NCOA6, A Novel Tumor Suppressor of Endometrial Cancer

NCOA6，子宫内膜癌的新型肿瘤抑制因子

基本信息

批准号：
9030156
负责人：
JIANMING XU
金额：
$ 37.4万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-12-01 至 2020-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9030156
关键词：
Apoptosis Automobile Driving Binding Binding Sites Bioinformatics Cancer cell line Cell Line Cell Proliferation ChIP-seq Chemotaxis Clinical DUSP6 protein Data Databases Development Diagnosis Diagnostic Diagnostic Neoplasm Staging Disease Down-Regulation Endometrial Endometrial Carcinoma Endometrial Hyperplasia Endometrial Neoplasms Endometrial adenocarcinoma Endometrium Epithelial Epithelial Cell Proliferation Epithelial Cells Estradiol Estrogen Receptor alpha Estrogens Event Exhibits Gene Expression Gene Targeting Genes Growth Growth and Development function Human Hyperplasia Immunohistochemistry Insulin Insulin Receptor Insulin-Like Growth Factor I Knock-out Knockout Mice MAP Kinase Gene MAPK3 gene Malignant - descriptor Malignant Neoplasms Measures Mediating Menopause Methodology Molecular Molecular Profiling Molecular Target Mus Mutate Mutation NCOA6 gene Neoplasm Metastasis Nuclear Receptors Oncogenic Ovariectomy PI3K/AKT PTEN gene Pathway interactions Patients Phosphoric Monoester Hydrolases Phosphotransferases Progesterone Prognostic Marker Proto-Oncogene Proteins c-akt Protocols documentation Recurrence Regulatory Pathway Repression Research Design Role Somatic Mutation Specimen Stromal Cells Survival Rate Testing The Cancer Genome Atlas Therapeutic Time Transgenic Mice Tumor Suppressor Proteins Tumor stage Up-Regulation Uterus Woman Work Xenograft procedure age related base cancer cell cancer initiation cancer risk carcinogenesis cell motility chromatin immunoprecipitation follow-up functional restoration knock-down migration molecular marker mortality mouse model natural Blastocyst Implantation novel novel diagnostics overexpression pre-clinical prevent progesterone receptor positive prognostic prognostic value protein expression public health relevance therapeutic target transcription factor transcriptome sequencing tumor tumor growth tumor progression

项目摘要

DESCRIPTION (provided by applicant): Endometrial cancer (EMC) is a malignant disease with high mortality in women. About 50,000 women in USA are annually diagnosed with EMC and ~8200 women die of this disease yearly. Thus, it is urgent to study the key molecular drivers and suppressors of EMC initiation, growth and metastasis for identifying new diagnostic/prognostic markers and therapeutic targets. NCOA6, a coactivator that works with multiple classes of transcription factors (TFs) to potentiate gene expression, appears to be frequently mutated and down- regulated in EMCs. Conditional knockout (KO) of Ncoa6 in the mouse endometrial epithelial (EC) and stromal cells causes estrogen super sensitivity, uterine epithelial hyperplasia and spontaneous EMC development. KO of Ncoa6 only in the endometrial ECs also triggered EMC development. Ncoa6 KO decreases the expression of DUSP6 and PTPRF, two phosphatases that inhibit the MAPK and PI3K/AKT pathways. NCOA6 KO also increases the expression of PRKCD, a PKC kinase that activates the Raf-ERK pathway and simulates cell migration and chemotaxis. We hypothesize that NCOA6 is a novel tumor suppressor of EMC, and it functions through controlling estrogen, MAPK and PI3K/AKT stimulated EC proliferation and carcinogenesis. In Aim 1, we will define the specific role of NCOA6 in suppressing estrogen-promoted EMC development. Transgenic mice with and without endometrial Ncoa6 KO will be produced to examine how the loss of Ncoa6 function will trigger and promote spontaneous EMC development in the endometrium with and without Pten expression under different estrogen conditions. Transgenic mice with a Ncoa6 mutation that prevents Ncoa6 interact with ERα will also be generated to test whether Ncoa6 relies on the interaction with ERα to suppress estrogen- promoted EMC development. In Aim 2, we will dissect the basic cellular and molecular mechanisms responsible for NCOA6-mediated repression of EMC. Specifically, we will use both bioinformatic and experimental approaches to identify TFs working with NCOA6 to regulate DUSP6, PRPTF and PRKCD genes. We will also use EMC cell lines and xenograft tumor growth mouse models to define the functional impacts of NCOA6-regulated expression of these 3 genes on the activities of MAPKs and AKT and on the capabilities of EMC cell proliferation, migration, invasion and tumor growth. In Aim 3, we will define the NCOA6 expression profile and its prognostic value in clinical subtypes of human endometrial tumors. We will semi-quantitatively measure NCOA6 protein expression levels in these specimens and determine the correlation/association relationships between NCOA6 expression levels and tumor grades, tumor stages, disease recurrence time or survival rates. These studies should generate significant impacts by establishing NCOA6 as an EMC suppressor and exploring its working mechanisms. These studies may also suggest NCOA6 as a diagnostic and a prognostic marker for EMC progression and offer a pre-clinical concept of principle to restore the function of NCOA6 or its regulatory pathways as a therapeutic strategy.

