NCOA6, A Novel Tumor Suppressor of Endometrial Cancer

NCOA6，子宫内膜癌的新型肿瘤抑制因子

• 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
• 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

 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(申请人提供)：子宫内膜癌(EMC)是一种死亡率很高的女性恶性疾病。在美国，每年约有50,000名妇女被诊断患有EMC，每年约有8200名妇女死于这种疾病。因此，迫切需要研究EMC启动、生长和转移的关键分子驱动因子和抑制因子，以寻找新的诊断/预后标志物和治疗靶点。NCOA6是一种共激活因子，可与多种转录因子(TF)协同作用，增强基因表达，在EMCs中似乎经常发生突变和下调。Ncoa6在小鼠子宫内膜上皮(EC)和间质细胞中的条件性基因敲除(KO)导致雌激素超敏、子宫上皮增生和自发的EMC发展。仅在子宫内膜上皮细胞中Ncoa6的KO也触发了EMC的发生。Ncoa6 KO降低DUSP6和PTPRF的表达，这两种磷酸酶抑制MAPK和PI3K/AKT通路。NCOA6 KO还增加了PRKCD的表达，这是一种激活Raf-ERK途径并模拟细胞迁移和趋化的PKC激酶。我们推测NCOA6是EMC的一种新的肿瘤抑制因子，它通过调控雌激素、MAPK和PI3K/AKT刺激EC增殖和致癌而发挥作用。在目标1中，我们将确定NCOA6在抑制雌激素促进的EMC发育中的具体作用。我们将建立带有和不带有子宫内膜Ncoa6 KO的转基因小鼠，研究在不同的雌激素条件下，Ncoa6功能的丧失如何在有和没有Pten表达的子宫内膜中触发和促进自发的EMC发育。还将产生带有阻止Ncoa6与ERα相互作用的Ncoa6突变的转基因小鼠，以测试Ncoa6是否依赖与ERα的相互作用来抑制雌激素促进的EMC发育。在目标2中，我们将剖析NCOA6介导的EMC抑制的基本细胞和分子机制。具体地说，我们将使用生物信息学和实验方法来确定与NCOA6一起调节DUSP6、PRPTF和PRKCD基因的转录因子。我们还将利用EMC细胞系和移植瘤小鼠模型来研究NCOA6调控的这3个基因的表达对MAPKs和AKT活性的功能影响，以及对EMC细胞的增殖、迁移、侵袭和肿瘤生长能力的影响。在《目标3》中，我们将 明确NCOA6在人类子宫内膜肿瘤临床亚型中的表达谱及其预后价值。我们将半定量检测这些标本中NCOA6蛋白的表达水平，并确定NCOA6表达水平与肿瘤分级、肿瘤分期、疾病复发时间或生存率之间的相关/关联关系。这些研究应该通过确立NCOA6作为EMC抑制因子并探索其工作机制来产生重大影响。这些研究还可能建议NCOA6作为EMC进展的诊断和预后标记物，并提供临床前的原则性概念，以恢复NCOA6的功能或其调节通路作为治疗策略。