The Role of Aberrant Epigenetic Alteration of the TGF-β Targets FBXO32 and ABCA1 In Ovarian Cancer

• Main Authors: Jian-Liang Chou, 周建良
• Other Authors: Michael W Chan
• Format: Others
• Language: en_US
• Published: 2013
• Online Access: http://ndltd.ncl.edu.tw/handle/19886517080024773013

博士 === 國立中正大學 === 分子生物研究所 === 101 === The Dysregulation of TGF-β signaling plays a key role in ovarian carcinogenesis and maintaining cancer stem cell properties. In this study, we utilized previous ChIP-chip, mDIP-chip, and expression array data to identify TGF-β/SMAD4 relative genes: FBXO32 and ABCA1. In the first part of study, we found that expression of FBXO32 was observed in normal ovarian surface epithelium but not in ovarian cancer cell lines. FBXO32 methylation was seen in ovarian cancer cell lines, and epigenetic drug treatment restored FBXO32 expression in ovarian cancer cell lines, suggesting that epigenetic modifications regulate the expression of this gene in ovarian cancer. In advanced stage ovarian tumors, significant (29.3%; p<0.05) methylation frequency of FBXO32 was observed and the association between FBXO32 methylation and shorter progression free survival was significant (Kaplan-Meier, p<0.05). Re-expression of FBXO32 markedly reduced proliferation of ovarian cancer line both in vitro and in vivo, due to increased apoptosis of the cells, and resensitized ovarian cancer cells to cisplatin. In the second part of the study, we identified ABCA1 by mDIP-Chip which was methylated in ovarian cancer cell line, A2780 and CP70. ABCA1 was expressed not only in IOSE, but in HeyC2, SKOV3, MCP3, and MCP2 ovarian cancer cell lines. In A2780 and CP70 ovarian cancer cell line, ABCA1 was down-regulated and was associated with promoter hypermethylation as demonstrated by bisulfite pyro-sequencing. Analysis of ABCA1 methylation in 8 normal OSE and 76 ovarian cancer patient samples demonstrated that patients with higher ABCA1 methylation is associated with high stage and high grade (p=0.0169 vs. p=0.0024). Importantly, patients with higher methylation of ABCA1 have shorter progression free survival (p=0.09) and overall survival (p=0.016). In conclusion, both of FBXO32 and ABCA1 were repressed by DNA methylation in ovarian cancer, and hypermethylation of them was associated with poor prognosis in cancer patients.