Department of Neurosurgery, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong, China.
Guangdong Provincial Key Laboratory of Biomedical Imaging, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong, China.
Cancer Med. 2023 Jun;12(11):12943-12959. doi: 10.1002/cam4.5947. Epub 2023 Apr 16.
Vesicle trafficking is a highly important process in numerous human diseases, especially in the central nervous system dysfunctions. However, as a key component of vesicle trafficking-related genes (VRGs), Cornichon family AMPA receptor auxiliary protein 4 (CNIH4) has not been systematically elucidated in glioma so far.
Differentially expressed VRGs were selected using molecular signatures database (MSigDB), The Cancer Genome Atlas (TCGA), and Genotype-Tissue Expression (GTEx) mRNA expression profiles. Further exploration of CNIH4 was determined using LASSO-Cox regression algorithms. Then Kaplan-Meier (K-M) plotter, receiver operating characteristic (ROC) curves, and multivariate Cox regression analyses were utilized to assess the independent significance of CNIH4 in the CGGA validation cohort. Functional exploration was performed with Gene Set Enrichment Analysis (GSEA) and then verified using a series of functional experiments in glioma cells. Finally, the consensus clustering algorithm was applied to identify clusters in glioma samples. After that, differences in prognosis, the tumor immune microenvironment (TIME), and therapy response were evaluated between clusters.
CNIH4 was shown to be overexpressed in malignant glioma variants and was frequently observed in GCSs and TMZ-resistant cell lines. Higher CNIH4 levels were significantly related to poor outcomes and positively correlated with adverse clinicopathological characteristics. Survival analyses revealed CNIH4 as an independent risk factor that outperformed traditional measures. Enrichment analysis indicated that overactive CNIH4 significantly gathered in stem cell processes. Furthermore, functional assays of silencing CNIH4 expression suppressed stem cell-like properties in vitro and inhibited tumorigenicity in vivo. Finally, the CNIH4-enriched subgroup negatively modulated immunotherapeutic response and reflected lower chemotherapy sensitivity for glioma patients.
Our study identified CNIH4 as a potential VRG that regulates tumor stemness, microenvironment immunity, and chemotherapy sensitivity. It may serve as a novel prognostic factor and a promising target against glioma therapy.
囊泡运输是许多人类疾病中非常重要的过程，尤其是在中枢神经系统功能障碍中。然而，作为囊泡运输相关基因（VRGs）的关键组成部分，角蛋白家族 AMPA 受体辅助蛋白 4（CNIH4）在迄今为止的神经胶质瘤中尚未得到系统阐述。
使用分子特征数据库（MSigDB）、癌症基因组图谱（TCGA）和基因型组织表达（GTEx）mRNA 表达谱筛选差异表达的 VRGs。使用 LASSO-Cox 回归算法进一步探索 CNIH4。然后使用 Kaplan-Meier（K-M）绘图器、接收者操作特征（ROC）曲线和多变量 Cox 回归分析评估 CNIH4 在 CGGA 验证队列中的独立意义。使用基因集富集分析（GSEA）进行功能探索，然后使用一系列胶质瘤细胞的功能实验进行验证。最后，应用共识聚类算法对胶质瘤样本进行聚类。之后，评估了不同聚类之间的预后、肿瘤免疫微环境（TIME）和治疗反应的差异。
CNIH4 在恶性神经胶质瘤变体中表达上调，在 GCSs 和 TMZ 耐药细胞系中频繁观察到。较高的 CNIH4 水平与不良预后显著相关，与不良临床病理特征呈正相关。生存分析表明，CNIH4 是一个独立的风险因素，优于传统指标。富集分析表明，过度活跃的 CNIH4 显著聚集在干细胞过程中。此外，沉默 CNIH4 表达的功能测定在体外抑制了干细胞样特性，并抑制了体内肿瘤发生。最后，CNIH4 富集亚组负调节免疫治疗反应，反映了胶质瘤患者化疗敏感性较低。
本研究鉴定出 CNIH4 是一种潜在的 VRG，可调节肿瘤干细胞特性、微环境免疫和化疗敏感性。它可能成为一种新的预后因素和治疗神经胶质瘤的有前途的靶点。
