Department of Biomedical Sciences and Biotechnologies and Interuniversity Institute of Myology (IIM), University of Brescia, viale Europa 11, 25123 Brescia, Italy.
Eur J Cancer. 2011 May;47(7):1095-105. doi: 10.1016/j.ejca.2010.12.010. Epub 2011 Jan 25.
Rhabdomyosarcoma (RMS) includes heterogeneous tumours of mesenchymal derivation which are genetically committed to the myogenic lineage, but fail to complete terminal differentiation. Previous works have reported on deregulated myostatin, p38 and extracellular regulated kinase (ERK) signalling in RMS cell lines; however, the functional link between these pathways and their relative contribution to RMS pathogenesis and/or maintenance of the transformed phenotype in vitro are unclear. Herein we show that the constitutive expression of a dominant-negative form of activin receptor type IIb (dnACTRIIb), which inhibits myostatin signalling, decreased proliferation and promoted differentiation of the human RMS RD cell line. DnACTRIIb-dependent differentiation of RD cells correlated with a reduced SMAD2/3 (small mother against decapentaplegic) and ERK signalling and the activation of p38 pathway. Conversely, the expression of a constitutively activated ALK5 (activin receptor-like kinase) (caALK5) form, activating SMAD3 and ERK pathways, led to further impairment of RD differentiation. Pharmacological blockade of ERK pathway in RD cells was sufficient to replicate the biological phenotype observed in dnACTRIIb-expressing RD cells, and also recovered the differentiation of caALK5-expressing RD cells. Conversely, deliberate activation of p38 signalling mimics the effect of dnActRIIb and overcame the differentiation block in RD cells. These data indicate the existence of a network formed by myostatin/SMAD2/3, ERK and p38 pathways that, when deregulated, might contribute to the pathogenesis of RMS. The components of this network might, therefore, be a valuable target for interventions towards correcting the malignant phenotype of RMS.
横纹肌肉瘤（RMS）包括源自间充质的异质性肿瘤，这些肿瘤在遗传上被认为是向肌源性谱系分化的，但未能完成终末分化。以前的研究报告了 RMS 细胞系中肌抑素、p38 和细胞外调节激酶（ERK）信号的失调；然而，这些途径之间的功能联系及其对 RMS 发病机制和/或体外转化表型的维持的相对贡献尚不清楚。本文表明，组成型表达一种抑制肌抑素信号的激活素受体 IIb 型（dnACTRIIb）的显性失活形式，可降低人类 RMS RD 细胞系的增殖并促进其分化。DnACTRIIb 依赖性 RD 细胞分化与 SMAD2/3（小母体对抗 decapentaplegic）和 ERK 信号的减少以及 p38 途径的激活相关。相反，表达一种组成型激活的 ALK5（激活素受体样激酶）（caALK5）形式，激活 SMAD3 和 ERK 途径，导致 RD 分化的进一步受损。在 RD 细胞中阻断 ERK 途径足以复制在 dnACTRIIb 表达的 RD 细胞中观察到的生物学表型，并且还恢复了 caALK5 表达的 RD 细胞的分化。相反，故意激活 p38 信号模拟了 dnActRIIb 的作用，并克服了 RD 细胞的分化阻滞。这些数据表明存在一个由肌抑素/SMAD2/3、ERK 和 p38 途径组成的网络，当失调时，可能有助于 RMS 的发病机制。因此，该网络的组成部分可能是纠正 RMS 恶性表型的干预措施的有价值的靶点。
