Targeting syndecan-1 in breast cancer inhibits osteoclast functions through up-regulation of osteoprotegerin
Targeting syndecan-1 in breast cancer inhibits osteoclast functions through up-regulation of osteoprotegerin
复制标题
DOI：
10.1016/j.jbo.2013.11.001
复制
发表时间：
2014-03-01
影响因子：
3.4
通讯作者：
Hofbauer, Lorenz C.
中科院分区：
文献类型：
--
作者：
Benad-Mehner, Peggy;Thiele, Stefanie;Hofbauer, Lorenz C.
背景：乳腺癌常转移到骨组织，并导致溶骨性病变。然而，潜在的机制是复杂的，并没有完全被理解。Syndecan-1是一种蛋白多糖，具有多种与肿瘤进展相关的功能，包括细胞通讯和细胞基质相互作用。此外，它的两个糖胺多聚糖结合位点表明它可能干扰糖蛋白，如骨保护素，一种有效的破骨细胞生成抑制因子。因此，我们假设肿瘤来源的Syndecan-1通过调节骨保护素而改变破骨细胞生物学。方法：通过siRNA下调Syndecan-1的表达，并观察乳腺癌MCF-7、T-47D和MDA-MB-231细胞的生长情况。此外，我们还确定了地塞米松对Syndecan-1的调节作用，地塞米松是乳腺癌治疗中常用的止吐药物。此外，我们分析了破骨细胞的发生和活性的间接共培养实验中，从MCF-7细胞上清液中缺乏和足够的Syndecan-1水平。结果：地塞米松时间和接近依赖地塞米松使Syndecan-1的表达增加4倍，但不改变细胞的行为。Synclecan-1上调不影响乳腺癌细胞的存活或迁移。使用siRNA去除Syndecan-1会导致孕激素受体阳性细胞系活力下降。在MCF-7细胞中，Syndecan-1基因被敲除后，护骨素的生成上调了2.5倍。破骨细胞前体与Syndecan-1水平降低的MCF-7细胞培养上清液一起培养，破骨细胞的形成和活性分别被抑制21%和23%。在乳腺癌培养上清液中加入护骨素的中和抗体可逆转破骨细胞的生成。结论：因此，我们确定肿瘤来源的syndecan-1是一种新的破骨细胞生成的正向调节因子和肿瘤-骨对话中的新参与者。(C)2013年爱思唯尔股份有限公司。版权所有。
Background: Breast cancer often metastasizes into bone and leads to osteolytic lesions. The underlying mechanisms, however, are complex and not fully understood. Syndecan-1 is a proteoglycan that has various functions relevant for tumor progression including cell cell communication and cell matrix interactions. Moreover, its two glycosaminoglycan-binding sites suggest that it may interfere with glycoproteins such as osteoprotegerin, a potent inhibitor of osteoclastogenesis. Thus, we hypothesize that tumor derived syndecan-1 alters osteoclast biology by modulating osteoprotegerin.Methods: Syndecan-1 expression was down regulated via siRNA and the cell fare of the breast cancer cell lines MCF-7, T-47D, and MDA-MB-231 was investigated. Furthermore, we determined the regulation of syndecan-1 by dexamethasone, a commonly used antiemetic in breast cancer therapy. Additionally, we analyzed the genesis and activity of osthoclasts in indirect co-culture experiments using supernatants from MCF-7 cells with deficient and sufficient levels of syndecan-1.Results: Dexamethasone time and close dependently increased syndecan-1 expression up to 4-fold but did not alter cell behavior. Synclecan-1 up regulation did not affect the survival or migration of breast cancer cells. Depletion of syndecan-1 using siRNA led to decreased vitality of progesterone receptor-positive cell lines. In MCF-7 cells osteoprotegerin production was up-regulated 2.5-fold after syndecan-1 knock-down. The culture of osteoclast precursors with the supernatant of MCF-7 cells with reduced syndecan-1 levels suppressed osteoclast formation and activity by 21% and 23%, respectively. Adding neutralizing antibodies to osteoprotegerin to the breast cancer supernatants reversed osteoclastogenesis.Conclusion: Thus, we identified tumor-derived syndecan-1 as a novel positive regulator of osteoclastogenesis and new player in the tumor-bone dialog. (C) 2013 Elsevier GmbH. All rights reserved.