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Int. J. Mol. Sci. 2015, 16(11), 27781-27795; doi:10.3390/ijms161126062

Epigenetic Repression of miR-218 Promotes Esophageal Carcinogenesis by Targeting ROBO1

1
Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing 210009, China
2
Huaian Center for Disease Control and Prevention, Huaian 223001, China
*
Author to whom correspondence should be addressed.
Academic Editor: Martin Pichler
Received: 30 September 2015 / Revised: 11 November 2015 / Accepted: 12 November 2015 / Published: 20 November 2015
(This article belongs to the Section Molecular Toxicology)
View Full-Text   |   Download PDF [2328 KB, uploaded 24 November 2015]   |  

Abstract

miR-218, consisting of miR-218-1 at 4p15.31 and miR-218-2 at 5q35.1, was significantly decreased in esophageal squamous cell carcinoma (ESCC) in our previous study. The aim of this study was to determine whether aberrant methylation is associated with miR-218 repression. Bisulfite sequencing analysis (BSP), methylation specific PCR (MSP), and 5-aza-2′-deoxycytidine treatment assay were applied to determine the methyaltion status of miR-218 in cells and clinical samples. In vitro assays were performed to explore the role of miR-218. Results showed that miR-218-1 was significantly CpG hypermethylated in tumor tissues (81%, 34/42) compared with paired non-tumor tissues (33%, 14/42) (p < 0.05). However, no statistical difference was found in miR-218-2. Accordingly, expression of miR-218 was negatively correlated with miR-218-1 methylation status (p < 0.05). After demethylation treatment by 5-aza-2′-deoxycytidine, there was a 2.53- and 2.40-fold increase of miR-218 expression in EC109 and EC9706, respectively. miR-218 suppressed cell proliferation and arrested cells at G1 phase by targeting 3′ untranslated region (3′UTR) of roundabout guidance receptor 1 (ROBO1). A negative correlation was found between miR-218 and ROBO1 mRNA expression in clinical samples. In conclusion, our results support that aberrant CpG hypermethylation at least partly accounts for miR-218 silencing in ESCC, which impairs its tumor-suppressive function. View Full-Text
Keywords: miR-218; CpG methylation; esophageal cancer; ROBO1 miR-218; CpG methylation; esophageal cancer; ROBO1
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Yang, M.; Liu, R.; Li, X.; Liao, J.; Pu, Y.; Pan, E.; Wang, Y.; Yin, L. Epigenetic Repression of miR-218 Promotes Esophageal Carcinogenesis by Targeting ROBO1. Int. J. Mol. Sci. 2015, 16, 27781-27795.

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