scholarly journals An Integrative Pan-Cancer Analysis Revealing LCN2 as an Oncogenic Immune Protein in Tumor Microenvironment

2020 ◽  
Vol 10 ◽  
Author(s):  
Wen-Xiu Xu ◽  
Jian Zhang ◽  
Yu-Ting Hua ◽  
Su-Jin Yang ◽  
Dan-Dan Wang ◽  
...  

BackgroundLipocalin 2 (LCN2), an innate immune protein, plays a pivotal role in promoting sterile inflammation by regulating immune responses. However, the role of LCN2 in diverse cancers remains poorly defined. This research aimed to investigate the correlation between LCN2 expression and immunity and visualize its prognostic landscape in pan-cancer.MethodsRaw data in regard to LCN2 expression in cancer patients were acquired from TCGA and GTEx databases. Besides, we investigated the genomic alterations, expression pattern, and survival analysis of LCN2 in pan-cancer across numerous databases, including cBioPortal and GEPIA database. The correlation between LCN2 expression and tumor immune infiltration was explored via TIMER, and we utilized CIBERSORT and ESTIMATE computational methods to assess the proportion of tumor-infiltrating immune cells (TIICs) and the amount of stromal and immune components from TCGA database. Protein–Protein Interaction analysis was performed in GeneMANIA database, and gene functional enrichment was performed by Gene Set Enrichment Analysis (GSEA).ResultsOn balance, tumor tissue had a higher LCN2 expression level compared with that in normal tissue. Elevated expression of LCN2 was related to poor clinical regimen with OS and RFS. There were significant positive correlations between LCN2 expression and TIICs, including CD8+ T cells, CD4+ T cells, B cells, neutrophils, macrophages, and dendritic cells. Moreover, markers of TIICs exhibited different LCN2-related immune infiltration patterns. GSEA analysis showed that the expression of LCN2 was related to retinol metabolism, drug metabolism cytochrome P450 and metabolism of xenobiotics by cytochrome P450.ConclusionsThese findings suggested that LCN2 might serve as a biomarker for immune infiltration and poor prognosis in cancers, shedding new light on therapeutics of cancers.

2021 ◽  
Vol 18 (6) ◽  
pp. 9336-9356
Author(s):  
Sidan Long ◽  
◽  
Shuangshuang Ji ◽  
Kunmin Xiao ◽  
Peng Xue ◽  
...  

<abstract> <sec><title>Background</title><p>LTB4 receptor 1 (LTB4R), as the high affinity leukotriene B4 receptor, is rapidly revealing its function in malignancies. However, it is still uncertain.</p> </sec> <sec><title>Methods</title><p>We investigated the expression pattern and prognostic significance of LTB4R in pan-cancer across different databases, including ONCOMINE, PrognoScan, GEPIA, and Kaplan-Meier Plotter, in this study. Meanwhile, we explored the significance of LTB4R in tumor metastasis by HCMDB. Then functional enrichment analysis of related genes was performed using GeneMANIA and DAVID. Lastly, utilizing the TIMER datasets, we looked into the links between LTB4R expression and immune infiltration in malignancies.</p> </sec> <sec><title>Results</title><p>In general, tumor tissue displayed higher levels of LTB4R expression than normal tissue. Although LTB4R had a negative influence on pan-cancer, a high expression level of LTB4R was protective of LIHC (liver hepatocellular carcinoma) patients' survival. There was no significant difference in the distribution of LTB4R between non-metastatic and metastatic tumors. Based on Gene Set Enrichment Analysis, LTB4R was implicated in pathways involved in inflammation, immunity, metabolism, and cancer diseases. The correlation between immune cells and LTB4R was found to be distinct across cancer types. Furthermore, markers of infiltrating immune cells, such as Treg, T cell exhaustion and T helper cells, exhibited different LTB4R-related immune infiltration patterns.</p> </sec> <sec><title>Conclusion</title><p>The LTB4R is associated with immune infiltrates and can be used as a prognostic biomarker in pan-cancer.</p> </sec> </abstract>


2021 ◽  
Author(s):  
Wen Gao ◽  
Sheng Yin ◽  
Haiyan Sun ◽  
Zhuyan Shao ◽  
Peipei Shi ◽  
...  

