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A Novel Defined Endoplasmic Reticulum Stress-Related lncRNA Signature for Prognosis Prediction and Immune Therapy in Glioma

ABSTRACT: Gliomas are a group of the most aggressive primary central nervous system tumors with limited treatment options. The abnormal expression of long non-coding RNA (lncRNA) is related to the prognosis of glioma. However, the role of endoplasmic reticulum (ER) stress-associated lncRNAs in glioma prognosis has not been reported. In this paper, we obtained ER stress-related lncRNAs by co-expression analysis, and then a risk signature composed of 6 ER stress-related lncRNAs was constructed using Cox regression analysis. Glioma samples in The Cancer Genome Atlas (TCGA) were separated into high- and low-risk groups based on the median risk score. Compared with the low-risk group, patients in the high-risk group had shorter survival times. Additionally, we verified the predictive ability of these candidate lncRNAs in the testing set. Three glioma patient subgroups (cluster 1/2/3) were identified by consensus clustering. We further analysed the abundance of immune-infiltrating cells and the expression levels of immune checkpoint molecules in both three subgroups and two risk groups, respectively. Immunotherapy and anticancer drug response prediction showed that ER stress-related lncRNA risk signature positively correlates with responding to immune checkpoints and chemosensitivity. Functional analysis showed that these gene sets are enriched in the malignant process of tumors. Finally, LINC00519 was chosen for functional experiments. The silence of LINC00519 restrained the migration and invasion of glioma cells. Hence, those results indicated that ER stress-related lncRNA risk signature could be a potential treatment target and a prognosis biomarker for glioma patients.

SUBMITTER: Zheng Y

PROVIDER: S-EPMC9282894 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundGlioma is the most common brain tumor in adults and is characterized by a short survival time and high resistance to chemotherapy. It is imperative to determine the prognosis and therapy-related targets for glioma. Endoplasmic reticulum stress (ERS), as an adaptive protective mechanism, indicates the unfolded protein response (UPR) to determine cell survival and affects chemotherapy sensitivity, which is related to the prognosis of glioma.MethodsOur research used the TCGA database as the training group and the CGGA database as the testing group. Lasso regression and Cox analysis were performed to construct an ERS signature-based risk score model in glioma. Three methods (time-dependent receiver operating characteristic analysis and multivariate and univariate Cox regression analysis) were applied to assess the independent prognostic effect of texture parameters. Consensus clustering was used to classify the two clusters. In addition, functional and immune analyses were performed to assess the malignant process and immune microenvironment. Immunotherapy and anticancer drug response prediction were adopted to evaluate immune checkpoint and chemotherapy sensitivity.ResultsThe results revealed that the 7-gene signature strongly predicts glioma prognosis. The two clusters have markedly distinct molecular and prognostic features. The validation group result revealed that the signature has exceptional repeatability and certainty. Functional analysis showed that the ERS-related gene signature was closely associated with the malignant process and prognosis of tumors. Immune analysis indicated that the ERS-related gene signature is strongly related to immune infiltration. Immunotherapy and anticancer drug response prediction indicated that the ERS-related gene signature is positively correlated with immune checkpoint and chemotherapy sensitivity.ConclusionsCollectively, the ERS-related risk model can provide a novel signature to predict glioma prognosis and treatment.

