SOX9 Mediation of AR and ERG Driven Prostate Cancer

描述(申请人提供)：以前来自其他人和我们的研究表明SOX9转录因子与前列腺癌(PCa)有关，我们最近发现SOX9是TMPRSS2中ERG的下游效应因子：ERG融合阳性的PCA进一步有力地支持了SOX9的主要作用。我们推测，SOX9通过调控多个基因参与了TMPRSS2：ERG融合阳性和阴性PCa的发生，这些基因介导了包括导管形态发生和干/祖细胞维持在内的多种功能。我们的总体目标是阐明SOX9在前列腺癌中的表达调节、作用和治疗意义。目的1重点研究SOX9在融合阳性和阴性前列腺癌或癌前病变中表达的调节机制，特别是基质生长因子，包括FGFs、HGF和WNTs。我们推测，由这些机制驱动的SOX9的异常表达可能是一个早期事件，可以作为治疗的靶点，并可能成为包括雄激素剥夺的治疗反应的预测性生物标志物。Aim 2将在我们初步的SOX9芯片序列和转录图谱研究的基础上，确定关键基因和 前列腺癌中受SOX9调控的通路。值得注意的是，我们的数据表明，SOX9通过典型的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信号的多个基因的表达，并负向调节Wnt5a。Aim 2还将扩展我们的初步研究，表明SOX9调节包括IL-8在内的一系列趋化因子，这些趋化因子可以刺激炎症反应和血管生成。最后，Aim 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Aim 2中确定的SOX9调控基因和途径的生物学意义。具体目的是：1)识别调控前列腺癌SOX9表达的分子机制，2)识别前列腺癌细胞中SOX9直接调控的基因和途径，以及3)确定SOX9调控基因在前列腺特异性PTEN缺失小鼠和患者样本前列腺癌发生中的作用。

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.