LncRNA RP3-525N10.2-NFKB1-PROS1 triplet-mediated low PROS1 expression is an onco-immunological biomarker in low-grade gliomas: a pan-cancer analysis with experimental verification

Zhou, Yujie; Xiao, Dongdong; Jiang, Xiaobing

doi:10.1186/s12967-022-03536-y

Cited by 8 publications

(7 citation statements)

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“…Glioma is called a “cold” tumor with poorly T cell-exhausted and less responsive to immune checkpoints ( 44 ). However, some studies have shown that targeted PROS1 might decrease immune checkpoint gene expression and increase the efficacy of immunotherapy ( 45 ). According to us, the expression of PROS1 is significantly related to marker genes of T cell exhaustion (PD-L1, HAVCR2, and CTLA4), and immunosuppressive immune cells (TAMs, MDSC, and Treg) ( Figures 6D, E ).…”

Section: Discussionmentioning

confidence: 99%

PROS1 shapes the immune-suppressive tumor microenvironment and predicts poor prognosis in glioma

Wang

Feng³

et al. 2023

Front. Immunol.

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BackgroundGlioma is the most malignant cancer in the brain. As a major vitamin-K-dependent protein in the central nervous system, PROS1 not only plays a vital role in blood coagulation, and some studies have found that it was associated with tumor immune infiltration. However, the prognostic significance of PROS1 in glioma and the underlying mechanism of PROS1 in shaping the tumor immune microenvironment (TIME) remains unclear.MethodsThe raw data (including RNA-seq, sgRNA-seq, clinicopathological variables and prognosis, and survival data) were acquired from public databases, including TCGA, GEPIA, CGGA, TIMER, GEO, UALCAN, and CancerSEA. GO enrichment and KEGG pathway analyses were performed using “cluster profiler” package and visualized by the “ggplot2” package. GSEA was conducted using R package “cluster profiler”. Tumor immune estimation resource (TIMER) and spearman correlation analysis were applied to evaluate the associations between infiltration levels of immune cells and the expression of PROS1. qRT-PCR and WB were used to assay the expression of PROS1. Wound-healing assay, transwell chambers assays, and CCK-8 assays, were performed to assess migration and proliferation. ROC and KM curves were constructed to determine prognostic significance of PROS1 in glioma.ResultsThe level of PROS1 expression was significantly increased in glioma in comparison to normal tissue, which was further certificated by qRT-PCR and WB in LN-229 and U-87MG glioma cells. High expression of PROS1 positively correlated with inflammation, EMT, and invasion identified by CancerSEA, which was also proved by downregulation of PROS1 could suppress cells migration, and proliferation in LN-229 and U-87MG glioma cells. GO and KEGG analysis suggested that PROS1 was involved in disease of immune system and T cell antigen receptor pathway. Immune cell infiltration analysis showed that expression of PROS1 was negatively associated with pDC and NK CD56 bright cells while positively correlated with Macrophages, Neutrophils in glioma. Immune and stromal scores analysis indicated that PROS1 was positively associated with immune score. The high level of PROS1 resulted in an immune suppressive TIME via the recruitment of immunosuppressive molecules. In addition, Increased expression of PROS1 was correlated with T-cell exhaustion, M2 polarization, poor Overall-Survival (OS) in glioma. And it was significantly related to tumor histological level, age, primary therapy outcome. The results of our experiment and various bioinformatics approaches validated that PROS1 was a valuable poor prognostic marker.ConclusionIncreased expression of PROS1 was correlated with malignant phenotype and associated with poor prognosis in glioma. Besides, PROS1 could be a possible biomarker and potential immunotherapeutic target through promoting the glioma immunosuppressive microenvironment and inducing tumor-associated macrophages M2 polarization.

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Section: Discussionmentioning

confidence: 99%

PROS1 shapes the immune-suppressive tumor microenvironment and predicts poor prognosis in glioma

Wang

Feng³

et al. 2023

Front. Immunol.

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“…PROS1 , a vital blood coagulation gene, was considered to promote the glioma immunosuppressive microenvironment ( 80 ). In addition, another study showed PROS1 was enriched in complement activation in LGG, indicating the critical role of CCC in the progression of LGG ( 81 ).…”

Section: Discussionmentioning

confidence: 99%

Complement and coagulation cascades are associated with prognosis and the immune microenvironment of lower-grade glioma

