Targeted Promoter Demethylation in Ovarian Cancer Cells

摘要 卵巢癌是所有妇科恶性肿瘤中最致命的，据估计是导致 每年有超过12.5万名妇女死亡。长期存活率并没有得到改善，因为 卵巢癌仍然缺乏令人满意的靶向治疗的生物标志物，这表明 更好的诊断和治疗工具对治疗这种妇科疾病的意义。损失 在许多人卵巢组织中观察到P150蛋白(SALL2基因产物)的表达 而正常卵巢上皮细胞维持高水平的P150，支持 P150在人卵巢中的重要肿瘤抑制作用。P150和P53蛋白 通过独立地诱导p21Cip1/Waf1和Bax来分享生长停滞和促凋亡功能， 而这两种蛋白都是人乳头瘤病毒16型的靶标，导致阻断 感染细胞的生长受阻。因此，P150似乎具有很强的小说潜力 肿瘤生物标记物用于早期诊断和风险预测，但其在调控中的作用 到目前为止，癌细胞生长的机制还没有得到充分的研究。在这项研究中，我建议 为了将我们的研究重点放在P150在DNA复制中的一种新功能上，这是一种没有共享的功能 通过P53或其他已知的肿瘤抑制因子(特异性靶标I)。我们还寻求开发一种新的 选择性靶向人卵巢癌SALL2启动子的表观遗传学技术 (具体目标二)。拟议研究的完成结果将使这一发现成为可能 P150在抑制人卵巢细胞DNA复制中的新作用。建议数 研究项目还将使我们能够对表观遗传学有一个丰富和广泛适用的理解。 抑制癌细胞生长的技术。

ABSTRACT Ovarian cancer is the deadliest of all gynecologic malignancies, estimated to be the cause of death in more than 125,000 women annually. Long-term survival rates have not improved as ovarian cancer continues to lack satisfying biomarkers for targeted therapies, demonstrating the significance of better diagnostic and therapeutic tools to treat this gynecological disease. Loss of the p150 protein (product of SALL2 gene) is observed in many cases of human ovarian carcinoma, whereas normal ovarian epithelial cells maintain high levels of p150, supporting an important tumor suppressive role for p150 in the human ovary. The p150 and p53 proteins share growth arrest and pro-apoptotic functions by independently inducing p21Cip1/Waf1 and BAX, and both proteins are targeted by human papilloma virus type 16, resulting in blockage of growth arrest in infected cells. Therefore, p150 seems to have strong potential as a novel cancer biomarker for early diagnosis and risk prediction, but its roles in the regulatory mechanisms of cancer cell growth have not been fully examined to date. In this study, I propose to focus our investigation on a novel function of p150 in DNA replication, a function not shared by p53 or other known tumor suppressors (Specific Aim I). We also seek to develop a new epigenetic technology that selectively targets the SALL2 promoter in human ovarian carcinomas (Specific Aim II). Results from the completion of the proposed studies will enable the discovery of new roles of p150 in inhibition of DNA replication in human ovarian cells. The proposed research projects will also enable a rich and widely-applicable understanding of epigenetic technologies for the suppression of cancer cell growth.