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: 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
• 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

 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.



项目成果

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

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

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

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
• 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