Abstract Background: Secreted phosphoprotein 1 (SPP1) plays a vital role in tumor progression of some cancer types, but little is known whether it is a bystander or an actual player on driving immune infiltration in ovarian cancer.Methods: In this study, the expression of SPP1 was identified by Oncomine, GEPIA and TIMER databases, and SPP1 immumohistochemical staining analysis was assessed by The HPA database. The clinical outcomes between SPP1 expression and ovarian cancer patients were evaluated via Kaplan-Meier Plotter and PrognoScan dataset. Immune infiltration analyses were explored using TIMER and TISIDB dataset. In addition, Functional enrichment analyses were performed with Metascape and GeneMANIA database.Results: SPP1 was found overexpressed in ovarian tumor tissues and high SPP1 expression was correlated with shorter OS and PFS survivals. Particularly, elevated SPP1 expression was significantly associated with stage III ovarian cancer. Notably, SPP1 expression was positively correlated with infiltrating levels of CD4+ T cells, CD8+ T cells, macrophages, neutrophils, and dendritic cells. Furthermore, SPP1 expression showed strong correlations with diverse immune hallmark sets in ovarian cancer. Of particular importance, functional enrichment analysis suggested that SPP1 strong related with immune response.Conclusions: These findings imply that SPP1 is correlated with prognosis and immune cell infiltrating, offering a new potential immunotherapeutic target in ovarian cancer.Trial registration: Not applicable.


2021 ◽  
Author(s):  
Sheng Fang ◽  
Xiao Fang ◽  
Xin Xu ◽  
Lin Zhong ◽  
An-quan Wang ◽  
...  

Abstract Relevance Rheumatoid arthritis (RA) is a systemic autoimmune disease with an aggressive, chronic synovial inflammation as the main pathological change. However, the specific etiology, pathogenesis, and related biomarkers in diagnosis and treatment are still not fully elucidated. This study attempts to provide new perspectives and insights into RA at the genetic, molecular, and cellular levels through the tenet of personalized medicine. Methods Gene expression profiles of four individual knee synovial tissues were downloaded from a comprehensive gene expression database, R language was used to screen for significantly differentially expressed genes (DEGs), Gene Ontology Enrichment Analysis, Kyoto Gene Encyclopedia, and Gene Set Enrichment Analysis were performed to analyze the biological functions and signaling pathways of these DEGs, STRING online database was used to establish protein-protein interaction networks, Cytoscape software to obtain ten hub genes, Goplot to get six inflammatory immune-related hub genes, and CIBERSORT algorithm to impute immune infiltration. Results Molecular pathways that play important roles in RA were obtained: Toll-like receptors, AMPK, MAPK, TNF, FoxO, TGF-beta, PI3K and NF-κB pathways, Ten hub genes: Ccr1, Ccr2, Ccr5, Ccr7, Cxcl5, Cxcl6, Cxcl13, Ccl13, Adcy2, and Pnoc. among which Adcy2 and Pnoc have not been reported in RA studies, suggesting that they may be worthy targets for further study. It was also found that among the synoviocytes in RA, the proportions of plasma cells, CD8 T cells, follicular helper T cells, monocytes, γ delta T cells, and M0 macrophages were higher, while the proportions of CD4 memory resting T cells, regulatory T cells (Tregs), activated NK cells, resting dendritic cells, M1 macrophages, eosinophils, activated mast cells, resting mast cells were lower in proportion, and each cell played an important role in RA. Conclusions This study may help understand the key genes, molecular pathways, the role of inflammatory immune infiltrating cells in RA’s pathogenesis and provide new targets and ideas for the diagnosis and personalized treatment of RA.


