Hypermethylation of miR-203 in endometrial carcinomas

Yi Wen Huang, Chieh Ti Kuo, Jo Hsin Chen, Paul J. Goodfellow, Tim H.M. Huang, Janet S. Rader, Denise S. Uyar

Research output: Contribution to journalArticle

42 Scopus 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.

Original languageEnglish (US)
Pages (from-to)340-345
Number of pages6
JournalGynecologic Oncology
Volume133
Issue number2
DOIs
StatePublished - May 2014

Keywords

  • DNA methylation
  • Endometrial carcinoma
  • SOX4
  • miR-203

ASJC Scopus subject areas

  • Oncology
  • Obstetrics and Gynecology

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    Huang, Y. W., Kuo, C. T., Chen, J. H., Goodfellow, P. J., Huang, T. H. M., Rader, J. S., & Uyar, D. S. (2014). Hypermethylation of miR-203 in endometrial carcinomas. Gynecologic Oncology, 133(2), 340-345. https://doi.org/10.1016/j.ygyno.2014.02.009