Epigenetic regulation research in ovarian cancer

• Main Authors: Su Her-Young, 蘇河仰
• Other Authors: Yu Mu-Hsien
• Format: Others
• Language: zh-TW
• Published: 2009
• Online Access: http://ndltd.ncl.edu.tw/handle/16619065316780351055

博士 === 國防醫學院 === 醫學科學研究所 === 98 === Aberrant CpG island hypermethylation is a common finding of cancers, which might be detectable in the tissue or serum of affected patients. We analyzed DNA methylation by methylation specific polymerase chain reaction of 7 genes, including secreted frizzled receptor proteins 1, 2, 4, 5 (SFRP1, 2, 4, 5), SRYbox 1 (SOX1), paired box gene 1 (PAX1) and LIM homeobox transcription factor 1, alpha (LMX1A) in primary tumor samples from 126 patients with ovarian cancer, 75 with benign tumor and 14 with borderline malignancy of an ovarian tumor, and in the serum from 26 patients with ovarian cancer and 20 with a benign tumor. Six of 7 genes had higher frequency of methylation in patients with ovarian cancer than in borderline malignancy or benign tumor (p <0.001). The methylation of SFRP1, SFRP2, SOX1 and LMX1A genes correlated with recurrence and overall survival of ovarian cancer patients. Combining the data for SFRP1, SFRP2 and SOX1 genes gave a relative risk for recurrence of 3.19 (p < 0.013) in patients with at least one gene methylation, and combining the data for SFRP1, SOX1 and LMX1A gave an RR for cancer-related death of 6.09 (p <0.010). Methylation analysis of tissues and serum revealed a significant correlation (kappa values, 0.332–0.598) and a highly sensitivity and specificity rates (73.08 and 75%) as a screening marker. Promoter hypermethylation of specific genes in critical pathways is common in ovarian cancer and has potential as a prognostic factor and a promising serum marker for early screening. Oncogenic activation of the Wnt signaling pathway is common in cancers, but mutation of β-catenin in ovarian cancer is rare. In addition to genetic events, epigenetic modification of secreted frizzled-related protein (SFRPs) family has been shown to be important in regulating Wnt signaling. Although high degree of homology in the same family, different SFRPs may have opposing effects on the same process. We reported recently that a Wnt antagonist, SFRP5, is downregulated frequently through promoter hypermethylation and that this hypermethylation is associated with overall survival in ovarian cancer. The aim of the present study was to analyze the function of SFRP5 in ovarian cancer. Functional assays including measuring cell proliferation, invasion, colony formation, and xenograft were performed using ovarian cancer cell lines with overexpression of SFRP5 or a short hairpin RNA (shRNA) silencing. The methylation status of SFRP5 in relation to cisplatin resistance in ovarian cancer patients was analyzed. Our data suggested that epigenetic silencing of SFRP5 leads to oncogenic activation of the Wnt pathway and contributes to ovarian cancer progression and chemoresistance through the TWIST-mediated EMT and AKT2 signaling.