Ragab Nada, Viehweger Florian, Bauer Julia, Geyer Natalie, Yang Mingya, Seils Anna, Belharazem Djeda, Brembeck Felix H, Schildhaus Hans-Ulrich, Marx Alexander, Hahn Heidi, Simon-Keller Katja
Institute of Pathology, University Medical Center Mannheim, University of Heidelberg, Mannheim, Germany.
Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Front Pediatr. 2018 Dec 5;6:378. doi: 10.3389/fped.2018.00378. eCollection 2018.
The development of skeletal muscle from immature precursors is partially driven by canonical WNT/β-catenin signaling. Rhabdomyosarcomas (RMS) are immature skeletal muscle-like, highly lethal cancers with a variably pronounced blockade of muscle differentiation. To investigate whether canonical β-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 β-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 expression, more distal steps including transcriptional activation of its key target genes were consistently impaired. In addition, activation or inhibition of canonical WNT/β-catenin only moderately affected proliferation, apoptosis or myodifferentiation of the RMS tumor cells and a conditional knockout of β-catenin in RMS of mice did not alter RMS incidence or multiplicity. Together our data indicates a subordinary role of the canonical WNT/β-catenin signaling for RMS proliferation, apoptosis or differentiation and thus aggressiveness of this malignant childhood tumor.
未成熟前体细胞向骨骼肌的发育部分受经典WNT/β-连环蛋白信号通路驱动。横纹肌肉瘤（RMS）是未成熟的骨骼肌样、高致死性癌症，其肌肉分化受到不同程度的明显阻滞。为了研究RMS中经典β-连环蛋白信号通路是否参与RMS的分化和侵袭性，我们分析了WNT3A以及小干扰RNA介导或药理学诱导的β-连环蛋白敲低对胚胎型和肺泡型RMS细胞系增殖、凋亡和分化的影响。虽然如WNT3A诱导表达所示，经典WNT通路在所有细胞系中均得以维持，但包括其关键靶基因转录激活在内的更远端步骤始终受损。此外，经典WNT/β-连环蛋白的激活或抑制仅对RMS肿瘤细胞的增殖、凋亡或肌分化产生适度影响，并且在小鼠RMS中条件性敲除β-连环蛋白并未改变RMS的发生率或多发性。我们的数据共同表明，经典WNT/β-连环蛋白信号通路在RMS增殖、凋亡或分化以及这种儿童恶性肿瘤的侵袭性方面作用不大。