Project description:AimsThe dysregulation of TGF-β signaling is a crucial pathophysiological process in tumorigenesis and progression. LncRNAs have diverse biological functions and are significant participants in the regulation of tumor signaling pathways. However, the clinical value of lncRNAs related to TGF-β signaling in glioma is currently unclear.MethodsData on glioma's RNA-seq transcriptome, somatic mutation, DNA methylation data, and clinicopathological information were derived from the CGGA and TCGA databases. A prognostic lncRNA signature was constructed by Cox and LASSO regression analyses. TIMER2.0 database was utilized to deduce immune infiltration characteristics. "ELMER v.2" was used to reconstruct TF-methylation-gene regulatory network. Immunotherapy and chemotherapy response predictions were implemented by the TIDE algorithm and GDSC database, respectively. In vitro and in vivo experiments were conducted to verify the results and clarify the regulatory mechanism of lncRNA.ResultsIn glioma, a TGF-β signaling-related 15-lncRNA signature was constructed, including AC010173.1, HOXA-AS2, AC074286.1, AL592424.1, DRAIC, HOXC13-AS, AC007938.1, AC010729.1, AC013472.3, AC093895.1, AC131097.4, AL606970.4, HOXC-AS1, AGAP2-AS1, and AC002456.1. This signature proved to be a reliable prognostic tool, with high risk indicating an unfavorable prognosis and being linked to malignant clinicopathological and genomic mutation traits. Risk levels were associated with different immune infiltration landscapes, where high risk was indicative of high levels of macrophage infiltration. In addition, high risk also suggested better immunotherapy and chemotherapy response. cg05987823 was an important methylation site in glioma progression, and AP-1 transcription factor family participated in the regulation of signature lncRNA expression. AGAP2-AS1 knockdown in in vitro and in vivo experiments inhibited the proliferation, migration, and invasion of glioma cells, as well as the growth of glioma, by downregulating the expression levels of NF-κB and ERK 1/2 in the TGF-β signaling pathway.ConclusionsA prognostic lncRNA signature of TGF-β signaling was established in glioma, which can be used for prognostic judgment, immune infiltration status inference, and immunotherapy response prediction. AGAP2-AS1 plays an important role in glioma progression.

Project description:BackgroundThe tumor immune microenvironment is closely related to the malignant progression and treatment resistance of glioma. Long non-coding RNA (lncRNA) plays a regulatory role in this process. We investigated the pathological mechanisms within the glioma microenvironment and potential immunotherapy resistance related to lncRNAs.MethodWe downloaded datasets derived from glioma patients and analyzed them by hierarchical clustering. Next, we analyzed the immune microenvironment of glioma, related gene expression, and patient survival. Coexpressed lncRNAs were analyzed to generate a model of lncRNAs and immune-related genes. We analyzed the model using survival and Cox regression. Then, univariate, multivariate, receiver operating characteristic (ROC), and principle component analysis (PCA) methods were used to verify the accuracy of the model. Finally, GSEA was used to evaluate which functions and pathways were associated with the differential genes.ResultsNormal brain tissue maintains a low-medium immune state, and gliomas are clearly divided into three groups (low to high immunity). The stromal, immune, and estimate scores increased along with immunity, while tumor purity decreased. Further, human leukocyte antigen (HLA), programmed cell death-1 (PDL1), T cell immunoglobulin and mucin domain 3 (TIM-3), B7-H3, and cytotoxic T lymphocyte-associated antigen-4 (CTLA4) expression increases concomitantly with immune state, and the patient prognosis worsens. Five immune gene-related lncRNAs (AP001007.1, LBX-AS1, MIR155HG, MAPT-AS1, and LINC00515) were screened to construct risk models. We found that risk scores are related to patient prognosis and clinical characteristics, and are positively correlated with PDL1, TIM-3, and B7-H3 expression. These lncRNAs may regulate the tumor immune microenvironment through cytokine-cytokine receptor interactions, complement, and coagulation cascades, and may promote CD8 + T cell, regulatory T cell, M1 macrophage, and infiltrating neutrophils activity in the high-immunity group. In vitro, the abnormal expression of immune-related lncRNAs and the relationship between risk scores and immune-related indicators (PDL1, CTLA4, CD3, CD8, iNOS) were verified by q-PCR and immunohistochemistry (IHC).ConclusionFor the first time, we constructed immune gene-related lncRNA risk models. The risk score may be a new biomarker for tumor immune subtypes and provide molecular targets for glioma immunotherapy.

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A Novel Defined Endoplasmic Reticulum Stress-Related lncRNA Signature for Prognosis Prediction and Immune Therapy in Glioma

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