Ovarian Cancer: Epithelial Dedifferentiation

卵巢癌：上皮去分化

基本信息

批准号：
8776677
负责人：
XiangXi Mike Xu
金额：
$ 32.64万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-12-10 至 2016-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8776677
关键词：
Accounting Acetylation Aneuploidy Animals Autophagosome Benign Biology Cancer Biology Chromosomal Instability Cultured Cells Development Diagnostic Epithelial Epithelial Cells Epithelial ovarian cancer Etiology Funding GATA4 transcription factor Genes Growth Histones Human Investigation Knock-out Knockout Mice Lead Link Malignant Neoplasms Malignant neoplasm of ovary Modeling Modification Molecular Mus Mutation Nuclear Nuclear Envelope Ovarian Ovarian Carcinoma Ovarian Surface Epithelial-Stromal Tumor Phenotype Prognostic Marker Proteins Regulation Role Staging Surface TP53 gene Testing Therapeutic Tissues Transcriptional Regulation Tumor Biology base cancer cell caspase-6 cell growth chromatin modification deviant emerin env Gene Products in vivo insight mouse model multicatalytic endopeptidase complex mutant ovarian neoplasm protein degradation protein structure public health relevance research study tumor tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Cancer cells often appear in a deviant stage of differentiation, and dedifferentiation is a feature of malignancy. In the last funding period, we investigated the loss of the developmental transcription factors GATA4 and GATA6 in ovarian cancer development. The hypothesis was that the loss of GATA4 and GATA6 lead to the dedifferentiation phenotypes in ovarian cancer cells, and that the loss of GATA4 and GATA6 is an important causative factor in ovarian tumorigenesis. Our results show that aberrant chromatin modifications/histone hypo-acetylation account for the loss of GATA4 and GATA6 in ovarian cancer cells. We also established the role of GATA6 in regulating Dab2 and the consequent loss of Dab2 in epithelial transformation in our proposed experiments. In searching for additional GATA4 and GATA6-regulated effectors, we found in ovarian surface epithelial cells that suppression of GATA6 leads to nuclear morphological deformation and aneuploidy, two hallmarks of ovarian cancer cells. The close correlation between loss of GATA6 and nuclear deformation and aneuploidy was also correlated in human ovarian cancer. Preliminary studies also suggest that the loss of the nuclear envelope protein emerin may account for the nuclear morphological deformation and aneuploidy. We present a proposal to continue our study of the loss of GATA4 and GATA6 in the transformation and tumorigenesis of ovarian surface epithelial cells using conditional GATA6 knockout models (Aim 1). We also propose to investigate the in vivo consequence of emerin loss in ovarian surface epithelial cells (Aim 2), and the mechanism for the loss of emerin in ovarian cancer cells (Aim 3) with a hypothesis that loss of emerin causes nuclear morphological deformation and results in chromosomal numerical instability and subsequent ovarian tumorigenesis. These experiments may establish the role and mechanism for the loss of GATA4 and GATA6 in ovarian epithelial dedifferentiation and tumorigenesis. The further understanding will reveal the molecular details in the initiation and development of ovarian epithelial cancer, leading to development of more advanced diagnostic and therapeutic approaches.

描述（由申请人提供）：癌细胞通常出现在分化的偏差阶段，而去分化是恶性肿瘤的特征。在最后一个资金期间，我们研究了卵巢癌发展中GATA4和GATA6发育转录因子的损失。假设是GATA4和GATA6的丧失导致卵巢癌细胞的去分化表型，并且GATA4和GATA6的丧失是卵巢肿瘤发生的重要原因因素。我们的结果表明，异常的染色质修饰/组蛋白低乙酰化解释了卵巢癌细胞中GATA4和GATA6的丧失。我们还确定了GATA6在调节DAB2中的作用以及在我们提出的实验中，在上皮转化中导致DAB2的损失。在寻找其他GATA4和GATA6调节的效应子时，我们在卵巢表面上皮细胞中发现GATA6导致核形态变形和非整倍性，这是卵巢癌细胞的两个标志。在人类卵巢癌中，GATA6损失与核变形与非整倍性之间的密切相关性也相关。初步研究还表明，核包膜蛋白埃默林的丧失可能解释了核形态变形和非整倍性。我们提出了一项建议，以继续研究使用条件GATA6敲除模型的卵巢表面上皮细胞的转化和肿瘤发生中GATA4和GATA6的丧失（AIM 1）。我们还建议研究卵巢表面上皮细胞中烯蛋白损失的体内后果（AIM 2），以及卵巢癌细胞中胺烯蛋白丧失的机制（AIM 3），假设丝网膜蛋白会导致核形态变形和染色体数值不稳定性和卵形卵巢卵形的结果。这些实验可能会确定卵巢上皮降解和肿瘤发生中GATA4和GATA6丧失的作用和机制。进一步的理解将揭示卵巢上皮癌的启动和发展的分子细节，从而发展更先进的诊断和治疗方法。