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

in Cancer cell international by Qi Wang, Chunyu Zhang, Ying Pang, Meng Cheng, Rui Wang, Xu Chen, Tongjie Ji, Yuntong Yang, Jing Zhang, Chunlong Zhong

TLDR

  • The study found that IER3 is a protein that plays a crucial role in glioma pathology. Gliomas are a type of brain tumor that can be deadly. The study found that IER3 is overexpressed and hypomethylated in gliomas, which means that it is produced in higher amounts and its DNA is not properly regulated. This can lead to the development of cancerous cells. The study also found that IER3 is associated with a poor prognosis for glioma patients. This means that if a patient has high levels of IER3, they are more likely to have a worse outcome. The study also found that IER3 is associated with a less invasive subtype of gliomas and favorable prognosis. This means that if a patient has low levels of IER3, they are more likely to have a less aggressive tumor and a better outcome. The study also found that IER3 is associated with increased sensitivity to Dabrafenib, an inhibitor of BRAF. This means that if a patient has high levels of IER3, they may be more responsive to certain treatments. The study also found that IER3 is associated with a low mutation rate of IDH, high gain rates of BRAF, ELTD1, and PDGFA. This means that if a patient has high levels of IER3, they may have certain genetic mutations that are associated with a worse outcome. The study also found that IER3 is co-localized and co-expressed with TGFBI. This means that if a patient has high levels of IER3, they may also have high levels of TGFBI, which is a protein that can promote the growth of cancerous cells. The study also found that siRNA-silenced IER3 cells had lower migration, invasion, proliferation, and cell viability than the control group. This means that if a patient's IER3 levels are reduced, their tumor may be less aggressive and have a better outcome. Overall, the study suggests that IER3 is an important biomarker for glioma pathology and could be a valuable target for future treatments.

Abstract

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

Overview

  • The study investigates the role of immediate early response 3 (IER3) in glioma pathology using immunohistochemistry (IHC) assay and publicly available glioma datasets. The study measures the cell viability and capacities of migration and invasion of glioma cells in vitro using wound healing, invasion and cell counting kit-8 (CCK8) assays. 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. The study found that 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. The study identifies IER3 upregulation as an essential biomarker that could assist in adjuvant therapy and prognosis prediction for gliomas.

Comparative Analysis & Findings

  • The study compared the outcomes observed under different experimental conditions or interventions detailed in the study. The results showed that 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. The study found that IER3 upregulation was an essential biomarker that could assist in adjuvant therapy and prognosis prediction for gliomas.

Implications and Future Directions

  • The study's findings suggest that IER3 plays a crucial role in glioma pathology and could be a valuable biomarker for adjuvant therapy and prognosis prediction. The study identified two subgroups of gliomas based on IER3 expression, with the high IER3 subgroup featuring increased infiltration of TAMMs and elevated sensitivity to Dabrafenib. The study also revealed that IER3 upregulation was associated with a less invasive subtype of gliomas and favorable prognosis. Future research could further explore the role of IER3 in glioma pathology, investigate the potential of IER3 as a therapeutic target, and evaluate the effectiveness of IER3-targeted therapies in clinical settings.
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