SOX9 Mediation of AR and ERG Driven Prostate Cancer

SOX9 介导 AR 和 ERG 驱动的前列腺癌

• 批准号: 8653225
• 负责人: Steven P. Balk
• 金额: $ 36.11万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-13 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8653225
• 关键词: Adult; Androgen Receptor; Androgens; Area; Biological; Biological Markers; Cell Line; Cells; ChIP-seq; Clinic; Clinical; Colon Carcinoma; Data; Development; Doxycycline; Ductal; Event; Fibroblast Growth Factor Receptors; Gene Targeting; Genes; Goals; Growth; Growth Factor; IL8 gene; Inflammatory Response; Lesion; MAP Kinase Gene; Maintenance; Malignant neoplasm of prostate; Mediating; Mediation; Molecular; Morphogenesis; Mus; Nuclear; PTEN gene; Pathway interactions; Patients; Physiological; Play; Production; Prostate; Regulation; Repression; Role; Sampling; Series; Signal Pathway; Signal Transduction; Site; Specimen; Stem cells; TMPRSS2 gene; Therapeutic; Translating; Xenograft Model; angiogenesis; autocrine; base; chemokine; deprivation; fetal; in vivo Model; novel; novel therapeutic intervention; overexpression; paracrine; progenitor; prostate cancer cell; public health relevance; response; response to injury; stem; transcription factor; tumor

Previous studies from others and us have implicated the SOX9 transcription factor in prostate cancer (PCa), and our recent identification of SOX9 as a downstream effector of ERG in TMPRSS2:ERG fusion positive PCa further strongly supports a major role for SOX9. We hypothesize that SOX9 contributes to both TMPRSS2:ERG fusion positive and negative PCa through its regulation of multiple genes that mediate functions including ductal morphogenesis and maintenance of stem/progenitor cells. Our overall goals are to elucidate the regulation, actions and therapeutic implications of SOX9 expression in PCa. Aim 1 focuses on further mechanisms that regulate SOX9 expression in fusion positive and negative PCa or precursor lesions, and in particular stromal growth factors including FGFs, HGF and Wnts. We hypothesize that the aberrant expression of SOX9 driven by these mechanisms may be an early event that can be targeted therapeutically, and may be a predictive biomarker for responses to therapies that incorporate androgen deprivation. Aim 2 will build on our preliminary SOX9 ChIP- seq and transcriptional profiling studies to identify the critical genes and pathways regulated by SOX9 in PCa. Significantly, our data indicate that SOX9 directly positively regulates the expression of multiple genes involved in Wnt signaling through the canonical Wnt/b-catenin/TCF pathway and an alternative Wnt/b-catenin/YAP1 pathway, and that it negatively regulates Wnt5a. Aim 2 will also extend our preliminary studies indicating that SOX9 regulates a series of chemokines including IL-8 that can stimulate inflammatory responses and angiogenesis. Finally, Aim 3 will use mice with prostate specific overexpression of SOX9 and clinical samples to evaluate the biological significance of SOX9 regulated genes and pathways identified in Aim 2. The specific aims are: 1) Identify molecular mechanisms regulating SOX9 expression in PCa, 2) Identify genes and pathways directly regulated by SOX9 in PCa cells, and 3) Determine the role of SOX9 regulated genes in PCa development in mice with prostate specific PTEN loss and in patient samples.

其他人和我们之前的研究表明，SOX9转录因子与前列腺癌有关 癌症(PCa)，以及我们最近发现的SOX9是ERG的下游效应因子 TMPRSS2：ERG融合阳性PCA进一步有力地支持了SOX9的主要作用。我们 假设SOX9参与TMPRSS2：ERG融合阳性和阴性PCa 通过调节多个基因来调节包括导管形态发生在内的功能 以及干细胞/祖细胞的维持。我们的总体目标是阐明这一规定， SOX9在前列腺癌中的表达及其治疗意义目标1侧重于进一步 融合阳性和阴性前列腺癌或前体中SOX9表达的调控机制 损伤，特别是间质生长因子，包括FGFs、HGF和WNTS。我们 假设由这些机制驱动的SOX9的异常表达可能是早期的 可作为治疗靶点的事件，并可作为预测生物标志物 包括雄激素剥夺的疗法。AIM 2将建立在我们初步的SOX9芯片上- SEQ和转录图谱研究以确定关键基因和受 在PCA中的SOX9。值得注意的是，我们的数据表明，SOX9直接正向调节 Wnt/b-catenin/Tcf参与Wnt信号转导的多个基因表达 Wnt/b-catenin/YAP1途径，它负性调节Wnt5a。 Aim 2还将扩展我们的初步研究，表明SOX9调节一系列 包括IL-8在内的能够刺激炎症反应和血管生成的趋化因子。最后， AIM 3将使用前列腺特异性SOX9过度表达的小鼠和临床样本 评估目标2中确定的SOX9调控基因和途径的生物学意义。 其具体目的是：1)确定调控前列腺癌SOX9表达的分子机制；2) 确定SOX9在前列腺癌细胞中直接调控的基因和途径，以及3)确定其作用 SOX9调控基因在前列腺特异性PTEN缺失和前列腺癌发生中的作用 病人样本。