Odero-Marah Valerie A, Wang Ruoxiang, Chu Gina, Zayzafoon Majd, Xu Jianchun, Shi Chunmeng, Marshall Fray F, Zhau Haiyen E, Chung Leland W K
Molecular Urology and Therapeutics Program, Department of Urology and Winship Cancer Institute, Emory University School of Medicine, 1365B Clifton Road, NE, Atlanta, GA 30322, USA.
Cell Res. 2008 Aug;18(8):858-70. doi: 10.1038/cr.2008.84.
Epithelial-mesenchymal transition (EMT) in cancer describes the phenotypic and behavioral changes of cancer cells from indolent to virulent forms with increased migratory, invasive and metastatic potential. EMT can be induced by soluble proteins like transforming growth factor beta1 (TGFbeta1) and transcription factors including Snail and Slug. We utilized the ARCaP(E)/ARCaP(M) prostate cancer progression model and LNCaP clones stably overexpressing Snail to identify novel markers associated with EMT. Compared to ARCaP(E) cells, the highly tumorigenic mesenchymal ARCaP(M) and ARCaP(M1) variant cells displayed a higher incidence of bone metastasis after intracardiac administration in SCID mice. ARCaP(M) and ARCaP(M1) expressed mesenchymal stromal markers of vimentin and N-cadherin in addition to elevated levels of Receptor Activator of NF-kappaB Ligand (RANKL). We observed that both epidermal growth factor (EGF) plus TGFbeta1 treatment and Snail overexpression induced EMT in ARCaP(E) and LNCaP cells, and EMT was associated with increased expression of RANKL protein. Finally, we determined that the RANKL protein was functionally active, promoting osteoclastogenesis in vitro. Our results indicate that RANKL is a novel marker for EMT during prostate cancer progression. RANKL may function as a link between EMT, bone turnover, and prostate cancer skeletal metastasis.
癌症中的上皮-间质转化（EMT）描述了癌细胞从惰性状态转变为具有更强迁移、侵袭和转移潜能的恶性状态时所发生的表型和行为变化。EMT可由可溶性蛋白如转化生长因子β1（TGFβ1）以及包括Snail和Slug在内的转录因子诱导。我们利用ARCaP(E)/ARCaP(M)前列腺癌进展模型以及稳定过表达Snail的LNCaP克隆来鉴定与EMT相关的新标志物。与ARCaP(E)细胞相比，具有高致瘤性的间充质ARCaP(M)和ARCaP(M1)变异细胞在SCID小鼠心内给药后发生骨转移的几率更高。ARCaP(M)和ARCaP(M1)除了高水平的核因子κB受体活化因子配体（RANKL）外，还表达波形蛋白和N-钙黏蛋白等间充质基质标志物。我们观察到，表皮生长因子（EGF）加TGFβ1处理以及Snail过表达均可在ARCaP(E)和LNCaP细胞中诱导EMT，且EMT与RANKL蛋白表达增加相关。最后，我们确定RANKL蛋白具有功能活性，可在体外促进破骨细胞生成。我们的结果表明，RANKL是前列腺癌进展过程中EMT的一个新标志物。RANKL可能作为EMT、骨转换和前列腺癌骨转移之间的一个联系纽带。
