Targeted Promoter Demethylation in Ovarian Cancer Cells

卵巢癌细胞中的靶向启动子去甲基化

基本信息

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
项目类别：
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

项目摘要

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 p150 蛋白（SALL2 基因的产物）在许多人类卵巢病例中观察到癌，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 DNA 复制中 p150 的一个新功能上，该功能尚未共享 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。