An integrative pan-cancer bioinformatics analysis of MSRB1 and its association with tumor immune microenvironment, prognosis, and immunotherapy
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ABSTRACT:
SUBMITTER: Jiang S
PROVIDER: S-EPMC10884410 | biostudies-literature | 2024 Feb
REPOSITORIES: biostudies-literature
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Project description:Glutaminase (GLS), a crucial gene regulating glutaminolysis, has received much attention as it was found to regulate tumor metabolism and copper-induced cell death. However, its biological roles and mechanisms in human cancers remain obscure. Consequently, the integrated pan-cancer analyses and biological experiments were conducted to elucidate its oncological functions. We found GLS was differentially expressed in human cancers and upregulated GLS predicted poor survival, clinicopathological progression, and tumor heterogeneity. Single-cell analysis found GLS was closely related to various biological functions and pathways. Spatial transcriptomic analysis found GLS expression was mainly derived from tumor cells, which implies tumor cells may have a stronger ability to utilize glutamine than antitumor immune cells in the tumor microenvironment (TME). Meanwhile, we noticed GLS expression was strongly related to the infiltration of various immune cells and stromal cells, the expression of immunomodulatory genes, the activity of some conventional antitumor agents, and the therapeutic response of immunotherapy. Moreover, enrichment analyses suggested GLS was related to various metabolic reprogramming, innate and adaptive immunity suppression, and extracellular matrix remodeling. Finally, we observed GLS was highly expressed in our gastric cancer (GC) cohort. As an independent risk factor for GC prognosis, high-GLS was closely related to pathological progression. Inhibiting GLS expression in GC cells effectively prevented proliferation, migration, and invasion and triggered apoptosis. In conclusion, GLS is an underlying biomarker for oncological progression, prognosis, TME, antitumor drug sensitivity, and immunotherapy response. Targeting GLS can facilitate the implementation of individualized and combined treatment strategies.
| S-EPMC11696030 | biostudies-literature
Project description:Autophagy is a catabolic pathway involved in the regulation of bone homeostasis. We explore clinical correlation of autophagy-related key molecules to establish risk signature for predicting the prognosis, tumor microenvironment (TME), and immunotherapy response of osteosarcoma. Single cell RNA sequencing data from GSE162454 dataset distinguished malignant cells from normal cells in osteosarcoma. Autophagy-related genes (ARGs) were extracted from the established risk signature of the Molecular Signatures Database of Gene Set Enrichment Analysis (GSEA) by univariate Cox and least absolute shrinkage and selection operator (LASSO) Cox regression analysis. Overall survival (OS), TME score, abundance of infiltrating immune cells, and response to immune-checkpoint blockade (ICB) treatment in patients with different risks were compared based on risk score. Nine ARGs were identified and risk signature was constructed. In all osteosarcoma datasets, the OS was significantly longer in the high-risk patients than low-risk onset. Risk signature significantly stratified clinical outcomes, including OS, metastatic status, and survival status. Risk signature was an independent variable for predicting osteosarcoma OS and showed high accuracy. A nomogram based on risk signature and metastases was developed. The calibration curve confirmed the consistency in 1-year, 3-year, and 5-year predicted OS and the actual OS. The risk score was related to 6 kinds of T cells and macrophages, myeloid-derived suppressor cell, natural killer cell, immune score, and stromal score in TME. The risk signature helped in predicting patients' response to anti-PD1/anti-PD-L1 treatment. The ARGs-led risk signature has important value for survival prediction, risk stratification, tumor microenvironment, and immune response evaluation of osteosarcoma.
| S-EPMC9303156 | biostudies-literature
Project description:BackgroundAlthough WD repeat and high-mobility group box DNA binding protein 1 (WDHD1) played an essential role in DNA replication, chromosome stability, and DNA damage repair, the panoramic picture of WDHD1 in human tumors remains unclear. Hence, this study aims to comprehensively characterize WDHD1 across 33 human cancers.MethodsBased on publicly available databases such as TCGA, GTEx, and HPA, we used a bioinformatics approach to systematically explore the genomic features and biological functions of WDHD1 in pan-cancer.ResultsWDHD1 mRNA levels were significantly increased in more than 20 types of tumor tissues. Elevated WDHD1 expression was associated with significantly shorter overall survival (OS) in 10 tumors. Furthermore, in uterine corpus endometrial carcinoma (UCEC) and liver hepatocellular carcinoma (LIHC), WDHD1 expression was significantly associated with higher histological grades and pathological stages. In addition, WDHD1 had a high diagnostic value among 16 tumors (area under the ROC curve [AUC] > 0.9). Functional enrichment analyses suggested that WDHD1 probably participated in many oncogenic pathways such as E2F and MYC targets (false discovery rate [FDR] < 0.05), and it was involved in the processes of DNA replication and DNA damage repair (p.adjust < 0.05). WDHD1 expression also correlated with the half-maximal inhibitory concentrations (IC50) of rapamycin (4 out of 10 cancers) and paclitaxel (10 out of 10 cancers). Overall, WDHD1 was negatively associated with immune cell infiltration and might promote tumor immune escape. Our analysis of genomic alterations suggested that WDHD1 was altered in 1.5% of pan-cancer cohorts and the "mutation" was the predominant type of alteration. Finally, through correlation analysis, we found that WDHD1 might be closely associated with tumor heterogeneity, tumor stemness, mismatch repair (MMR), and RNA methylation modification, which were all processes associated with the tumor progression.ConclusionsOur pan-cancer analysis of WDHD1 provides valuable insights into the genomic characterization and biological functions of WDHD1 in human cancers and offers some theoretical support for the future use of WDHD1-targeted therapies, immunotherapies, and chemotherapeutic combinations for the management of tumors.
