Role of Runx2 in prostate tumorigenesis and metastasis

Runx2在转移性前列腺癌细胞中优先表达，而在非转移性细胞中不表达。 促进侵袭性肿瘤行为并诱导一系列与癌症相关的基因。因此，项目3 将检验前列腺癌进展高度依赖于Runx2的假设，并且这一信号 网络为翻译方法提供了一个可行的靶点，以抑制前列腺癌的发生和 转移。将采用最先进的实验策略，包括前列腺特异基因组学， 使用荧光素酶转基因的活体生物成像，以及使用Runx2 shRNA在前列腺和 转移性骨肿瘤对Runx2介导的前列腺癌控制的力学表征 肿瘤的发生和转移以及建立抑制RUNX-2的治疗潜力。实验 在Aim 1中，将描述Runx2在体外促进前列腺癌细胞生长和 亚传人的特性。这将涉及分析Runx2在细胞调控中的表达和功能 生存(与项目1合作)。黏附和侵袭(与雄激素依赖的项目2合作 和-非依赖性模型前列腺癌细胞。表达谱分析和生物信息学分析 将确定在这些环境中诱导的Runx2相关通路，并且Valiidafion研究将集中在TGPp上， 整合素和由Runx2激活的Src信号通路。AIM 2中的实验将在体内进行测试 Runx2促进前列腺癌进展和转移性骨病的机制。这个 Runx2依赖基因在不同的前列腺和骨骼中差异表达的假说 微环境将在原位模型中进行研究。骨损伤分析(溶骨性VS 成骨细胞)，肿瘤生长的调节，以及阐明受抑制或激活的基因通路 操纵Runx2的水平将通过分子成像、激光捕获显微切割、 TGPp/SMAD或Src/WW信号的定量组织病理学和生化特征。目标3 将研究Runx2在TraMP小鼠体内的致瘤特性和治疗潜力 TraMP小鼠和预形成的原位前列腺和骨骼中的耗竭(由shRNA Runx2引起) SCID小鼠体内的肿瘤。这项研究将提供对Runx2信令控制的机械性见解 介导原发性前列腺癌和已转移到骨的前列腺癌生长的途径。 这将为通过shRNA抑制靶向Runx2治疗前列腺癌的临床前评估提供依据。 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.