Lin You-Cheng, Chu Yin-Hung, Liao Wen-Chieh, Chen Chia-Hua, Hsiao Wen-Chuan, Ho Ying-Jui, Yang Meng-Yin, Liu Chiung-Hui
Doctoral Program in Tissue Engineering and Regenerative Medicine, College of Medicine, National Chung Hsing University Taichung, Taiwan.
Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University Taichung, Taiwan.
Am J Cancer Res. 2023 Jul 15;13(7):2998-3012. eCollection 2023.
Aberrant chondroitin sulfate (CS) accumulation in glioblastoma (GBM) tissue has been documented, but the role of excessive CS in GBM progression and whether it can be a druggable target are largely unknown. The aim of this study is to clarify the biological functions of CHST11 in GBM cells, and evaluate therapeutic effects of blocking CHST11-derived chondroitin 4-sulfate (C4S). We investigated the expression of CHST11 in glioma tissue by immunohistochemistry, and analyzed CHST11 associated genes using public RNA sequencing datasets. The effects of CHST11 on aggressive cell behaviors have been studied and . We demonstrated that CHST11 is frequently overexpressed in GBM tissue, promoting GBM cell mobility and modulating C4S on GBM cells. We further discovered that CSPG4 is positively correlated with CHST11, and CSPG4 involved in CHST11-mediated cell invasiveness. In addition, GBM patients with high expression of CHST11 and CSPG4 have a significantly shorter survival time. We examined the effects of treating C4S-specific binding peptide (C4Sp) as a therapeutic agent and . C4Sp treatment attenuated GBM cell invasiveness and, notably, improved survival rate of orthotopic glioma cell transplant mice. Our results propose a possible mechanism of CHST11 in regulating GBM malignancy and highlight a novel strategy for targeting aberrant chondroitin sulfate in GBM cells.
已证实胶质母细胞瘤（GBM）组织中存在异常硫酸软骨素（CS）积累，但过量CS在GBM进展中的作用以及它是否可作为药物靶点在很大程度上尚不清楚。本研究的目的是阐明CHST11在GBM细胞中的生物学功能，并评估阻断CHST11衍生的硫酸软骨素4-硫酸酯（C4S）的治疗效果。我们通过免疫组织化学研究了CHST11在胶质瘤组织中的表达，并使用公共RNA测序数据集分析了与CHST11相关的基因。研究了CHST11对侵袭性细胞行为的影响。我们证明CHST11在GBM组织中经常过度表达，促进GBM细胞迁移并调节GBM细胞上的C4S。我们进一步发现CSPG4与CHST11呈正相关，且CSPG4参与CHST11介导的细胞侵袭。此外，CHST11和CSPG4高表达的GBM患者生存时间明显缩短。我们研究了将C4S特异性结合肽（C4Sp）作为治疗剂的效果。C4Sp治疗减弱了GBM细胞的侵袭性，并且显著提高了原位胶质瘤细胞移植小鼠的存活率。我们的结果提出了CHST11调节GBM恶性肿瘤的可能机制，并突出了针对GBM细胞中异常硫酸软骨素的新策略。
