Epigenetic Changes during Ovarian Cancer Development and Progression : BRCA1 Methylation and S100A4 Hypomethylation

NDL Digital Collections 20 References
  • HORIUCHI,Akiko
    Department of Obstetrics and Gynecology, Shinshu University School of Medicine

Bibliographic Information

Other Title
  • (2)卵巣癌の発生および進展のエピジェネティクス解析 : BRCA1メチル化およびS100A4脱メチル化の臨床的意義(講演要旨,<特集>第60回学術講演会シンポジウム3「婦人科腫瘍とエピジェネティクス-臨床へのトランスレーション-」)

Search this article

Abstract

The epigenetic changes regulate gene expression. Although the importance of DNA methylation in the transcriptional silencing of tumor suppressor genes is recognized. Genome-wide hypomethylation has also been reported in human malignancy and has been associated with genetic instability. In this study, we analyzed both methylation of tumor suppressor gene, BRCA1 and hypomethylation of metastasis associated gene, S100A4. BRCA1 is a tumor suppressor which plays a crucial role in the repair of DNA damages, and its abnormality is responsible for hereditary ovarian cancer syndrome. To clarify the possible involvement of BRCA1 in the development of sporadic ovarian neoplasms, we analyzed the immunohistochemical expression of BRCA1 protein, loss of heterozygosity (LOH) and it's promoter methylation in normal ovarian surface epithelium (OSE) and 119 epithelial ovarian tumors. We showed that decreased expression of BRCA1 was observed in carcinomas and reduced expression of BRCA1 was correlated with methylation of BRCA1 promoter. These findings suggest that reduced expression of BRCA1 protein along with epigenetic changes might plays an important role in development of sporadic ovarian carcinomas. From prognostic analysis, ovarian carcinoma patients negative for BRCA1 expression showed favorable prognosis. To address if BRCA1 expression plays a role in the chemotherapeutic response, we analyzed the effect of BRCA1 suppression by siRNA on the sensitivity to cisplatin and paclitaxel in ovarian cancer cells. We found the reduced expression of BRCA1 enhances the cisplatin sensitivity and apoptosis. Accordingly, expression of BRCA1 might be an important biomarker for cisplatin resistance in ovarian carcinoma. Previously, we reported that hypoxia attenuates the "metastatic phenotypes" of ovarian cancer cells and found the increased expression of S100A4 under hypoxia. The S100A4 protein which belongs to calcium binding S100 protein family and has reportedly been associated with cell motility and invasion. In this study, we investigated expression of S100A4 and subcellular localization in 113 epithelial ovarian neoplasms and analyzed its prognostic significance in patients with ovarian carcinoma. Immunohistochemical analysis showed that both cytoplasmic and nuclear expressions of S100A4 were significantly stronger in carcinomas than those in benign and borderline tumors. Ovarian carcinoma patients with strong nuclear S100A4 expression showed a significantly shorter survival than those without. Moreover, the in vivo analysis showed that the nuclear expression of S100A4 is involved in the aggressive behavior of ovarian cancer cells. To analyze the mechanisms of S100A4 expression, we examined methylation of S100A4 by Bisulfite Sequence methods. Hypomethylation of these sequences was associated with overexpression of S100A4. Since hypoxia increased ovarian cancer invasiveness with increased S100A4 expression, we examined the change of methylation status of S100A under hypoxia. Hypoxia increase hypomethylation of S100A4 1^<St> intron and increased bindings between HIF-1α and hypomethylated hypoxia-response elements in S100A4 1^<St> intron. From our findings, up-regulation of S100A4 expression was associated with hypomethylation, along with increased the malignancy during the ovarian cancer progression.

Journal

References(20)*help

See more

Keywords

Details 詳細情報について

Report a problem

Back to top