Szabo Dora Julianna, Toth Eniko, Szabo Kitti, Hegedus Zsofia Kata, Bozsity-Farago Noemi, Zupko Istvan, Rovo Laszlo, Xiao Xue, Xu Lin, Keller-Pinter Aniko
Department of Biochemistry, Faculty of Medicine, University of Szeged, 6720 Szeged, Hungary.
Centre of Excellence for Interdisciplinary Research, Development and Innovation, University of Szeged, 6720 Szeged, Hungary.
Int J Mol Sci. 2025 Feb 27;26(5):2137. doi: 10.3390/ijms26052137.
Rhabdomyosarcoma (RMS), the most common soft tissue sarcoma in children, arises from skeletal muscle cells that fail to differentiate terminally. Two subgroups of RMS, fusion-positive and fusion-negative RMS (FPRMS and FNRMS, respectively), are characterized by the presence or absence of the fusion gene. RMSs frequently exhibit increased expression of human epidermal growth factor receptor-2 (HER2). Trastuzumab is a humanized monoclonal antibody targeting HER2, and its potential role in RMS treatment remains to be elucidated. Syndecan-4 (SDC4) is a heparan sulfate proteoglycan (HSPG) affecting myogenesis via Rac1-mediated actin remodeling. Previously, we demonstrated that the SDC4 gene is amplified in 28% of human FNRMS samples, associated with high mRNA expression, suggesting a tumor driver role. In this study, after analyzing the copy numbers and mRNA expressions of other HSPGs in human RMS samples, we found that in addition to SDC4, syndecan-1, syndecan-2, and glypican-1 were also amplified and highly expressed in FNRMS. In RD (human FNRMS) cells, elevated SDC4 expression was accompanied by low levels of phospho-Ser179 of SDC4, leading to high Rac1-GTP activity. Notably, this high SDC4 expression in RD cells decreased following trastuzumab treatment. Trastuzumab decreased the levels of G1/S checkpoint regulators cyclin E and cyclin D1 and reduced the cell number; however, it also downregulated the cyclin-dependent kinase inhibitor p21. The level of MyoD, a transcription factor essential for RMS cell survival, also decreased following trastuzumab administration. Our findings contribute to the understanding of the role of SDC4 in FNRMS. Since HER2 is expressed in about half of RMSs, the trastuzumab-mediated changes observed here may have therapeutic implications.
横纹肌肉瘤（RMS）是儿童最常见的软组织肉瘤，起源于未能终末分化的骨骼肌细胞。RMS的两个亚组，即融合阳性和融合阴性RMS（分别为FPRMS和FNRMS），其特征在于融合基因的存在与否。RMS经常表现出人类表皮生长因子受体2（HER2）表达增加。曲妥珠单抗是一种靶向HER2的人源化单克隆抗体，其在RMS治疗中的潜在作用仍有待阐明。Syndecan-4（SDC4）是一种硫酸乙酰肝素蛋白聚糖（HSPG），通过Rac1介导的肌动蛋白重塑影响肌生成。此前，我们证明SDC4基因在28%的人类FNRMS样本中扩增，与高mRNA表达相关，提示其具有肿瘤驱动作用。在本研究中，分析人类RMS样本中其他HSPG的拷贝数和mRNA表达后，我们发现除SDC4外，syndecan-1、syndecan-2和glypican-1在FNRMS中也有扩增和高表达。在RD（人类FNRMS）细胞中，SDC4表达升高伴随着SDC4磷酸化Ser179水平降低，导致Rac1-GTP活性升高。值得注意的是，曲妥珠单抗治疗后RD细胞中这种高SDC4表达降低。曲妥珠单抗降低了G1/S期检查点调节因子细胞周期蛋白E和细胞周期蛋白D1的水平并减少了细胞数量；然而，它也下调了细胞周期蛋白依赖性激酶抑制剂p21。MyoD是RMS细胞存活所必需的转录因子，曲妥珠单抗给药后其水平也降低。我们的研究结果有助于理解SDC4在FNRMS中的作用。由于HER2在约一半的RMS中表达，此处观察到的曲妥珠单抗介导的变化可能具有治疗意义。
