SNAIL-MEDIATED SIGNALING IN HUMAN PROSTATE CANCER

该子项目是利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 中心，不一定是研究者的机构。 上皮-间质转化（EMT）发生在正常胚胎发育和上皮肿瘤进展过程中。与EMT相关的几个因素有助于运动、侵袭和血管生成，并且可能是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转录因子已被鉴定为可在乳腺癌和结肠癌中诱导EMT的重要因子。 然而，EMT在前列腺癌中的作用还没有很好的定义，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。本研究的目的是研究Snail转录因子在前列腺癌进展和转移中的作用。我们已经发现，蜗牛诱导的EMT在前列腺癌细胞涉及活性氧（ROS）和NF κ B受体激活剂（RANKL），这两个因素是重要的癌症疾病进展和骨转移病变，分别。本研究将阐明Snail的生物学意义，特别是其在前列腺癌骨转移中的作用。此外，我们将表征Snail诱导的EMT的信号通路，并最终在体外和体内研究拮抗Snail表达对肿瘤侵袭性的影响。我们相信这些研究将确定Snail作为一个有吸引力的治疗靶点，不仅用于原发肿瘤进展期间的EMT，而且用于继发部位的骨转移病变。

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.