Yang,

Shen,

Yang

et al. 2024

Transl Cancer Res

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Background Abnormal coagulation is a common feature of glioma. There is a strong correlation between coagulation and the complement system, named complement and coagulation cascades (CCC). However, the role of CCC genes in lower-grade glioma (LGG) remains unclear. This study aimed to investigate the role of CCC genes in LGG. Methods In total, 5,628 differential expressed genes were identified between 498 LGG tissues from The Cancer Genome Atlas (TCGA) and 207 normal brain tissues from Genotype-Tissue Expression Project (GTEx). Among them, 20 overlapped CCC genes were identified as differentially expressed CCC genes. Then, comprehensive bioinformatics analysis was used to investigate the role of CCC genes in LGG; 271 LGG tissues from the Chinese Glioma Genome Atlas (CGGA) were used as the validation dataset. Cell Counting Kit-8 (CCK8) proliferation assay, colony formation assay, and wound healing assay were conducted to explore the anti-glioma effect of the sensitive drugs we predicted. Results We constructed a risk signature consisting of six CCC genes, including F2R , SERPINA1 , TFPI , C1QC , C2 , and C3AR1 . The CCC gene-based risk signature could accurately predict the prognosis of patients with LGG. In addition, we found that the JAK-STAT, NOD-like receptor, Notch, PI3K-Akt, and Rap1 signaling pathways might be activated and had crosstalk with CCC in the high-risk group. Our findings analyses demonstrated that samples in high- and low-risk groups had different immune landscapes. Moreover, patients in the high-risk group might have greater resistance to immunotherapy. We validated the accuracy of the risk signature in predicting immunotherapy response in two public immunotherapy cohorts, GSE135222 and GSE78220. By means of oncoPredict, MG-132, BMS-536924, PLX-4720, and AZD6482 were identified as potential sensitive drugs for high-risk patients, of which MG-132 was particularly recommended for high-risk patients. We performed in vitro experiments to explore the anti-glioma effect of MG-132, and the results demonstrated MG-132 could inhibit the proliferation and migration of glioma cells. Conclusions Our findings show that CCC genes are associated with the prognosis and immune infiltration of LGG and provide possible immunotherapeutic and novel chemotherapeutic strategies for patients with LGG based on the risk signature.

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“…The assay complies with the protocol described in a previous article [ 16 ]. Short hairpin RNA (shRNA) against EREG (shEREG) and a negative control shRNA (sh NC) were designed and synthesized by GeneCreate (Wuhan, China).…”

Section: Methodsmentioning

confidence: 99%

EREG is the core onco-immunological biomarker of cuproptosis and mediates the cross-talk between VEGF and CD99 signaling in glioblastoma

et al. 2023

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Background Glioma is the most prevalent primary tumor of the central nervous system. Glioblastoma multiforme (GBM) is the most malignant form of glioma with an extremely poor prognosis. A novel, regulated cell death form of copper-induced cell death called “cuproptosis” provides a new prospect for cancer treatment by regulating cuproptosis. Methods Data from bulk RNA sequencing (RNA-seq) analysis (The Cancer Genome Atlas cohort and Chinese Glioma Genome Atlas cohort) and single cell RNA-seq (scRNA-seq) analysis were integrated to reveal their relationships. A scoring system was constructed according to the cuproptosis-related gene expression, and core genes were experimentally verified using real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR), Western blot (WB), immunohistochemistry (IHC), and immunofluorescence (IF). Moreover, cell counting kit-8 (CCK8), colony formation, 5-ethynyl-2’-deoxyuridine (EdU) incorporation, transwell, and flow cytometry cell cycle were performed to evaluate cell proliferation, invasion, and migration. Results The Cuproptosis Activation Scoring (CuAS) Model has stable and independent prognostic efficacy, as verified by two CGGA datasets. Epiregulin (EREG), the gene of the model has the most contributions in the principal component analysis (PCA), is an onco-immunological gene that can affect immunity by influencing the expression of programmed death-ligand 1 (PD-L1) and mediate the process of cuproptosis by influencing the expression of ferredoxin 1 (FDX1). Single cell transcriptome analysis revealed that high CuAS GBM cells are found in vascular endothelial growth factor A (VEGFA) + malignant cells. Oligodendrocyte transcription factor 1 (OLIG1) + malignant is the original clone, and VEGF and CD99 are the differential pathways of specific cell communication between the high and low CuAS groups. This was also demonstrated by immunofluorescence in the tissue sections. Furthermore, CuAS has therapeutic potential for immunotherapy, and we predict that many drugs (methotrexate, NU7441, KU -0063794, GDC-0941, cabozantinib, and NVP-BEZ235) may be used in patients with high CuAS. Conclusion EREG is the core onco-immunological biomarker of CuAS and modulates the cross-talk between VEGF and CD99 signaling in glioblastoma, and CuAS may provide support for immunotherapy and chemotherapy.

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LncRNA RP3-525N10.2-NFKB1-PROS1 triplet-mediated low PROS1 expression is an onco-immunological biomarker in low-grade gliomas: a pan-cancer analysis with experimental verification

Cited by 8 publications

References 43 publications

PROS1 shapes the immune-suppressive tumor microenvironment and predicts poor prognosis in glioma

PROS1 shapes the immune-suppressive tumor microenvironment and predicts poor prognosis in glioma

Complement and coagulation cascades are associated with prognosis and the immune microenvironment of lower-grade glioma

EREG is the core onco-immunological biomarker of cuproptosis and mediates the cross-talk between VEGF and CD99 signaling in glioblastoma

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