Author(s):  
Cong Luo ◽  
Zhixiong Liu ◽  
Wenrui Ye ◽  
Fangkun Liu

Background: Tumor microenvironment, especially infiltrating immune cell, is crucial for solid tumors including glioma. However, the hub genes as well as their effects on patient prognosis and immunotherapy efficacy remain obscure.Methods: We employed a total of 952 lower grade glioma (LGG) patients from The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) databases, and 24 samples in our hospital for subsequent analyses. Abundances of immune infiltrates were evaluated using CIBERSORT and ImmuCellAI. Their correlations with prognosis were assessed by log-rank test. Immune infiltration-related hub genes were obtained from overlapped differential expressed genes (DEGs) in various subsets of survival-related immune cell types. The risk signature was constructed by Least Absolute Shrinkage and Selection Operator (LASSO) Cox regression analysis. The functional analyses were estimated by GVSA and Gene Set Enrichment Analysis (GSEA) algorithms. And protein–protein interaction enrichment analysis was carried out with the Metascape database integrating STRING, BioGrid, OmniPath, and InWeb_IM.Results: Among the 21 infiltrates, the abundances of five immune infiltrates were correlated with overall survival (OS) in LGG patients. Higher abundances of naïve CD4+ T cells (p = 0.002), activated mast cells (p = 0.015), and monocytes (p = 0.014) were correlated with better prognosis, while higher abundances of resting memory CD4+ T cells (p = 0.015) and M1 macrophages (p = 0.020) correlated with poorer OS. We finally obtained 44 hub genes and constructed an immune infiltration-related signature (IIRS). The IIRS correlates with clinicopathological characteristics and exhibited potential power in predicting the immunotherapy efficacy. The IRRS correlates with cancer related pathways, especially “epithelial-mesenchymal transition (EMT),” and cytotoxic T lymphocytes.Conclusion: Our study constructed and validated a novel signature for risk stratification and prediction of immunotherapy response in grade II and III gliomas, which was closely associated with glioma immune microenvironment and could serve as a promising prognostic biomarker for glioma patients.


2021 ◽  
Author(s):  
Xiaofeng Wang ◽  
Kun Zhang ◽  
Li Geng ◽  
DongLi Liu

Abstract Background: Secreted phosphoprotein 1 (SPP1) functions as a tumor promoter in varies tumors, but little is known whether it is an actual player on driving immune infiltration in hepatocellular carcinoma. Methods: In this study, we identified the expression of SPP1 by Oncomine, GEPIA and TIMER databases, and assessed SPP1 immumohistochemical staining analysis by The HPA database. We evaluated the clinical outcomes between SPP1 expression and hepatocellular carcinoma patients via Kaplan-Meier Plotter. We also tested the relationship between SPP1 and critical oncogenes by TIMER and GEPIA databases. Then we explored immune infiltration analyses using TIMER and TISIDB datasets. In addition, we performed functional enrichment analyses with Metascape and GeneMANIA databases. Results: We found that SPP1 overexpressed in hepatocellular carcinoma tissues and high SPP1 expression was correlated with shorter OS and PFS survivals in hepatocellular carcinoma patients. SPP1 expression is positive correlation with critical oncogenes related stemness associated genes, cell cycle and proliferation, therapeutic resistance, metastasis, and tumor angiogenesis in hepatocellular carcinoma. Importantly, SPP1 expression was positively correlated with infiltrating levels of CD4+ T cells, CD8+ T cells, macrophages, neutrophils, and dendritic cells. Furthermore, SPP1 expression showed strong correlations with diverse immune hallmark sets in hepatocellular carcinoma. Notably, functional enrichment analysis suggested that SPP1 strong related with immune response. Conclusions: These findings imply that SPP1 is correlated with prognosis and immune cell infiltrating, offering a new potential immunotherapeutic target in hepatocellular carcinoma.


2021 ◽  
Author(s):  
Long-Jiang Chen ◽  
Lu-Lu Zhai ◽  
Wei Wang ◽  
Lun Wu ◽  
Li-Chao Yao ◽  
...  

