Role of Runx2 in prostate tumorigenesis and metastasis

Runx 2优先在转移性前列腺癌细胞中表达，但不在非转移性细胞中表达， 促进侵袭性肿瘤行为并诱导一系列癌症相关基因。项目3 将检验前列腺癌进展高度依赖Runx 2的假设， 网络为抑制前列腺肿瘤发生的翻译方法提供了可行的靶点， 转移将采用最先进的实验策略，包括前列腺特异性基因组学， 使用荧光素酶转基因的体内生物成像，以及使用Runx 2 shRNA在前列腺中的RNA干扰， 转移性骨肿瘤以机械表征Runx 2介导的前列腺癌控制 肿瘤发生和转移以及建立Runx 2抑制的治疗潜力。实验 目的1将在体外表征Runx 2促进前列腺癌细胞生长的机制， 变质性质。这将涉及分析Runx 2表达和在细胞凋亡调控中的功能。 生存（与项目1合作）。粘附和侵袭（与雄激素依赖的Proiect 2合作） 和非依赖性模型前列腺癌细胞。表达谱和生物信息学分析 将确定在这些环境中诱导的Runx 2相关通路，验证研究将集中在TGPp， 整合素和Src信号通路由Runx 2激活。目标2中的实验将在体内检查 Runx 2促进前列腺癌进展和转移性骨疾病的机制。的 假设Runx 2依赖基因表达在不同的前列腺和骨中受到不同的调节 将在原位模型中研究微环境。骨病变分析（溶骨性与 成骨细胞），肿瘤生长的调节，以及阐明基因途径抑制或激活 操纵Runx 2水平将通过分子成像，激光捕获显微切割， TGPp/SMAD或Src/WW信号传导的定量组织病理学和生物化学表征。目标3 将研究Runx 2在TRAMP小鼠中的致瘤特性和Runx 2的治疗潜力 TRAMP小鼠和预形成的原位前列腺和骨中的缺失（通过shRNA Runx 2） SCID小鼠的肿瘤。这项研究将为Runx 2控制信号传导提供机制上的见解 介导原发性前列腺肿瘤和已转移至骨的前列腺肿瘤生长的途径。 为靶向Runx 2的shRNA抑制治疗前列腺癌的临床前评价提供依据 在获得转移特性之前的细胞。

Runx2 is preferentially expressed in metastatic prostate cancer cells, but not in non-metastafic cells, promotes aggressive tumor behavior and induces a spectrum of cancer-related genes. Therefore, Project 3 will test the hypothesis that prostate cancer progression is highily Runx2-dependent and this signaling network provides a viable target for translational approaches to inhibit prostate tumorigenesis and metastasis. State-of-the-art experimental strategies will be employed including prostate specific genomics, in vivo bioimaging using luciferase transgenes, and RNA interference using Runx2 shRNA in prostate and metastatic bone tumors to mechanistically characterize Runx2-mediated control of prostate cancer tumorigenesis and metastasis as well as to establish therapeutic potential for Runx 2 inhibition. Experiments in Aim 1 will characterize mechanisms in vitro by which Runx2 contributes to prostate cancer cell growth and metastafic properties. This will involve analysis of Runx2 expression and function in the regulation of cell survival (in collaboration with Proiect 1). adhesion and invasion (in collaboration with Proiect 2\ of androgendependent and -independent model prostate cancer cells. Expression profiling and bioinformatic analysis will identify Runx2-related pathways induced in these settings, and validafion studies will focus on TGPp, integrin, and Src signaling pathways activated by Runx2. Experiments in Aim 2 will examine in vivo mechanisms by which Runx2 contributes to prostate cancer progression and metastatic bone disease. The hypothesis that Runx2-dependent gene expression is differentially modulated in distinct prostate and bone microenvironments will be investigated in orthotopic models. Analysis of bone lesions (osteolytic versus osteoblastic), modulation of tumor growth, and elucidation of gene pathways suppressed or activated by manipulating Runx2 levels will be determined by molecular imaging, laser-capture microdissection, quantitative histopathology and biochemical characterization of TGPp/SMAD or Src/WW signaling. Aim 3 will investigate the tumorigenic properties of Runx2 in TRAMP mice and the therapeutic potential of Runx2 depletion (by shRNA Runx2) in both the TRAMP mouse and in pre-formed orthotopic prostate and bone tumors in the SCID mouse. This study will provide mechanistic insight into Runx2 control of signaling pathways mediating growth of primary prostate tumors and prostate tumors that have metastasized to bone. A basis will be provided for pre-clinical evaluation of targeting Runx2 by shRNA inhibition in prostate cancer cells before acquisition of metastatic properties.