Tetraspanins predict the prognosis and characterize the tumor immune microenvironment of glioblastoma.

Glioblastoma (GBM) is the most aggressive and lethal primary brain tumor. Conventional treatments have not achieved breakthroughs in improving survival. Therefore, novel molecular targets and biomarkers need to be identified. As signal transduction docks on the cell membrane, tetraspanins (TSPANs) are associated with various tumors; however, research on their role in GBM remains extremely scarce. Gene expression and clinicopathological characteristic data were obtained from GEPIA, CGGA, HPA, cBioPortal, and GSCA databases to analyze the mRNA and protein expression levels, prognostic value, clinical relevance, mutation status, and targeted drug sensitivity of TSPANs in GBM. Gene set enrichment analysis (GSEA), Gene Ontology (GO), and the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were used for biological process enrichment. Data from TCGA and TCIA were used to construct the tumor immune microenvironment landscape of TSPANs. Different R software algorithms were used to analyze the immune score, immune cell infiltration, and immune checkpoint correlation. Univariate and multivariate analyses were performed for TSPAN4, which had the most significant predictive prognostic value, and a nomogram model was constructed to predict individual outcomes. The expression and function of TSPAN4 were verified in vitro. TSPAN3/4/6/11/12/18/23/24/25/26/27/28/29/30/31expressions were significantly upregulated in GBM, and TSPAN3/4/6/11/18/24/25/26/29/30 were strongly correlated with prognosis. The expression of multiple TSPANs significantly correlated with 1p/19q co-deletion status, IDH mutation status, recurrence, age, and tumor grade. GSEA and GO analyses revealed the potential contribution of TSPANs in cell adhesion and migration. Immune correlation analysis revealed that TSPANs are related to the formation of the GBM tumor microenvironment (TME) and may influence immunotherapy outcomes. TSPAN4 is an independent prognostic factor and TSPAN4 knockdown has been demonstrated to strongly inhibit glioma cell proliferation, invasion, and migration in vitro. We comprehensively elaborated the prognostic value and potential role of differentially expressed TSPANs in GBM, including molecules that scientists have previously overlooked. This study provides a novel and comprehensive perspective on the pathological mechanisms of GBM and the future direction of individualized tumor immunotherapy, which may be a critical link between GBM malignant progression and TME remodeling.

胶质母细胞瘤（GBM）是最具侵略性和致命的原发性脑肿瘤。传统的治疗方法尚未在改善生存方面取得突破。因此，需要鉴定新的分子靶标和生物标志物。作为细胞膜上的信号转导码头，四跨果蛋白（TSPAN）与各种肿瘤有关。但是，研究其在GBM中的作用仍然非常稀缺。基因表达和临床病理学特征数据是从GEPIA，CGGA，HPA，CBIOPORTAL和GSCA数据库中获得的，以分析MRNA和蛋白质表达水平，预后价值，临床相关性，突变状态以及GBM中TSPAN的靶向药物敏感性。基因集富集分析（GSEA），基因本体论（GO）和基因和基因组的京都百科全书（KEGG）分析用于生物学过程富集。来自TCGA和TCIA的数据用于构建TSPAN的肿瘤免疫微环境景观。不同的R软件算法用于分析免疫评分，免疫细胞浸润和免疫检查点相关性。对TSPAN4进行了单变量和多变量分析，该分析具有最重要的预测性预后值，并构建了一个诺姆图模型以预测个体结果。 TSPAN4的表达和功能在体外验证。 TSPAN3/4/6/11/12/12/12/23/24/24/26/26/26/27/28/29/30/30/30/31表达在GBM中显着上调，TSPAN3/4/6/11/11/11/18/18/24/25/26/29/30与预后密切相关。多个TSPAN的表达与1P/19Q共脱落状态，IDH突变状态，复发，年龄和肿瘤等级显着相关。 GSEA和GO分析揭示了TSPAN在细胞粘附和迁移中的潜在贡献。免疫相关分析表明，TSPAN与GBM肿瘤微环境（TME）的形成有关，并可能影响免疫疗法的结果。 TSPAN4是一个独立的预后因素，已证明TSPAN4敲低可以在体外强烈抑制神经胶质瘤细胞的增殖，侵袭和迁移。我们全面阐述了差异表达的TSPAN在GBM中的预后价值和潜在作用，包括科学家以前忽略的分子。这项研究为GBM的病理机制和个性化肿瘤免疫疗法的未来方向提供了一种新颖而全面的观点，这可能是GBM恶性进展与TME重塑之间的关键联系。