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: 9477598
• 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/9477598
• 关键词: Adult; Androgen Receptor; Androgens; Area; Biological; Cell Line; Cells; ChIP-seq; Clinic; Clinical; Colon Carcinoma; Data; Development; Doxycycline; Duct (organ) structure; Ductal; Event; Fibroblast Growth Factor Receptors; Gene Expression Profiling; 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; Ras/Raf; Regulation; Repression; Role; Sampling; Series; Signal Transduction; Site; Specimen; Stem cells; TMPRSS2 gene; Therapeutic; Translating; WNT Signaling Pathway; Xenograft Model; angiogenesis; autocrine; base; beta catenin; chemokine; deprivation; fetal; in vivo Model; novel; novel therapeutic intervention; overexpression; paracrine; predictive marker; progenitor; prostate cancer cell; public health relevance; response; response biomarker; response to injury; stem; targeted treatment; transcription factor; tumor

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：其他人和我们之前的研究表明 SOX9 转录因子与前列腺癌 (PCa) 有关，并且我们最近将 SOX9 鉴定为 TMPRSS2:ERG 融合阳性 PCa 中 ERG 的下游效应子，进一步有力地支持了 SOX9 的主要作用。我们假设 SOX9 通过调节介导功能（包括导管形态发生和干/祖细胞维持）的多个基因，对 TMPRSS2:ERG 融合阳性和阴性 PCa 做出贡献。我们的总体目标是阐明 PCa 中 SOX9 表达的调节、作用和治疗意义。目标 1 重点关注在融合阳性和阴性 PCa 或前体病变中调节 SOX9 表达的进一步机制，特别是基质生长因子，包括 FGF、HGF 和 Wnt。我们假设这些机制驱动的 SOX9 异常表达可能是一个可以作为治疗目标的早期事件，并且可能是对雄激素剥夺治疗反应的预测生物标志物。目标 2 将建立在我们初步的 SOX9 ChIP-seq 和转录谱研究的基础上，以确定关键基因和 PCa 中 SOX9 调节的通路。值得注意的是，我们的数据表明 SOX9 通过经典的 Wnt/b-catenin/TCF 途径和替代的 Wnt/b-catenin/YAP1 途径直接正向调节参与 Wnt 信号传导的多个基因的表达，并且它负向调节 Wnt5a。目标 2 还将扩展我们的初步研究，表明 SOX9 调节一系列趋化因子，包括可以刺激炎症反应和血管生成的 IL-8。最后，目标 3 将使用前列腺特异性过表达 SOX9 的小鼠和临床样本来评估目标 2 中确定的 SOX9 调节基因和通路的生物学意义。具体目标是：1）确定 PCa 中调节 SOX9 表达的分子机制，2）确定 PCa 细胞中 SOX9 直接调节的基因和通路，以及 3）确定 SOX9 调节基因在小鼠 PCa 发育中的作用 前列腺特异性 PTEN 丢失以及患者样本中的情况。