SOX9 Mediation of AR and ERG Driven Prostate Cancer

我们和其他人的研究表明，SOX 9转录因子在前列腺中起重要作用。 癌症（PCa），以及我们最近鉴定的SOX 9作为ERG的下游效应物， TMPRSS 2：ERG融合阳性PCa进一步强烈支持S 0X 9的主要作用。我们 假设SOX 9有助于TMPRSS 2：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 和维持干/祖细胞。我们的总体目标是阐明监管， SOX 9在前列腺癌中表达的作用和治疗意义。目标1侧重于进一步 在融合阳性和阴性PCa或前体中调节SOX 9表达的机制 病变，特别是基质生长因子，包括FGF、HGF和Wnt。我们 我假设由这些机制驱动的SOX 9的异常表达可能是一种早期的 可以在治疗上靶向的事件，并且可以是对以下反应的预测性生物标志物： 结合雄激素剥夺的疗法。目标2将建立在我们初步的SOX 9芯片上- seq和转录谱研究，以确定关键基因和途径调控 SOX 9在PCa中。值得注意的是，我们的数据表明，SOX 9直接正向调节 通过经典Wnt/b-连环蛋白/TCF参与Wnt信号传导的多个基因的表达 途径和替代Wnt/b-连环蛋白/YAP 1途径，并且它负调节Wnt 5a。 目标2还将扩展我们的初步研究，表明SOX 9调节一系列 趋化因子，包括IL-8，可以刺激炎症反应和血管生成。最后， 目的3将使用具有前列腺特异性过表达SOX 9的小鼠和临床样品， 评估目标2中确定的SOX 9调控基因和途径的生物学意义。 具体目标是：1）鉴定调节前列腺癌中SOX 9表达的分子机制，2） 鉴定前列腺癌细胞中由SOX 9直接调控的基因和途径，以及3）确定作用 SOX 9调控基因在前列腺特异性PTEN缺失小鼠PCa发育中的作用， 患者样本。

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.