| S-EPMC10523704 | biostudies-literature
Project description:BackgroundCD73 is adenosine generation molecule, which is involved in the immune regulation. However, the roles of CD73 in the tumor microenvironment remain unknown.MethodsCD73 expression levels in pan-cancers were analyzed, based on The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx) and Human Protein ALTAS (HPA) databases. Kaplan-Meier (KM) plotter was used to analyze the prognostic values of CD73. Immune scores in pan-cancers was evaluated by ESTIMATE. TIMER2.0 and UCSCXena were used to explore the correlation between CD73 and immune infiltration/immune checkpoints/tumor mutation burden (TMB)/microsatellite instability (MSI). CD73 expression correlated genes in tumor tissues were screened by using LinkedOmics tool.ResultsFirstly, CD73 was significant increased in following cancer types: esophageal carcinoma (ESCA), glioblastoma multiforme (GBM), head and neck squamous cell carcinoma (HNSC), brain lower grade glioma (LGG), lung adenocarcinoma (LUAD), pancreatic adenocarcinoma (PAAD) and stomach adenocarcinoma (STAD). Secondly, high CD73 expression was associated with poor overall survival in patients with breast invasive carcinoma (BRCA), CESC, HNSC, liver hepatocellular carcinoma (LIHC), LUAD, lung squamous cell carcinoma (LUSC), PAAD and STAD. However, in KIRC and UCEC, patients high CD73 expression showed a favorable prognosis. Thirdly, the immune scores of the high CD73 expression in bladder urothelial carcinoma (BLCA), BRCA, kidney chromophobe (KICH), LUAD, LUSC, ovarian serous cystadenocarcinoma (OV), pheochromocytoma and paraganglioma (PCPG), prostate adenocarcinoma (PRAD), and skin cutaneous melanoma (SKCM) were significant higher than that of patients with low CD73 expression. Furthermore, we observed a positive correlation between CD73 and the multiple immune cells infiltration, including CD4+ memory T cells, CD8+ T cells, Treg cells, myeloid DC and macrophage, particularly in BRCA and LUAD. There was no strong correlation between CD73 and TMB/MSI. In LUAD, CD73 expression correlated genes were mainly enrichment in positive regulation of cell proliferation, cell adhesion, positive regulation of kinase activity, cellular response to LPS. However, in UCEC, CD73 correlated genes were mainly associated with fatty acid omega-oxidation, protein localization to endoplasmic reticulum exit site, endoplasmic reticulum to Golgi vesicle-mediated transport.ConclusionCD73 could be used to predict the prognosis of patients with several cancers. The potential functional mechanism of CD73 involved in cancer progress may not only dependent on its immunomodulatory effects.
| S-EPMC11609644 | biostudies-literature
Project description:BackgroundThe human insulin-like growth factor 2 mRNA binding proteins 1-3 (IGF2BP1-3, also called IMP1-3) play essential roles in mRNA regulation, including its splicing, translocation, stability, and translation. However, knowledge regarding the involvement of IGF2BPs in tumor immunity and stemness across cancer types is still lacking.MethodsIn this study, we comprehensively analyzed pan-cancer multi-omic data to determine the correlation of IGF2BPs mRNA and protein expression with various cancer parameters such as mutation frequency, prognostic value, the tumor microenvironment (TME), checkpoint blockade, tumor immune infiltration, stemness and drug sensitivity. Validation of the expression of IGF2BPs in cancer samples and glioma cells were performed by quantitative real-time (qRT)-PCR, and immunofluorescence staining. Investigation of the functional role of IGF2BP3 in glioma stem cells(GSCs) were performed by sphere formation, cytotoxicity, transwell, and wound healing assays.ResultsWe found that IGF2BP1 and 3 are either absent or expressed at very low levels in most normal tissues. However, IGF2BP1-3 can be re-expressed in a broad range of cancer types and diverse cancer cell lines, where their expression often correlates with poor prognosis. Immunofluorescence staining and qRT-PCR analyses also showed that the expression of IGF2BP2 and IGF2BP3 were higher in cancer tissues than that in adjacent normal tissues. Moreover, IGF2BPs are associated with TME and stemness in human pan-cancer. Remarkably, IGF2BP3 participated in the maintenance and self-renewal of glioma stem cell (GSCs). Knockdown of IGF2BP3 attenuated GSC and glioma cell proliferation, invasion, and migration.ConclusionsOur systematic pan-cancer study confirmed the identification of IGF2BPs as therapeutic targets and highlighted the need to study their association with stemness, and the TME, which contribute to the cancer drug-discovery research. Especially, preliminary studies demonstrate the IGF2BP3 as a potential negative regulator of glioma tumorigenesis by modulating stemness.