Abstract While previous studies have suggested that B3GNT3 is associated with tumorigenesis and progression of several tumors, its expression level and clinical significance in pancreatic adenocarcinoma (PAAD) remains unclear. Our study aimed to investigate the role of B3GNT3 in PAAD. B3GNT3 RNA sequencing and clinicopathological data were collected from the TCGA, GEO and GTEx databases. We assessed the expression and prognostic value of B3GNT3 in PAAD using R program and attached packages. Additionally, we investigate the correlation between B3GNT3 expression and tumor-infiltrating immune cells using CIBERSORT and the “correlation” module of GEPIA. Finally, gene set enrichment analysis (GSEA) was used to elucidate B3GNT3 related signaling pathways in PAAD. Results showed that B3GNT3 expression was significantly higher in tumor tissues compared to normal tissues (P <0.05). Increased B3GNT3 expression was correlated with advanced histologic grade and stage (Ⅰ Vs Ⅱ). Patients with high B3GNT3 expression had a worse OS (HR = 1.713, P = 0.0005). Moreover, a negative correlation between increased B3GNT3 expression and immune infiltrating level of naive B cells, CD8 T cells, and CD4 memory activated T cells was revealed by CIBERSORT analysis. Then, further analysis verified the correlation using the “correlation” module of GEPIA. Finally, GSEA suggested that functional enrichment of B3GNT3 was mainly involved in pathways in cancer, p53 signaling pathway, TGF beta signaling pathway, catabolic and transport processes of proteins, etc. Collectively, these results suggested that overexpression of B3GNT3 might affect the infiltration of immune cells and could act as a potential prognostic biomarker of PAAD.


2021 ◽  
Vol 11 ◽  
Author(s):  
Yi Liu ◽  
YuCai Wu ◽  
PeiPei Zhang ◽  
ChaoJie Xu ◽  
ZeSen Liu ◽  
...  

Bladder cancer (BLCA) represents the ninth most common malignant tumor in the world and is characterized by high recurrence risk. Tumor microenvironment (TME) plays an important role in regulating the progression of BLCA. Immunotherapy, including Bacillus Calmette-Guerin (BCG) and programmed cell death protein 1 (PD-1)/programmed death ligand 1 (PD-L1), is closely associated with TME and is widely used for treating BLCA. But parts of BLCA patients have no response to these treatment ways, thus a better understanding of the complex TME of BLCA is still needed. We downloaded the gene expression profile and corresponding clinical information of 414 BLCA patients from the TCGA database. Via the ESTIMATE and CIBERSORT algorithm, we identified the two hub genes (CXCL12 and CD3E) and explored their correlations with immune infiltration. We found that BLCA patients with higher expression of CXCL12 and lower expression of CD3E had prolonged survival. Gene set enrichment analysis (GSEA) revealed that both CXCL12 and CD3E were enriched in immune-related pathways. We also discovered that stromal score and the level of CXCL12 were higher in luminal subtype, and immune score and the level of CD3E were higher in the basal subtype. Furtherly, we found that CXCL12 was associated with naive B cells, resting mast cell, M2 macrophages, follicular helper T cells, and dendritic cells. CD8+ T cells, CD4+ T cells, regulatory T cells (Tregs), and macrophages were correlated with CD3E. In conclusions, we found that CXCL12 and CD3E might serve as indicators of TME modulation in BLCA. Therapy targeting CXCL12 and CD3E had the potential as novel therapeutic strategy.


2021 ◽  
Author(s):  
Chunpei Ou ◽  
Qin Peng ◽  
Changchun Zeng

Abstract Background: PTPRD plays an indispensable role in the occurrence of multiple tumors. However, pan-cancer analysis is unavailable. The purpose of this research was to investigate the relationship between PTPRD and immunity and describe its prognostic landscape across various tumors. Methods: We explored expression profile, survival analysis, and genomic alterations of PTPRD based on the TIMER, GEPIA, UALCAN, PrognoScan, and cBioPortal database. The frequency of PTPRD mutation and its correlation with response to immunotherapy were evaluated using the cBioPortal database. The relationship between PTPRD and immune-cell infiltration was analyzed by the TIMER and TISIDB databases. A protein interaction network was constructed by the STRING database. GO and KEGG enrichment analysis was executed by the Metascape database.Results: A significant correlation between PTPRD expression and prognosis was found in various cancers. Aberrant PRPRD expression was closely related to immune infiltration. Importantly, the patients who harbored PTPRD mutation and received immune checkpoint inhibitors had worse overall survival, especially in non-small cell lung cancer and melanoma, and had a higher TMB score. Moreover, PTPRD mutation was involved in numerous biological processes, including immunological signaling pathways. Additionally, a PTPRD protein interaction network was constructed, and genes that interacted with PTPRD were identified. Functional enrichment analysis demonstrated that a variety of GO biological processes and KEGG pathways of PTPRD were primarily involved in the therapeutic mechanisms. Conclusions: These results revealed that PRPRD might function as a biomarker for prognosis and immune infiltration in cancers, throwing new light on cancer therapeutics.


