Yonsei Med J.  2014 Sep;55(5):1206-1213. 10.3349/ymj.2014.55.5.1206.

Overexpression of Mucin 13 due to Promoter Methylation Promotes Aggressive Behavior in Ovarian Cancer Cells

• Sung HY
• Park AK
• Ju W
• Ahn JH

• KMID: 1799482
• DOI: http://doi.org/10.3349/ymj.2014.55.5.1206

Abstract

PURPOSE
Recent discoveries suggest that aberrant DNA methylation provides cancer cells with advanced metastatic properties. However, the precise regulatory mechanisms controlling metastasis genes and their role in metastatic transformation are largely unknown. To address epigenetically-regulated gene products involved in ovarian cancer metastasis, we examined the mechanisms regulating mucin 13 (MUC13) expression and its influence on aggressive behaviors of ovarian malignancies.
MATERIALS AND METHODS
We injected SK-OV-3 ovarian cancer cells peritoneally into nude mice to mimic human ovarian tumor metastasis. Overexpression of MUC13 mRNA was detected in metastatic implants from the xenografts by expression microarray analysis and quantitative reverse-transcription polymerase chain reaction (qRT-PCR). The DNA methylation status within the MUC13 promoter region was determined using bisulfite sequencing PCR and quantitative methylation-specific PCR. We evaluated the effects of exogenous MUC13 on cell invasion and migration using in vitro transwell assays.
RESULTS
MUC13 mRNA expression was up-regulated, and methylation of specific CpG sites within the promoter was reduced in the metastatic implants relative to those in wild-type SK-OV-3 cells. Addition of a DNA methyltransferase inhibitor to SK-OV-3 cells induced MUC13 expression, thereby implying epigenetic regulation of MUC13 by promoter methylation. MUC13 overexpression increased migration and invasiveness, compared to control cells, suggesting aberrant up-regulation of MUC13 is strongly associated with progression of aggressive behaviors in ovarian cancer.
CONCLUSION
We provide novel evidence for epigenetic regulation of MUC13 in ovarian cancer. We suggest that the DNA methylation status within the MUC13 promoter region may be a potential biomarker of aggressive behavior in ovarian cancer.

Keyword

Ovarian cancer; mouse xenograft; MUC13; DNA methylation

MeSH Terms

Animals
Cell Line, Tumor
*DNA Methylation
Epigenesis, Genetic
Female
*Gene Expression Regulation, Neoplastic
Heterografts/metabolism
Humans
Mice
Mice, Nude
Mucins/*genetics/metabolism/physiology
Neoplasm Invasiveness/genetics
Ovarian Neoplasms/genetics/*metabolism/pathology
RNA, Messenger/metabolism
Mucins
RNA, Messenger

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