Guo Xing, Guo Shuhua, Tian Feng, Gao Zijie, Fan Yang, Wang Chuanxin, Xu Shuo
Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, Shandong, China.
Department of Clinical Laboratory, The Second Hospital of Shandong University, Jinan, Shandong, China.
CNS Neurosci Ther. 2024 Dec;30(12):e70128. doi: 10.1111/cns.70128.
The presence of glioma stem cells (GSCs) and the occurrence of mesenchymal phenotype transition contribute to the miserable prognosis of glioblastoma (GBM). Cellular communication network factor 1 (CCN1) is upregulated within various malignancies and associated with cancer development and progression, while the implications of CCN1 in the phenotype transition and tumorigenicity of GSCs remain unclear.
Data for bioinformatic analysis were obtained from The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) databases. A range of primary GBM and GSC cell models were then used to demonstrate the regulatory role of CCN1 via the phenotype validation, tumor sphere formation assays, extreme limiting dilution assays (ELDA), and transwell assays. To screen out the downstream signaling pathway, we employed high-throughput RNA-seq. Intracranial xenograft GSC mouse models were used to investigate the role of CCN1 in vivo.
Among the CCN family members, CCN1 was highly expressed in MES-GBM/GSCs and was correlated with a poor prognosis. Both in vitro and in vivo assays indicated that knockdown of CCN1 in MES-GSCs reduced the tumor stemness, proliferation, invasion, and tumorigenicity, whereas CCN1 overexpression in PN-GSCs exhibited the opposite effects. Mechanistically, CCN1 triggered the FAK/STAT3 signaling in autocrine and paracrine manners to upregulate the expression of S100A8. Knockdown of S100A8 inactivated NF-κB/p65 pathway and significantly suppressed the tumorigenesis of MES-GSCs.
Our findings reveal that CCN1 may be an important factor in the enhanced invasiveness and MES phenotype transition of GSCs and highlight the potential to target CCN1 for treating GBM.
胶质瘤干细胞（GSCs）的存在以及间充质表型转变的发生导致胶质母细胞瘤（GBM）预后不佳。细胞通讯网络因子1（CCN1）在多种恶性肿瘤中上调，并与癌症的发生和发展相关，而CCN1在GSCs表型转变和致瘤性中的作用仍不清楚。
从癌症基因组图谱（TCGA）和中国胶质瘤基因组图谱（CGGA）数据库中获取生物信息学分析数据。然后使用一系列原发性GBM和GSC细胞模型，通过表型验证、肿瘤球形成试验、极限稀释分析（ELDA）和Transwell试验来证明CCN1的调节作用。为了筛选出下游信号通路，我们采用了高通量RNA测序。采用颅内异种移植GSC小鼠模型研究CCN1在体内的作用。
在CCN家族成员中，CCN1在间充质型GBM/GSCs中高表达，且与预后不良相关。体外和体内试验均表明，敲低间充质型GSCs中的CCN1可降低肿瘤干性、增殖、侵袭和致瘤性，而在原神经型GSCs中过表达CCN1则表现出相反的效果。机制上，CCN1以自分泌和旁分泌方式触发FAK/STAT3信号，上调S100A8的表达。敲低S100A8可使NF-κB/p65通路失活，并显著抑制间充质型GSCs的肿瘤发生。
我们的研究结果表明，CCN1可能是GSCs侵袭性增强和间充质表型转变的重要因素，并突出了靶向CCN1治疗GBM的潜力。
