Liao Wen-Chieh, Liao Chih-Kai, Tseng To-Jung, Ho Ying-Jui, Chen Ying-Ru, Lin Kuan-Hung, Lai Te-Jen, Lan Chyn-Tair, Wei Kuo-Chen, Liu Chiung-Hui
Faculty of Medicine, Department of Anatomy, Chung Shan Medical University, Taichung, Taiwan.
Department of Medical Education, Chung Shan Medical University Hospital, Taichung, Taiwan.
Oncogenesis. 2020 Feb 4;9(2):9. doi: 10.1038/s41389-020-0197-0.
Chondroitin sulfate synthases, a family of enzyme involved in chondroitin sulfate (CS) polymerization, are dysregulated in various human malignancies, but their roles in glioma remain unclear. We performed database analysis and immunohistochemistry on human glioma tissue, to demonstrate that the expression of CHSY1 was frequently upregulated in glioma, and that it was associated with adverse clinicopathologic features, including high tumor grade and poor survival. Using a chondroitin sulfate-specific antibody, we showed that the expression of CHSY1 was significantly associated with CS formation in glioma tissue and cells. In addition, overexpression of CHSY1 in glioma cells enhanced cell viability and orthotopic tumor growth, whereas CHSY1 silencing suppressed malignant growth. Mechanistic investigations revealed that CHSY1 selectively regulates PDGFRA activation and PDGF-induced signaling in glioma cells by stabilizing PDGFRA protein levels. Inhibiting PDGFR activity with crenolanib decreased CHSY1-induced malignant characteristics of GL261 cells and prolonged survival in an orthotopic mouse model of glioma, which underlines the critical role of PDGFRA in mediating the effects of CHSY1. Taken together, these results provide information on CHSY1 expression and its role in glioma progression, and highlight novel insights into the significance of CHSY1 in PDGFRA signaling. Thus, our findings point to new molecular targets for glioma treatment.
硫酸软骨素合酶是一类参与硫酸软骨素（CS）聚合的酶，在多种人类恶性肿瘤中表达失调，但其在胶质瘤中的作用仍不清楚。我们对人类胶质瘤组织进行了数据库分析和免疫组化，以证明CHSY1在胶质瘤中经常上调表达，并且它与不良临床病理特征相关，包括高肿瘤分级和低生存率。使用硫酸软骨素特异性抗体，我们表明CHSY1的表达与胶质瘤组织和细胞中的CS形成显著相关。此外，CHSY1在胶质瘤细胞中的过表达增强了细胞活力和原位肿瘤生长，而CHSY1沉默则抑制了恶性生长。机制研究表明，CHSY1通过稳定PDGFRA蛋白水平选择性调节胶质瘤细胞中PDGFRA的激活和PDGF诱导的信号传导。用克伦洛尼抑制PDGFR活性可降低CHSY1诱导的GL261细胞的恶性特征，并延长胶质瘤原位小鼠模型的生存期，这强调了PDGFRA在介导CHSY1作用中的关键作用。综上所述，这些结果提供了关于CHSY1表达及其在胶质瘤进展中的作用的信息，并突出了对CHSY1在PDGFRA信号传导中的意义的新见解。因此，我们的发现指出了胶质瘤治疗的新分子靶点。