| S-EPMC9846525 | biostudies-literature
Project description:Paired immunoglobulin-like type 2 receptor alpha (PILRA) plays a vital role in regulating broad immune responses. However, the roles of PILRA in cancer immunity remain unexplored yet. In the current study, we comprehensively analyzed the oncogenic and immunologic roles of PILRA at a pan-cancer level based on the Cancer Genome Atlas and Gene Expression Omnibus datasets. PILRA was significantly dysregulated and frequently mutated in pan-cancer. Its expression and mutation status significantly impacted patient prognosis in several cancers. Besides, PILRA expression was positively correlated with ESTIMATE scores and the abundances of tumor-infiltrating immune cells. Concurrently, PILRA expression was significantly associated with predictive biomarkers of cancer immunotherapy, and positively correlated with the prognostic outcomes of cancer patients receiving immunotherapy. Mechanistically, enrichment analysis implied that PILRA might be involved in the regulation of immune response and metabolic process. This study uncovered the immunological roles of PILRA in cancers and its potential as a novel biomarker and therapeutic target for cancer immunotherapy.
| S-EPMC10471747 | biostudies-literature
Project description:Drugs that target immune checkpoints (ICPs) have become the most popular weapons in cancer immunotherapy; however, they are only beneficial for a small fraction of patients. Accumulating evidence suggests that the tumor immune microenvironment (TIME) plays a critical role in anti-cancer immunity. This study aimed to assess the potential merits and feasibility of combinational targeting ICPs and TIME in cancer immunotherapy. A total of 31 cancer type-specific datasets in TCGA were individually collected by the publicly available web servers for multiple bioinformatic analyses of ICPs and TIME factors. GEPIA was used to calculate the prognostic indexes, STRING was used to construct protein-protein interactions, cBioPortal was used for visualization and comparison of genetic alterations, and TISIDB was used to explore the correlation to tumor-infiltrating lymphocytes (TILs). Intriguingly, TIME factors were identified to have more global coverage and prognostic significance across multiple cancer types compared with ICPs, thus offering more general targetability in clinical therapy. Moreover, TIME factors showed interactive potential with ICPs, and genomic alteration of TIME factors coupled with that of ICPs, at least in pancreatic cancer. Furthermore, TIME factors were found to be significantly associated with TILs, including but not limited to pancreatic cancer. Finally, the clinical significance and translational potential of further combination therapies that incorporate both ICP inhibitors and TIME factor-targeted treatments were discussed. Together, TIME factors are promising immunotherapeutic targets, and a combination strategy of TIME factors-targeted therapies with ICP inhibitors may benefit more cancer patients in the future.
| S-EPMC7666137 | biostudies-literature
Project description:In the treatment of cancer, anti-programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) immunotherapy has achieved unprecedented clinical success. However, the significant response to these therapies is limited to a small number of patients. This study aimed to predict immunotherapy response and prognosis using immunologic gene sets (IGSs). The enrichment scores of 4,872 IGSs in 348 patients with metastatic urothelial cancer treated with anti-PD-L1 therapy were computed using gene set variation analysis (GSVA). An IGS-based classification (IGSC) was constructed using a nonnegative matrix factorization (NMF) approach. An IGS-based risk prediction model (RPM) was developed using the least absolute shrinkage and selection operator (LASSO) method. The IMvigor210 cohort was divided into three distinct subtypes, among which subtype 2 had the best prognosis and the highest immunotherapy response rate. Subtype 2 also had significantly higher PD-L1 expression, a higher proportion of the immune-inflamed phenotype, and a higher tumor mutational burden (TMB). An RPM was constructed using four gene sets, and it could effectively predict prognosis and immunotherapy response in patients receiving anti-PD-L1 immunotherapy. