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Aberrant Hypomethylation of Solute Carrier Family 6 Member 12 Promoter Induces Metastasis of Ovarian Cancer
- Aberrant Hypomethylation of Solute Carrier Family 6 Member 12 Promoter Induces Metastasis of Ovarian Cancer
- Sung, Hye Youn; Yang, San-Duk; Park, Ae Kyung; Ju, Woong; Ahn, Jung-Hyuck
- Ewha Authors
- 주웅; 안정혁; 성혜윤
- SCOPUS Author ID
- 주웅; 안정혁; 성혜윤
- Issue Date
- Journal Title
- YONSEI MEDICAL JOURNAL
- 0513-5796; 1976-2437
- vol. 58, no. 1, pp. 27 - 34
- Ovarian cancer; metastasis; mouse xenograft; SLC6A12; DNA methylation
- YONSEI UNIV COLL MEDICINE
- SCI; SCIE; SCOPUS; KCI
- Purpose: Ovarian cancer (OC) is the most fatal of gynecological malignancies with a high rate of recurrence. We aimed to evaluate the expression of solute carrier family 6, member 12 (SLC6A12) and methylation of its promoter CpG sites in a xenograft mouse model of metastatic OC, and to investigate the regulatory mechanisms that promote aggressive properties during OC progression. Materials and Methods: Expression of SLC6A12 mRNA was determined by reverse-transcription quantitative polymerase chain reaction (RT-qPCR), and DNA methylation status of its promoter CpGs was detected by quantitative methylation-specific PCR. The metastatic potential of SLC6A12 was evaluated by in vitro migration/invasion transwell assays. Gene expression and DNA methylation of SLC6A12 and clinical outcomes were further investigated from publicly available databases from curatedOvarianData and The Cancer Genome Atlas. Results: SLC6A12 expression was 8.1-14.0-fold upregulated and its DNA methylation of promoter CpG sites was 41-62% decreased in tumor metastases. After treatment with DNA methyltransferase inhibitor and/ or histone deacetylase inhibitor, the expression of SLC6A12 was profoundly enhanced (similar to 8.0-fold), strongly supporting DNA methylation-dependent epigenetic regulation of SLC6A12. Overexpression of SLC6A12 led to increased migration and invasion of ovarian carcinoma cells in vitro, approximately 2.0-fold and 3.3-fold, respectively. The meta-analysis showed that high expression of SLC6A12 was significantly associated with poor overall survival [hazard ratio (HR)=1.07, p value=0.016] and that low DNA methylation levels of SLC6A12 at specific promoter CpG site negatively affected patient survival. Conclusion: Our findings provide novel evidence for the biological and clinical significance of SLC6A12 as a metastasis-promoting gene.
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