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Gynecol Oncol. 2014 May;133(2):340-5. doi: 10.1016/j.ygyno.2014.02.009. Epub 2014 Feb 14.

Hypermethylation of miR-203 in endometrial carcinomas.

Author information

1
Department of Obstetrics and Gynecology, Medical College of Wisconsin, Milwaukee, WI 53226, USA. Electronic address: ywhuang@mcw.edu.
2
Department of Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
3
Department of Obstetrics and Gynecology, The Ohio State University, Columbus, OH 43210, USA.
4
Department of Molecular Medicine and Cancer Therapy & Research Center, University of Texas Health Science Center, San Antonio, TX 78229, USA.
5
Department of Obstetrics and Gynecology, Medical College of Wisconsin, Milwaukee, WI 53226, USA.

Abstract

OBJECTIVES:

Aberrant expression of SOX4 in endometrial cancer has been identified and partially was contributed to hypermethylation of miR-129-2. Other miRNAs are suspected to influence SOX 4 as well. The current study seeks to identify other hypermethylated miRNAs that regulate SOX4 in endometrial carcinomas.

METHODS:

Methylation levels of miRNA promoter regions were measured by combined bisulfite restriction analysis (COBRA) and pyrosequencing assays. Gene expression was determined by RT-qPCR. Methylation level of a miRNA locus was corrected with clinicopathologic factors for 252 gynecological specimens.

RESULTS:

In silico analysis identified 13 miRNA loci bound on the 3'-UTR of SOX4. Using COBRA assays, increased methylation of miR-203, miR-219-2, miR-596, and miR-618 was detected in endometrial cancer cells relative to those seen in a normal cell line and in normal endometrium. Transfection of a miR-203 mimic decreased SOX4 gene expression. Hypermethylation of miR-203 was detected in 52% of type I endometrioid endometrial carcinomas (n=131) but was not seen in any of 10 uninvolved normal endometria (P<0.001). Methylation status of miR-203 was significantly associated with microsatellite instability and MLH1 methylation in endometrial tumors (P<0.001). Furthermore, hypermethylation of miR-203 was found in endometrioid and clear endometrial subtype tumors, but not in cervical squamous cell and ovarian carcinomas.

CONCLUSIONS:

Hypermethylation of miR-203 is a frequent event in endometrial carcinomas and is strongly associated with microsatellite instability and MLH1 methylation status. Thus, miR-203 methylation level might represent a marker for patients with endometrioid and clear endometrial sub-cancers.

KEYWORDS:

DNA methylation; Endometrial carcinoma; SOX4; miR-203

PMID:
24530564
PMCID:
PMC4015135
DOI:
10.1016/j.ygyno.2014.02.009
[Indexed for MEDLINE]
Free PMC Article
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