Receptor activator of NF-κB Ligand (RANKL) expression is associated with epithelial to mesenchymal transition in human prostate cancer cells
Receptor activator of NF-κB Ligand (RANKL) expression is associated with epithelial to mesenchymal transition in human prostate cancer cells
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DOI：
10.1038/cr.2008.84
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发表时间：
2008-08-01
期刊：
影响因子：
44.1
通讯作者：
Chung, Leland W. K.
中科院分区：
文献类型：
--
作者：
Odero-Marah, Valerie A.;Wang, Ruoxiang;Chung, Leland W. K.
癌症的上皮-间质转化（EMT）描述了癌细胞从惰性到毒性形式的表型和行为变化，具有增加的迁移，侵袭和转移潜力。EMT可由可溶性蛋白如转化生长因子β 1 （TGF β 1）和转录因子如Snail和Slug诱导。我们利用ARCaP(E)/ARCaP(M)前列腺癌进展模型和稳定过表达Snail的LNCaP克隆来鉴定与EMT相关的新标记。与ARCaP(E)细胞相比，高致瘤性间充质ARCaP(M)和ARCaP（M1）变异细胞在SCID小鼠心内给药后表现出更高的骨转移发生率。ARCaP(M)和ARCaP（M1）表达vimentin和N-cadherin的间质基质标志物，nf - κ B配体受体激活因子（RANKL）水平升高。我们观察到表皮生长因子(EGF) + TGF β 1处理和Snail过表达均可诱导ARCaP(E)和LNCaP细胞的EMT， EMT与RANKL蛋白表达增加有关。最后，我们确定RANKL蛋白在体外具有功能活性，促进破骨细胞的发生。我们的研究结果表明RANKL是前列腺癌进展过程中EMT的新标志物。RANKL可能在EMT、骨转换和前列腺癌骨骼转移之间起联系作用。
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 beta 1 (TGF beta 1) 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-kappa B Ligand (RANKL). We observed that both epidermal growth factor (EGF) plus TGF beta 1 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.