografts. CONCLUSIONS: Our results suggest that RERG is frequently silenced by promoter CpG methylation in NPC, and acts as a functional tumor suppressor by suppressing the ERK/NF-κB signaling pathway. These findings support the potential use of RERG as a novel molecular target in NPC therapy. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13046-017-0554-9) contains supplementary material, which is available to authorized users. BioMed Central 2017-06-28 /pmc/articles/PMC5490152/ /pubmed/28659184 http://dx.doi.org/10.1186/s13046-017-0554-9 Text en © The Author(s). 2017 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
Zhao, Weilin
Ma, Ning
Wang, Shumin
Mo, Yingxi
Zhang, Zhe
Huang, Guangwu
Midorikawa, Kaoru
Hiraku, Yusuke
Oikawa, Shinji
Murata, Mariko
Takeuchi, Kazuhiko
RERG suppresses cell proliferation, migration and angiogenesis through ERK/NF-κB signaling pathway in nasopharyngeal carcinoma
title RERG suppresses cell proliferation, migration and angiogenesis through ERK/NF-κB signaling pathway in nasopharyngeal carcinoma
title_full RERG suppresses cell proliferation, migration and angiogenesis through ERK/NF-κB signaling pathway in nasopharyngeal carcinoma
title_fullStr RERG suppresses cell proliferation, migration and angiogenesis through ERK/NF-κB signaling pathway in nasopharyngeal carcinoma
title_full_unstemmed RERG suppresses cell proliferation, migration and angiogenesis through ERK/NF-κB signaling pathway in nasopharyngeal carcinoma
title_short RERG suppresses cell proliferation, migration and angiogenesis through ERK/NF-κB signaling pathway in nasopharyngeal carcinoma
title_sort rerg suppresses cell proliferation, migration and angiogenesis through erk/nf-κb signaling pathway in nasopharyngeal carcinoma
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5490152/
https://www.ncbi.nlm.nih.gov/pubmed/28659184
http://dx.doi.org/10.1186/s13046-017-0554-9
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