Snail Signalling in Human Prostate Cancer

项目概述（见说明）：蜗牛转录因子可以通过诱导上皮间充质转化（EMT）促进癌细胞迁移和进展，在这个过程中，上皮标志物如e -钙粘蛋白（E-cadherin）丢失，而间充质标志物如vimentin获得。我们观察到蜗牛在前列腺癌骨转移患者样本中的表达增加。我们最近利用ARCaP人类前列腺癌细胞过表达Snail，建立了前列腺癌的EMT模型，并发现RANKL、cathepsin-S和-L增加。RANKL和组织蛋白酶- l先前与骨吸收有关。与对照Neo载体的ARCaP细胞相比，过表达Snail的ARCaP细胞在体外和体内均能诱导破骨细胞发生。Maspin是一种肿瘤抑制因子，在乳腺癌和前列腺癌中经常丢失。我们在体外观察到Snail和maspin的表达呈反比关系。我们假设蜗牛介导的cathepsin-S和-L的上调以及maspin的下调对于前列腺癌的进展和骨转移瘤的生长是重要的，并且抑制蜗牛信号可能是治疗激素难治性和骨转移性病变的一种可行的替代方法，而且副作用更小。首先，我们将分析蜗牛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，以及该途径是否在非裔美国人中比白种人更活跃（Specific Aim 1）。其次，蜗牛负调控maspin的机制将被阐明（Specific Aim 2）。最后，我们将研究蜗牛信号传导，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蜗牛信号传导，以研究这是否能阻止骨肿瘤的生长（Specific Aim 3）。由于成体细胞除了在损伤期间不需要Snail，因此靶向主要由癌细胞表达的Snail可以拮抗骨转移病变，而不会影响身体其他部位的正常骨，从而避免了颌骨骨坏死等副作用。

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.