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

IF 5.3 2区医学 Q1 ONCOLOGY Cancer Cell International Pub Date : 2024-10-01 DOI:10.1186/s12935-024-03511-1

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

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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.

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通过对体细胞、单细胞 RNA 测序和空间转录组学的综合分析，发现 IER3 可用于预测胶质瘤的恶性进展和免疫疗法疗效。

背景：据报道，作为应激触发分子的一部分，即时早期反应3（IER3）失调可维持促癌通路，并在恶性转化之前发生。然而，IER3 在胶质瘤病理学中的作用尚不明确：方法：使用免疫组化（IHC）检测和公开的胶质瘤数据集来计算胶质瘤中IER3的表达水平。采用伤口愈合、侵袭和细胞计数试剂盒-8（CCK8）测定法来测量胶质瘤细胞在体外的活力以及迁移和侵袭能力。免疫荧光（IF）测定用于评估IER3与CCL2和TGFBI的表达关系。研究引入了Cox回归分析和Kaplan-Meier（K-M）曲线来计算IER3的预后预测价值。分析了拷贝数（CNVs）、单核苷酸（SNVs）和甲基化的变化，以说明IER3的表观遗传学修饰。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：在胶质瘤中过表达和低甲基化，与胶质瘤样本的不良预后显著相关。高 IER3 亚组样本的特点是肿瘤相关单核细胞/巨噬细胞（TAMMs）浸润增加，以及对 BRAF 抑制剂达拉非尼（Dabrafenib）的敏感性升高。此外，该亚组的IDH突变率较低，BRAF、ELTD1和PDGFA的增益率较高。IER3表达相对较低的胶质瘤属于侵袭性较低的亚型，预后良好，对免疫疗法和辅助化疗加放疗的反应较强。IF检测显示，IER3与TGFBI共定位和共表达。与对照组相比，小干扰RNA（siRNA）沉默IER3的胶质瘤细胞显示出较低的迁移、侵袭、增殖和细胞活力：在这项研究中，我们发现IER3上调是一种重要的生物标志物，有助于胶质瘤的辅助治疗和预后预测。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cancer Cell International ONCOLOGY-

CiteScore

10.90

自引率

1.70%

发文量

360

审稿时长

1 months

期刊介绍： Cancer Cell International publishes articles on all aspects of cancer cell biology, originating largely from, but not limited to, work using cell culture techniques. The journal focuses on novel cancer studies reporting data from biological experiments performed on cells grown in vitro, in two- or three-dimensional systems, and/or in vivo (animal experiments). These types of experiments have provided crucial data in many fields, from cell proliferation and transformation, to epithelial-mesenchymal interaction, to apoptosis, and host immune response to tumors. Cancer Cell International also considers articles that focus on novel technologies or novel pathways in molecular analysis and on epidemiological studies that may affect patient care, as well as articles reporting translational cancer research studies where in vitro discoveries are bridged to the clinic. As such, the journal is interested in laboratory and animal studies reporting on novel biomarkers of tumor progression and response to therapy and on their applicability to human cancers.