Targeted Promoter Demethylation in Ovarian Cancer Cells

卵巢癌细胞中的靶向启动子去甲基化

• 批准号: 9279642
• 负责人: Chang Kyoo Sung
• 金额: $ 13.8万
• 依托单位: TEXAS A&M UNIVERSITY-KINGSVILLE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9279642
• 关键词: Apoptosis; Apoptotic; BAX gene; Binding; Biological Assay; Bromodeoxyuridine; Cancer Cell Growth; Cause of Death; Cell Cycle Arrest; Cell Cycle Progression; Cell Cycle Regulation; Cells; Chromatin; Clustered Regularly Interspaced Short Palindromic Repeats; Complex; CpG Islands; DNA Replication Inhibition; DNA biosynthesis; DNA replication origin; Data; Development; Diagnostic; Early Diagnosis; Epigenetic Process; Epithelial Cells; Female Genital Diseases; Gene Activation; Genes; Genetic Transcription; Goals; Growth; Human; Human Papillomavirus; Human papillomavirus 16; Immunoblotting; Investigation; Lead; Licensing; Licensing Factor; MCM2 gene; Maintenance; Malignant Epithelial Cell; Malignant Female Reproductive System Neoplasm; Malignant Neoplasms; Malignant neoplasm of ovary; Methylation; Morbidity - disease rate; Oncogenic; Ovarian; Ovarian Carcinoma; Ovarian Serous Adenocarcinoma; Ovarian Serous Tumor; Ovary; Pathway interactions; Promoter Regions; Protein p53; Proteins; Recruitment Activity; Regulation; Research Project Grants; Research Proposals; Risk; Role; SKOV3 cells; Serous; Survival Rate; System; TP53 gene; Technology; Testing; Therapeutic; Transcription Coactivator; Translations; Tumor Suppressor Proteins; United States; Woman; Xenopus; Xenopus oocyte; Zinc Fingers; base; cancer biomarkers; cancer cell; demethylation; egg; helicase; human DNA; mortality; mouse polyomavirus; mutant; new technology; novel; novel marker; novel therapeutics; promoter; pyrosequencing; targeted biomarker; targeted treatment; tool; transcription factor; tumor; vector

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.

抽象的 卵巢癌是所有妇科恶性肿瘤中最致命的，估计是导致 每年有超过 125,000 名女性死亡。长期生存率并未提高 卵巢癌仍然缺乏令人满意的靶向治疗生物标志物，这表明 更好的诊断和治疗工具对治疗这种妇科疾病具有重要意义。损失 在许多人类卵巢病例中观察到 p150 蛋白（SALL2 基因的产物）的存在 癌，而正常卵巢上皮细胞维持高水平的 p150，支持 p150 在人类卵巢中具有重要的肿瘤抑制作用。 p150 和 p53 蛋白 通过独立诱导 p21Cip1/Waf1 和 BAX 来共享生长停滞和促凋亡功能， 这两种蛋白都是 16 型人乳头瘤病毒的靶标，导致 受感染细胞生长停滞。因此，p150作为小说似乎有很强的潜力 用于早期诊断和风险预测的癌症生物标志物，但其在监管中的作用 迄今为止，癌细胞生长的机制尚未得到充分研究。在这项研究中，我建议 将我们的研究重点放在 p150 在 DNA 复制中的一个新功能上，这是一个尚未共享的功能 p53 或其他已知的肿瘤抑制因子（具体目标 I）。我们还寻求开发一种新的 选择性靶向人类卵巢癌中 SALL2 启动子的表观遗传技术 （具体目标二）。完成拟议研究的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。拟议的 研究项目还将促进对表观遗传学的丰富且广泛应用的理解 抑制癌细胞生长的技术。