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：
10057354
负责人：
JIANMING XU
金额：
$ 28.75万
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 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10057354
关键词：
Aging Apoptosis Automobile Driving Binding Binding Sites Bioinformatics Cancer cell line Cell Line Cell Proliferation ChIP-seq Chemotaxis DUSP6 protein Data Databases Development Diagnosis Diagnostic 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 Genes Genetic Transcription 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 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 Role Somatic Mutation Specimen Statistical Data Interpretation Stromal Cells Survival Rate Testing The Cancer Genome Atlas Therapeutic Time Transgenic Mice Tumor Suppressor Proteins Tumor stage Up-Regulation Uterus Woman Work base cancer cell cancer initiation cancer risk carcinogenesis cell motility chromatin immunoprecipitation clinical diagnostics clinical subtypes conditional knockout design follow-up functional restoration immunoreactivity 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 tumor xenograft

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（由申请人提供）：子宫内膜癌（EMC）是一种女性死亡率很高的恶性疾病，美国每年约有 50,000 名女性被诊断患有 EMC，每年约有 8200 名女性死于这种疾病。 EMC 起始、生长和转移的关键分子驱动因素和抑制因素，用于识别新的诊断/预后标记物和治疗靶标，NCOA6 是一种与多种转录因子一起作用的共激活剂。小鼠子宫内膜上皮 (EC) 和基质细胞中 Ncoa6 的条件性敲除 (KO) 会导致雌激素超敏感性、子宫上皮增生和自发性 EMC 发展。仅在子宫内膜 EC 中敲除 Ncoa6 也会引发 EMC 发展。 PTPRF 是两种抑制 MAPK 和 PI3K/AKT 通路的磷酸酶，NCOA6 KO 还会增加 PRKCD 的表达，PRKCD 是一种激活 Raf-ERK 通路并模拟细胞迁移和趋化性的 PKC 激酶。 EMC，它通过控制雌激素、MAPK和PI3K/AKT刺激的EC增殖和癌变发挥作用。在目标1中，我们将定义具体的。 NCOA6 在抑制雌激素促进的 EMC 发育中的作用将产生具有和不具有子宫内膜 Ncoa6 KO 的转基因小鼠，以研究 Ncoa6 功能的丧失如何在不同雌激素条件下触发和促进具有和不具有 Pten 表达的子宫内膜中的自发 EMC 发育。还将产生具有阻止 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。具体来说，我们将使用生物信息学和实验方法来鉴定与 NCOA6 一起调节 DUSP6、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定义这 3 个基因的 NCOA6 调节表达对 MAPK 和 AKT 活性的功能影响在目标3中，我们将研究EMC细胞的增殖、迁移、侵袭和肿瘤生长的能力。定义NCOA6表达谱及其在人类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NCOA6蛋白表达水平，并确定NCOA6表达水平与肿瘤分级、肿瘤分期、疾病复发之间的相关/关联关系。这些研究应该通过将 NCOA6 确立为 EMC 抑制剂并探索其工作机制来产生重大影响。这些研究也可能表明 NCOA6 作为 EMC 进展的诊断和预后标志物。作为一种治疗策略，恢复 NCOA6 功能或其调节途径的临床前原则概念。

项目成果

期刊论文数量（22）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Anoctamin 4 channel currents activate glucose-inhibited neurons in the mouse ventromedial hypothalamus during hypoglycemia.

DOI：
10.1172/jci163391
发表时间：
2023-07-17
期刊：
JOURNAL OF CLINICAL INVESTIGATION
影响因子：
15.9
作者：
Tu, Longlong;Bean, Jonathan C.;He, Yang;Liu, Hailan;Yu, Meng;Liu, Hesong;Zhang, Nan;Yin, Na;Han, Junying;Scarcelli, Nikolas A.;Conde, Kristine M.;Wang, Mengjie;Li, Yongxiang;Feng, Bing;Gao, Peiyu;Cai, Zhao-Lin;Fukuda, Makoto;Xue, Mingshan;Tong, Qingchun;Yang, Yongjie;Liao, Lan;Xu, Jianming;Wang, Chunmei;He, Yanlin;Xu, Yong
通讯作者：
Xu, Yong

Common Genomic Aberrations in Mouse and Human Breast Cancers with Concurrent P53 Deficiency and Activated PTEN-PI3K-AKT Pathway.

DOI：
10.7150/ijbs.65763
发表时间：
2022
期刊：
International journal of biological sciences
影响因子：
9.2
作者：
Martinez JD;Mo Q;Xu Y;Qin L;Li Y;Xu J
通讯作者：
Xu J

Knockout of the Histone Demethylase Kdm3b Decreases Spermatogenesis and Impairs Male Sexual Behaviors.

DOI：
10.7150/ijbs.13795
发表时间：
2015
期刊：
International journal of biological sciences
影响因子：
9.2
作者：
Liu Z;Oyola MG;Zhou S;Chen X;Liao L;Tien JC;Mani SK;Xu J
通讯作者：
Xu J

Tamoxifen inhibits ER-negative breast cancer cell invasion and metastasis by accelerating Twist1 degradation.

DOI：
10.7150/ijbs.11380
发表时间：
2015
期刊：
International journal of biological sciences
影响因子：
9.2
作者：
Ma G;He J;Yu Y;Xu Y;Yu X;Martinez J;Lonard DM;Xu J
通讯作者：
Xu J

GRK3 is a direct target of CREB activation and regulates neuroendocrine differentiation of prostate cancer cells.

DOI：
10.18632/oncotarget.9359
发表时间：
2016-07-19
期刊：
Oncotarget
影响因子：
0
作者：
Sang M;Hulsurkar M;Zhang X;Song H;Zheng D;Zhang Y;Li M;Xu J;Zhang S;Ittmann M;Li W
通讯作者：
Li W