对批量、单细胞RNA测序和空间转录组学的综合分析揭示了IER3可用于预测胶质瘤的恶性进展和免疫治疗疗效。

Comprehensive analysis of bulk, single-cell RNA sequencing, and spatial transcriptomics revealed IER3 for predicting malignant progression and immunotherapy efficacy in glioma.

作者信息

Wang Qi, Zhang Chunyu, Pang Ying, Cheng Meng, Wang Rui, Chen Xu, Ji Tongjie, Yang Yuntong, Zhang Jing, Zhong Chunlong

机构信息

Department of Neurosurgery, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China.

Institute for Advanced Study, Tongji University, Shanghai, China.

出版信息

Cancer Cell Int. 2024 Oct 1;24(1):332. doi: 10.1186/s12935-024-03511-1.

DOI:10.1186/s12935-024-03511-1

PMID:39354533

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11443732/

Abstract

BACKGROUND

As part of stress-triggered molecules, immediate early response 3 (IER3) dysregulation has been reported to sustain pro-oncogenic pathways and precede malignant transformation. However, the role of IER3 in glioma pathology is ill-defined.

METHODS

Immunohistochemistry (IHC) assay and publicly available glioma datasets were used to calculate the IER3 expression level in glioma. Wound healing, invasion and cell counting kit-8 (CCK8) assays were applied to measure the cell viability and capacities of migration and invasion of glioma cells in vitro. The immunofluorescence (IF) assay was used to assess the expression associations of IER3 with CCL2 and TGFBI. Cox regression analysis and Kaplan-Meier (K-M) curve were introduced to compute the prognosis-predicting value of IER3. Variations in copy number (CNVs), single nucleotide (SNVs), and methylation profiles were analyzed to illustrate the epigenetic modifications of IER3. Gliomas were divided into two subgroups using the restricted cubic spline (RCS) method. RESULTS IER3: was overexpressed and hypomethylated in gliomas and significantly associated with the dismal prognosis of glioma samples. Samples in the high IER3 subgroup were characterized by increased infiltration of tumor-associated monocytes/macrophages (TAMMs), as well as the elevated sensitivity to Dabrafenib, an inhibitor of BRAF. In addition, this subgroup demonstrated a low mutation rate of IDH, high gain rates of BRAF, ELTD1, and PDGFA. Gliomas with relatively low IER3 expression demonstrated a less invasive subtype and were featured by favorable prognosis, increased response to immunotherapy, and adjuvant chemotherapy plus radiotherapy. The IF assay revealed that IER3 was co-localized and co-expressed with TGFBI. The glioma cells with small interfering RNA (siRNA)-silenced IER3 displayed lower migration, invasion, proliferation, and cell viability than the control group.

CONCLUSIONS

In this study, we identified IER3 upregulation as an essential biomarker that could assist in adjuvant therapy and prognosis prediction for gliomas.

摘要

背景

作为应激触发分子的一部分，据报道，即刻早期反应3（IER3）失调会维持促癌途径并先于恶性转化。然而，IER3在胶质瘤病理学中的作用尚不明确。

方法

采用免疫组织化学（IHC）检测和公开可用的胶质瘤数据集来计算胶质瘤中IER3的表达水平。应用伤口愈合、侵袭和细胞计数试剂盒-8（CCK8）检测来测量胶质瘤细胞在体外的细胞活力、迁移和侵袭能力。免疫荧光（IF）检测用于评估IER3与CCL2和TGFBI的表达相关性。引入Cox回归分析和Kaplan-Meier（K-M）曲线来计算IER3的预后预测价值。分析拷贝数变异（CNV）、单核苷酸变异（SNV）和甲基化谱的变化，以阐明IER3的表观遗传修饰。使用限制性立方样条（RCS）方法将胶质瘤分为两个亚组。

结果

IER3在胶质瘤中过表达且低甲基化，与胶质瘤样本的不良预后显著相关。高IER3亚组的样本特征是肿瘤相关单核细胞/巨噬细胞（TAMM）浸润增加，以及对BRAF抑制剂达拉非尼的敏感性升高。此外，该亚组显示异柠檬酸脱氢酶（IDH）突变率低，BRAF、ELTD1和血小板衍生生长因子A（PDGFA）的高增益率。IER3表达相对较低的胶质瘤表现出侵袭性较小的亚型，其特征是预后良好、对免疫治疗的反应增加以及辅助化疗加放疗。IF检测显示IER3与TGFBI共定位并共表达。用小干扰RNA（siRNA）沉默IER3的胶质瘤细胞比对照组表现出更低的迁移、侵袭、增殖和细胞活力。