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（由申请人提供）：子宫内膜癌（EMC）是一种女性死亡率高的恶性疾病。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，以确定新的诊断/预后标志物和治疗靶点。NCOA 6是一种与多种转录因子（TF）协同作用以增强基因表达的共激活因子，在EMCs中似乎经常发生突变和下调。在小鼠子宫内膜上皮细胞和间质细胞中条件性敲除（KO）Ncoa 6可导致雌激素超敏感性、子宫上皮增生和自发性EMC的发生。仅在子宫内膜EC中KO Ncoa 6也触发了EMC的发展。Ncoa 6 KO降低DUSP 6和PTPRF的表达，这两种磷酸酶抑制MAPK和PI 3 K/AKT途径。NCOA 6 KO还增加PRKCD的表达，PRKCD是一种激活Raf-ERK途径并刺激细胞迁移和趋化性的PKC激酶。我们推测NCOA 6是一种新的EMC抑癌基因，它通过调控雌激素、MAPK和PI 3 K/AKT刺激EC增殖和癌变而发挥作用。在目标1中，我们将定义NCOA 6在抑制雌激素促进的EMC发展中的具体作用。将产生具有和不具有子宫内膜Ncoa 6 KO的转基因小鼠，以检查在不同雌激素条件下，Ncoa 6功能的丧失将如何触发和促进具有和不具有Pten表达的子宫内膜中的自发EMC发展。还将产生具有阻止Ncoa 6与ERα相互作用的Ncoa 6突变的转基因小鼠，以测试Ncoa 6是否依赖于与ERα的相互作用来抑制雌激素促进的EMC发展。在目标2中，我们将剖析负责NCOA 6介导的EMC抑制的基本细胞和分子机制。具体来说，我们将使用生物信息学和实验方法来鉴定与NCOA 6一起调节DUSP 6，PRPTF和PRKCD基因的TF。我们还将使用EMC细胞系和异种移植肿瘤生长小鼠模型来确定NCOA 6调节的这3种基因表达对MAPK和AKT活性以及EMC细胞增殖、迁移、侵袭和肿瘤生长能力的功能影响。在目标3中，我们 明确NCOA 6表达谱及其在人子宫内膜肿瘤临床亚型中的预后价值。我们将半定量测量这些标本中的NCOA 6蛋白表达水平，并确定NCOA 6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性/关联关系。这些研究将产生重大影响，建立作为EMC抑制剂，并探讨其工作机制。这些研究还可能表明NCOA 6是EMC进展的诊断和预后标志物，并提供了恢复NCOA 6功能或其调节途径作为治疗策略的临床前原则概念。