Snail Signalling in Human Prostate Cancer

项目总结（见说明书）：Snail转录因子可以通过诱导上皮间质转化（EMT）促进癌细胞迁移和进展，EMT是一个上皮标志物（如E-钙粘蛋白）丢失和间质标志物（如波形蛋白）获得的过程。我们已经观察到Snail在前列腺癌骨转移人类患者样品中的表达增加。我们最近利用过表达Snail的ARCaP人前列腺癌细胞生成了前列腺癌的EMT模型，并鉴定了RANKL、组织蛋白酶-S和-L的增加。RANKL和组织蛋白酶-L先前已涉及骨吸收。与含有对照Neo载体的ARCaP细胞相比，过表达Snail的ARCaP细胞可在体外和体内诱导破骨细胞生成。Maspin是一种在乳腺癌和前列腺癌中经常丢失的肿瘤抑制因子。我们已经观察到Snail和maspin在体外表达之间的反比关系。我们假设Snail介导的组织蛋白酶-S和-L的上调以及maspin的下调对于前列腺癌进展和骨转移性肿瘤生长是重要的，并且抑制Snail信号传导可能是治疗激素难治性和骨转移性病变的可行替代方案，副作用较少。首先，将分析Snail介导的组织蛋白酶表达在前列腺肿瘤进展中的作用和机制，以及与高加索人相比，该途径在非洲裔美国人中是否更活跃（具体目标1）。其次，将阐明Snail负调节maspin的机制（具体目的2）。最后，将检查Snail信号传导，特别是在非裔美国人前列腺癌细胞系中，是否促进向更高骨密度的迁移和转移，以及利用组织蛋白酶抑制剂拮抗Snail信号传导，以研究这是否阻止骨肿瘤生长（具体目标3）。由于Snail除了在损伤期间之外不被成体细胞所需要，因此靶向主要由癌细胞表达的Snail可能会拮抗骨中的转移性病变，而不会影响身体其他区域的正常骨，从而避免副作用，如颌骨骨坏死。

PROJECT SUMMARY (See instructions): Snail transcription factor can promote cancer cell migration and progression by inducing epithelial mesenchymal transition (EMT), a process by which epithelial markers such as E-cadherin are lost, and mesenchymal markers such as vimentin are acquired. We have observed increased expression of Snail in prostate cancer bone metastatic human patient samples. We recently generated an EMT model for prostate cancer utilizing the ARCaP human prostate cancer cells overexpressing Snail and identified increased RANKL, cathepsin-S and -L. RANKL and cathepsin-L have been previously implicated in bone resorption. ARCaP cells overexpressing Snail could induce osteoclastogenesis both in vitro and in vivo, as compared to ARCaP cells with control Neo vector. Maspin is a tumor suppressor frequently lost in breast and prostate cancer. We have observed an inverse relationship between Snail and maspin expression in vitro. We hypothesize that Snail-mediated upregulation of cathepsin-S and -L, and downregulation of maspin is important for prostate cancer progression and bone metastatic tumor growth and that inhibiting Snail signaling may be a feasible alternative to treat hormone refractory and bone metastatic lesions with less side effects. Firstly, the role and mechanism of Snail-mediated cathepsin expression in prostate tumor progression will be analyzed and whether this pathway is more active in African Amercians as compard to Caucasians (Specific Aim 1). Secondly, the mechanism by which Snail negatively regulates maspin will be elucidated (Specific Aim 2). Finally, whether Snail signaling, especially in an African American prostate cancer cell line, promotes migration to higher bone density and metastasis will be examined, as well as antagonism of Snail signaling utilizing cathepsin inhibitors to investigate whether this prevents bone tumor growth (Specific Aim 3). Since Snail is not required by adult cells except during injury, targeting Snail that is mainly expressed by cancer cells may antagonize metastatic lesions in bone without affecting normal bone in other areas of the body, thus avoiding side effects such as osteonecrosis of the jaw.