Canonical WNT/β-Catenin Signaling Plays a Subordinate Role in Rhabdomyosarcomas
Canonical WNT/β-Catenin Signaling Plays a Subordinate Role in Rhabdomyosarcomas
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DOI：
10.3389/fped.2018.00378
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发表时间：
2018-12-05
影响因子：
2.6
通讯作者：
Simon-Keller, Katja
中科院分区：
文献类型：
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作者：
Ragab, Nada;Viehweger, Florian;Simon-Keller, Katja
骨骼肌从未成熟前体的发育部分由经典WNT/β-连环蛋白信号传导驱动。横纹肌肉瘤（RMS）是一种不成熟的骨骼肌样高致死性癌症，具有明显的肌肉分化阻滞。为了研究RMS中的经典β-连环蛋白信号传导是否参与RMS的分化和侵袭性，我们分析了WNT 3A和siRNA介导或siRNA诱导的β-连环蛋白敲低对胚胎和肺泡RMS细胞系的增殖、凋亡和分化的影响。尽管如WNT 3A诱导的轴蛋白表达所示，经典WNT途径在所有细胞系中得以维持，但包括其关键靶基因的转录激活在内的更远端步骤始终受损。此外，激活或抑制经典WNT/β-连环蛋白仅中度影响RMS肿瘤细胞的增殖、凋亡或肌分化，并且Ptch（del/+）小鼠RMS中β-连环蛋白的条件性敲除不改变RMS发病率或多样性。总之，我们的数据表明，典型的WNT/β-连环蛋白信号传导对于RMS增殖、凋亡或分化以及这种恶性儿童肿瘤的侵袭性具有非同寻常的作用。
The development of skeletal muscle from immature precursors is partially driven by canonical WNT/beta-catenin signaling. Rhabdomyosarcomas (RMS) are immature skeletal muscle-like, highly lethal cancers with a variably pronounced blockade of muscle differentiation. To investigate whether canonical beta-catenin signaling in RMS is involved in differentiation and aggressiveness of RMS, we analyzed the effects of WNT3A and of a siRNA-mediated or pharmacologically induced beta-catenin knock-down on proliferation, apoptosis and differentiation of embryonal and alveolar RMS cell lines. While the canonical WNT pathway was maintained in all cell lines as shown by WNT3A induced AXIN expression, more distal steps including transcriptional activation of its key target genes were consistently impaired. In addition, activation or inhibition of canonical WNT/beta-catenin only moderately affected proliferation, apoptosis or myodifferentiation of the RMS tumor cells and a conditional knockout of beta-catenin in RMS of Ptch(del/+) mice did not alter RMS incidence or multiplicity. Together our data indicates a subordinary role of the canonical WNT/beta-catenin signaling for RMS proliferation, apoptosis or differentiation and thus aggressiveness of this malignant childhood tumor.