Faculty Collaboration Database

Hypermethylation of miR-203 in endometrial carcinomas. Gynecol Oncol 2014 May;133(2):340-5

Date

02/18/2014

Pubmed ID

24530564

Pubmed Central ID

PMC4015135

DOI

10.1016/j.ygyno.2014.02.009

Scopus ID

2-s2.0-84899624704 (requires institutional sign-in at Scopus site)   50 Citations

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.

Author List

Huang YW, Kuo CT, Chen JH, Goodfellow PJ, Huang TH, Rader JS, Uyar DS

Authors

Janet Sue Rader MD Chair, Professor in the Obstetrics and Gynecology department at Medical College of Wisconsin
Denise S. Uyar MD Professor in the Obstetrics and Gynecology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adenocarcinoma, Clear Cell
Biomarkers, Tumor
Carcinoma, Endometrioid
Carcinoma, Squamous Cell
Case-Control Studies
Cell Line, Tumor
DNA Methylation
Endometrial Neoplasms
Endometrium
Female
Gene Expression Regulation, Neoplastic
Humans
MicroRNAs
Microsatellite Instability
Ovarian Neoplasms
Promoter Regions, Genetic
SOXC Transcription Factors
Uterine Cervical Neoplasms