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.

其他和美国的研究已将Sox9转录因子引入前列腺 癌症（PCA），以及我们最近将Sox9鉴定为ERG的下游效应子 TMPRSS2：ERG融合阳性PCA进一步支持SOX9的主要作用。我们 假设SOX9有助于TMPRSS2：ERG融合阳性和负PCA 通过调节多个介导功能（包括导管形态发生）的基因 和茎/祖细胞的维护。我们的总体目标是阐明法规， PCA中SOX9表达的作用和治疗意义。目标1专注于进一步 调节融合阳性和负PCA或前体的SOX9表达的机制 病变，尤其是基质生长因子，包括FGF，HGF和WNT。我们 假设这些机制驱动的Sox9的异常表达可能是早期的 可以针对治疗的事件，并且可能是对响应的预测生物标志物 结合雄激素剥夺的疗法。 AIM 2将基于我们的初步Sox9芯片 - SEQ和转录分析研究，以识别由 PCA中的Sox9。值得注意的是，我们的数据表明SOX9直接对 通过规范Wnt/B-catenin/tcf参与WNT信号传导的多个基因的表达 途径和替代的Wnt/b-catenin/Yap1途径，并且对WNT5A进行负调节。 AIM 2还将扩展我们的初步研究，表明Sox9调节了一系列 趋化因子在内，包括IL-8，可以刺激炎症反应和血管生成。最后， AIM 3将使用具有前列腺特异性Sox9和临床样本过表达的小鼠 评估SOX9调控基因和AIM 2中识别的途径的生物学意义。 具体目的是：1）确定调节PCA中SOX9表达的分子机制，2） 识别PCA细胞中SOX9直接调控的基因和途径，3）确定作用 在患有前列腺特异性PTEN损失的小鼠中PCA发育中SOX9调节的基因 病人样本。