SNAIL-MEDIATED SIGNALING IN HUMAN PROSTATE CANCER

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 上皮-间充质转化(EMT)发生在正常胚胎发育和上皮性肿瘤进展过程中。一些与EMT相关的因子参与了运动、侵袭和血管生成，并可能成为前列腺癌转移的重要治疗靶点。了解导致EMT和前列腺癌转移的因素对于癌症治疗的发展至关重要。例如，Snail转录因子已被确定为在乳腺癌和结肠癌中诱导EMT的重要因素。然而，EMT在前列腺癌中的作用尚未明确，也缺乏良好的EMT模型。最近，我们使用过表达Snail的ARCaP细胞模型建立了前列腺癌进展的EMT模型。这项建议的目的是研究Snail转录因子在前列腺癌进展和转移中的作用。我们发现，Snail诱导的前列腺癌细胞EMT涉及活性氧(ROS)和NFkB受体激活物(RANKL)，这两个因子分别在癌症疾病进展和骨转移病变中起重要作用。这项建议将阐明Snail的生物学意义，重点是它在前列腺癌骨转移中的作用。此外，我们还将对Snail诱导的EMT的信号通路进行表征，并在体内外检测拮抗Snail表达对肿瘤侵袭性的影响。我们相信，这些研究将确定Snail不仅是原发肿瘤进展期间EMT的有吸引力的治疗靶点，也是次要部位骨转移病变的治疗靶点。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Epithelial-mesenchymal transition (EMT) occurs during normal embryonic development and epithelial tumor progression. Several factors associated with EMT contribute to motility, invasion, and angiogenesis, and may be important therapeutic targets for prostate cancer metastasis. Understanding the factors that contribute to EMT and prostate cancer metastasis is crucial for development of cancer therapies. For example, Snail transcription factor has been identified as an important factor that can induce EMT in breast and colon cancer. However, the role of EMT in prostate cancer is not well defined and good EMT models are lacking. Recently we have established an EMT model for prostate cancer progression using the ARCaP cell model overexpressing Snail. The goal of this proposal is to study the role of Snail transcription factor in prostate cancer progression and metastasis. We have found that Snail-induced EMT in prostate cancer cells involves reactive oxygen species (ROS) and receptor activator of NFkB (RANKL), two factors that are important in cancer disease progression and bone metastatic lesions, respectively. This proposal will elucidate the biological significance of Snail, with emphasis of its role in prostate cancer bone metastasis. In addition, we will characterize the signaling pathway of Snail-induced EMT, and finally examine the effect of antagonizing Snail expression on tumor aggressiveness in vitro and in vivo. We believe these studies will identify Snail as an attractive therapeutic target not only for EMT during primary tumor progression but also for bone metastatic lesions at the secondary site.