Castellana Bàrbara, Aasen Trond, Moreno-Bueno Gema, Dunn Sandra E, Ramón y Cajal Santiago
Molecular Pathology, Vall d'Hebron Research Institute (VHIR), Universidad Autonoma of Barcelona, Barcelona, Spain.
Department of Obstetrics and Gynecology, Child and Family Research Institute, University of British Columbia, Vancouver, BC, Canada.
Oncotarget. 2015 Nov 10;6(35):38239-56. doi: 10.18632/oncotarget.5664.
Epithelial to mesenchymal transition (EMT) induces cell plasticity and promotes metastasis. The multifunctional oncoprotein Y-box binding protein-1 (YB-1) and the pleiotropic cytokine interleukin 6 (IL-6) have both been implicated in tumor cell metastasis and EMT, but via distinct pathways. Here, we show that direct interplay between YB-1 and IL-6 regulates breast cancer metastasis. Overexpression of YB-1 in breast cancer cell lines induced IL-6 production while stimulation with IL-6 increased YB-1 expression and YB-1 phosphorylation. Either approach was sufficient to induce EMT features, including increased cell migration and invasion. Silencing of YB-1 partially reverted the EMT and blocked the effect of IL-6 while inhibition of IL-6 signaling blocked the phenotype induced by YB-1 overexpression, demonstrating a clear YB-1/IL-6 interdependence. Our findings describe a novel signaling network in which YB-1 regulates IL-6, and vice versa, creating a positive feed-forward loop driving EMT-like metastatic features during breast cancer progression. Identification of signaling partners or pathways underlying this co-dependence may uncover novel therapeutic opportunities.
上皮-间质转化（EMT）诱导细胞可塑性并促进转移。多功能癌蛋白Y盒结合蛋白1（YB-1）和多效细胞因子白细胞介素6（IL-6）均与肿瘤细胞转移和EMT有关，但途径不同。在此，我们表明YB-1和IL-6之间的直接相互作用调节乳腺癌转移。乳腺癌细胞系中YB-1的过表达诱导IL-6产生，而IL-6刺激增加YB-1表达和YB-1磷酸化。这两种方法中的任何一种都足以诱导EMT特征，包括增加细胞迁移和侵袭。YB-1的沉默部分逆转了EMT并阻断了IL-6的作用，而IL-6信号传导的抑制则阻断了YB-1过表达诱导的表型，表明YB-1/IL-6存在明显的相互依赖性。我们的研究结果描述了一种新型信号网络，其中YB-1调节IL-6，反之亦然，在乳腺癌进展过程中形成一个正向反馈回路，驱动类似EMT的转移特征。确定这种共同依赖性背后的信号伙伴或途径可能会发现新的治疗机会。