描述（由适用提供）：子宫内膜癌（EMC）是一种恶性疾病，女性死亡率很高。每年在美国约有50,000名妇女被诊断出患有EMC，每年约有8200名妇女死于这种疾病。这是迫切需要研究EMC计划的关键分子驱动因素和补充，以鉴定新的诊断/预后标记和治疗靶标。 NCOA6是一种与潜在基因表达的多种转录因子（TF）一起工作的共激活因子，在EMC中似乎经常被突变和下调。小鼠子宫内膜上皮（EC）和基质细胞中NCOA6的条件敲除（KO）会导致雌激素超敏感性，子宫上皮增生和赞助EMC的发育。仅在子宫内膜EC中，NCOA6的KO也触发了EMC的开发。 NCOA6 KO降低了DUSP6和PTPRF的表达，这两种磷酸酶抑制了MAPK和PI3K/AKT途径。 NCOA6 KO还增加了PRKCD的表达，PRKCD是一种激活RAF-ERK途径并模拟细胞迁移和趋化性的PKC激酶。我们假设NCOA6是EMC的新型肿瘤抑制剂，它通过控制雌激素，MAPK和PI3K/AKT刺激EC的增殖和癌变来发挥作用。在AIM 1中，我们将定义NCOA6在抑制雌激素促进的EMC发育中的特定作用。将产生有或没有子宫内膜NCOA6 KO的转基因小鼠，以检查NCOA6功能的损失将如何触发并促进子宫内膜中的赞助商自发EMC发育，并在不同的雌激素条件下有和不具有PTEN表达。 NCOA6突变的转基因小鼠还将生成NCOA6与ERα相互作用的转基因小鼠，以测试NCOA6是否依赖于与ERα的相互作用来抑制雌激素促进EMC的发展。在AIM 2中，我们将剖析负责NCOA6介导的EMC表示的基本细胞和分子机制。具体而言，我们将使用生物信息学和实验方法来识别与NCOA6一起使用的TF来调节DUSP6，PRPTF和PRKCD基因。我们还将使用EMC细胞系和异种移植肿瘤生长小鼠模型来定义这三个基因对MAPK和AKT的活性以及EMC细胞增殖，迁移，入侵和肿瘤生长的功能的NCOA6调节表达的功能影响。在AIM 3中，我们将定义NCOA6表达谱及其在人子宫内膜肿瘤的临床亚型中的预后价值。我们将在这些物种的NCOA6蛋白表达水平上进行半定量测量，并确定NCOA6表达水平与肿瘤级别，肿瘤阶段，疾病复发时间或存活率之间的相关/关联关系。这些研究应通过建立NCOA6作为EMC抑制器并探索其工作机制来产生重大影响。这些研究还可能表明NCOA6是EMC进展的诊断和预后标记，并提供了临床前原理概念，以恢复NCOA6或其调节途径作为治疗策略的功能。