2021 ◽  
Vol 8 ◽  
Author(s):  
Peng Wang ◽  
Liying Han ◽  
Moxin Yu ◽  
Zhengyu Cao ◽  
Xiaoning Li ◽  
...  

Background: Protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) is a type I transmembrane protein that functions as an endoplasmic reticulum (ER) stress sensor to regulate global protein synthesis. Recent research studies suggest that PERK, as an important receptor protein of unfolded protein response, is involved in the pathogenesis of many cancers. This study aimed to investigate PERK expression and its relationship with prognosis in pan-cancer and attempted to explore the relevant mechanism of PERK involved in the regulation of cancer pathogenesis.Methods: The Oncomine and TIMER databases were used to analyze the expression of PERK between pan-cancer samples and normal samples. Survival analysis was performed using the PrognoScan, Kaplan–Meier (K-M) plotter, and UALCAN databases. Gene set enrichment analysis (GSEA) was used to perform the functional enrichment analysis of the PERK gene in breast invasive carcinoma (BRCA), head and neck squamous cell carcinoma (HNSC), and thyroid carcinoma (THCA). The TIMER database was used to investigate the correlation between PERK expression and tumor-infiltrating immune cells and analyze the relationship of PERK with marker genes of immune cells which were downloaded from the CellMarker database in BRCA, HNSC, and THCA.Results: PERK was differentially expressed in various cancers, such as breast cancer, liver cancer, lung cancer, gastric carcinoma, lymphoma, thyroid cancer, leukemia, and head and neck squamous cell carcinomas. The high expression of PERK was associated with a poor prognosis in KIRP, LGG, BRCA, and THCA and with a favorable prognosis in HNSC. The results of GSEA indicated that PERK was mainly enriched in immune-related signaling pathways in BRCA, HNSC, and THCA. Moreover, PERK expression was significant positively correlated with infiltrating levels of macrophages and dendritic cells and was strongly associated with a variety of immune markers, especially macrophage mannose receptor 1 (MRC1, also called CD206) and T-helper cells (Th).Conclusion: The high expression of PERK could promote the infiltration of multiple immune cells in the tumor microenvironment and could deteriorate the outcomes of patients with breast and thyroid cancers, suggesting that PERK as well as tumor-infiltrating immune cells could be taken as potential biomarkers of prognosis.


2022 ◽  
Vol 12 ◽  
Author(s):  
Meng-Di Xia ◽  
Rui-Ran Yu ◽  
Dong-Ming Chen

BackgroundAntineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a systemic autoimmune disease that generally induces the progression of rapidly progressive glomerulonephritis (GN). The purpose of this study was to identify key biomarkers and immune-related pathways involved in the progression of ANCA-associated GN (ANCA-GN) and their relationship with immune cell infiltration.MethodsGene microarray data were downloaded from the Gene Expression Omnibus (GEO). Hub markers for ANCA-GN were mined based on differential expression analysis, weighted gene co-expression network analysis (WGCNA) and lasso regression, followed by Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Set Enrichment Analysis (GSEA) of the differential genes. The infiltration levels of 28 immune cells in the expression profile and their relationship to hub gene markers were analysed using single-sample GSEA (ssGSEA). In addition, the accuracy of the hub markers in diagnosing ANCA-GN was subsequently evaluated using the receiver operating characteristic curve (ROC).ResultsA total of 651 differential genes were screened. Twelve co-expression modules were obtained via WGCNA; of which, one hub module (black module) had the highest correlation with ANCA-GN. A total of 66 intersecting genes were acquired by combining differential genes. Five hub genes were subsequently obtained by lasso analysis as potential biomarkers for ANCA-GN. The immune infiltration results revealed the most significant relationship among monocytes, CD4+ T cells and CD8+ T cells. ROC curve analysis demonstrated a prime diagnostic value of the five hub genes. According to the functional enrichment analysis of the differential genes, hub genes were mainly enhanced in immune- and inflammation-related pathways.ConclusionB cells and monocytes were closely associated with the pathogenesis of ANCA-GN. Hub genes (CYP3A5, SLC12A3, BGN, TAPBP and TMEM184B) may be involved in the progression of ANCA-GN through immune-related signal pathways.


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