Syndecan-1 (CD138) modulates triple-negative breast cancer stem cell properties via regulation of LRP-6 and IL-6-mediated STAT3 signaling.
Syndecan-1 (CD138) modulates triple-negative breast cancer stem cell properties via regulation of LRP-6 and IL-6-mediated STAT3 signaling.
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DOI：
10.1371/journal.pone.0085737
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Götte M
中科院分区：
文献类型：
--
作者：
Ibrahim SA;Hassan H;Vilardo L;Kumar SK;Kumar AV;Kelsch R;Schneider C;Kiesel L;Eich HT;Zucchi I;Reinbold R;Greve B;Götte M
Syndecan-1（CD 138）是一种硫酸乙酰肝素蛋白多糖，作为生长因子和趋化因子的辅助受体，是发育和癌变过程中上皮-间质转化相关的分子标志物。Syndecan-1缺陷小鼠对实验诱导的肿瘤发生的抗性与改变的Wnt响应性前体细胞库有关，表明Syndecan-1在乳腺癌细胞干细胞功能中的潜在作用。然而，精确的分子机制仍然难以捉摸。在这里，我们破译的功能影响Syndecan-1敲低使用RNA干扰对乳腺癌干细胞表型的人三阴性MDA-MB-231和激素受体阳性MCF-7细胞在体外采用分析流式细胞术的方法。通过流式细胞术证实成功的Syndecan-1 siRNA敲低。通过Hoechst染料排除和醛脱氢酶-1活性进行的侧群测量显示，与对照相比，MDA-MB-231细胞中的Syndecan-1敲低分别使推定的癌症干细胞库显著减少60%和27%。在MCF-7细胞中，Syndecan-1消耗分别使侧群减少40%和醛脱氢酶-1减少50%。在MDA-MB-231细胞中，在siRNA介导的Syndecan-1耗竭后，CD 44（+）CD 24（-/低）表型显著降低6%。有趣的是，参与调节干细胞相关途径的IL-6、其受体sIL-6 R和趋化因子CCL 20在Syndecan-1沉默的MDA-MB-231细胞中下调>40%，这显示出对IL-6诱导的E-钙粘蛋白和波形蛋白表达变化的失调反应。此外，与对照相比，在Syndecan-1耗尽的细胞中STAT-3和NFkB转录因子的活化以及Wnt信号传导的辅助受体LRP-6的表达降低了>45%。在功能水平上，Syndecan-1 siRNA减少了悬浮培养中生长的MCF-7细胞中球体和包囊的形成。我们的研究证明了流式细胞术方法在分析癌症干细胞功能中的可行性。由于Syndecan-1通过调节Wnt和IL-6/STAT 3信号通路调节癌症干细胞表型，因此它成为治疗方法的有希望的新靶标。
Syndecan-1 (CD138), a heparan sulfate proteoglycan, acts as a coreceptor for growth factors and chemokines and is a molecular marker associated with epithelial-mesenchymal transition during development and carcinogenesis. Resistance of Syndecan-1-deficient mice to experimentally-induced tumorigenesis has been linked to altered Wnt-responsive precursor cell pools, suggesting a potential role of Syndecan-1 in breast cancer cell stem function. However, the precise molecular mechanism is still elusive. Here, we decipher the functional impact of Syndecan-1 knockdown using RNA interference on the breast cancer stem cell phenotype of human triple-negative MDA-MB-231 and hormone receptor-positive MCF-7 cells in vitro employing an analytical flow cytometric approach. Successful Syndecan-1 siRNA knockdown was confirmed by flow cytometry. Side population measurement by Hoechst dye exclusion and Aldehyde dehydrogenase-1 activity revealed that Syndecan-1 knockdown in MDA-MB-231 cells significantly reduced putative cancer stem cell pools by 60% and 27%, respectively, compared to controls. In MCF-7 cells, Syndecan-1 depletion reduced the side population by 40% and Aldehyde dehydrogenase-1 by 50%, repectively. In MDA-MB-231 cells, the CD44(+)CD24(-/low) phenotype decreased significantly by 6% upon siRNA-mediated Syndecan-1 depletion. Intriguingly, IL-6, its receptor sIL-6R, and the chemokine CCL20, implicated in regulating stemness-associated pathways, were downregulated by >40% in Syndecan-1-silenced MDA-MB-231 cells, which showed a dysregulated response to IL-6-induced shifts in E-cadherin and vimentin expression. Furthermore, activation of STAT-3 and NFkB transcription factors and expression of a coreceptor for Wnt signaling, LRP-6, were reduced by >45% in Syndecan-1-depleted cells compared to controls. At the functional level, Syndecan-1 siRNA reduced the formation of spheres and cysts in MCF-7 cells grown in suspension culture. Our study demonstrates the viability of flow cytometric approaches in analyzing cancer stem cell function. As Syndecan-1 modulates the cancer stem cell phenotype via regulation of the Wnt and IL-6/STAT3 signaling pathways, it emerges as a promising novel target for therapeutic approaches.
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Syndecan-1（CD138），E-钙粘蛋白和C-MET的表达特征与现场导管乳腺癌中的血管生成和淋巴管生成因子有关。
影响因子：
7.4
作者：
Goette, Martin;Kersting, Christian;Radke, Isabel;Kiesel, Ludwig;Wuelfing, Pia
通讯作者：
Wuelfing, Pia
DOI：
10.1097/01.npr.0000407602.29522.d7
发表时间：
2011-12-16
期刊：
The Nurse practitioner
影响因子：
--
作者：
Downs-Holmes, Catherine;Silverman, Paula
通讯作者：
Silverman, Paula
影响因子：
4.8
作者：
Gustafson, B;Smith, U
通讯作者：
Smith, U
影响因子：
2.7
作者：
Hao, J;Li, TG;Zhao, GQ
通讯作者：
Zhao, GQ
影响因子：
3.4
作者：
Giatromanolaki, Alexandra;Sivridis, Efthimios;Koukourakis, Michael I.
通讯作者：
Koukourakis, Michael I.