Li Jia, Lv Fangfang, Jin Ting
Department of Neurology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
Department of Pediatric Pulmonology, The Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, Wenzhou, China.
Front Neurol. 2022 Nov 3;13:1024869. doi: 10.3389/fneur.2022.1024869. eCollection 2022.
Recent studies indicate that cell mechanics are associated with malignancy through its impact on cell migration and adhesion. Gliomas are the most common primary malignant brain tumors. Low-grade gliomas (LGGs) include diffuse LGGs (WHO grade II) and intermediate-grade gliomas (WHO grade III). Few studies have focused on membrane tension in LGGs. Herein, we assessed the prognostic value of plasma membrane tension-related genes (MTRGs) in LGGs.
We selected plasma MTRGs identified in previous studies for analysis. Based on LGG RNA sequencing (RNA-seq) data in The Cancer Genome Atlas, a prognostic signature containing four genes was constructed log-rank testing, LASSO regression and stepwise multivariate Cox regression and was validated with other datasets. Additionally, functional annotation, pathway enrichment and immune and molecular characteristics of the prognostic model defined subgroups were analyzed. Thereafter, a predictive nomogram that integrated baseline characteristics was constructed to determine the 3, 5, and 10-year overall survival (OS) of patients with LGG. Differentially expressed genes were confirmed quantitative reverse-transcription polymerase chain reaction (qRT-PCR) and immunohistochemistry (IHC).
Our MTRG prognostic signature was based on ARFIP2, PICK1, SH3GL2, and SRGAP3 expression levels. The high-risk group was more positively associated with apoptosis and cell adhesion pathways and exhibited a low IDH1 mutation rate, high TP53 mutation rate and a low 1p19q co-deletion rate. The high-risk group also exhibited incremental infiltration of immune cells, more forceful immune activities and high expression of immune checkpoints as well as benefited less from immune therapy compared with the low-risk group. Our prognostic model had better forecasting ability than other scoring systems. We found that the nomogram was a better tool for predicting outcomes for patients with LGG. Finally, qRT-PCR confirmed that SH3GL2 and SRGAP3 expression levels in glioma tissues were significantly lower than those in normal brain tissues. The results of IHC analysis confirmed that SH3GL2 protein expression was higher in patients with longer survival.
Our plasma membrane tension-related gene prognostic signature is a prospective tool that can differentiate between prognosis, gene mutation landscape, immune microenvironment, immune infiltration and immunotherapeutic efficacy in LGG.
最近的研究表明，细胞力学通过对细胞迁移和黏附的影响与恶性肿瘤相关。神经胶质瘤是最常见的原发性恶性脑肿瘤。低级别神经胶质瘤（LGG）包括弥漫性LGG（世界卫生组织二级）和中级神经胶质瘤（世界卫生组织三级）。很少有研究关注LGG中的细胞膜张力。在此，我们评估了细胞膜张力相关基因（MTRG）在LGG中的预后价值。
我们选择了先前研究中确定的血浆MTRG进行分析。基于癌症基因组图谱中的LGG RNA测序（RNA-seq）数据，通过对数秩检验、LASSO回归和逐步多变量Cox回归构建了一个包含四个基因的预后特征，并在其他数据集上进行了验证。此外，还分析了预后模型定义亚组的功能注释、通路富集以及免疫和分子特征。此后，构建了一个整合基线特征的预测列线图，以确定LGG患者的3年、5年和10年总生存期（OS）。通过定量逆转录聚合酶链反应（qRT-PCR）和免疫组织化学（IHC）证实了差异表达基因。
我们的MTRG预后特征基于ARFIP2、PICK1、SH3GL2和SRGAP3的表达水平。高危组与凋亡和细胞黏附通路的相关性更强，IDH1突变率低，TP53突变率高，1p19q共缺失率低。与低危组相比，高危组还表现出免疫细胞浸润增加、免疫活性更强、免疫检查点高表达，且从免疫治疗中获益较少。我们的预后模型比其他评分系统具有更好的预测能力。我们发现列线图是预测LGG患者预后的更好工具。最后，qRT-PCR证实神经胶质瘤组织中SH3GL2和SRGAP3的表达水平明显低于正常脑组织。IHC分析结果证实，生存期较长的患者SH3GL2蛋白表达较高。
我们的细胞膜张力相关基因预后特征是一种前瞻性工具，可区分LGG的预后、基因突变格局、免疫微环境、免疫浸润和免疫治疗疗效。
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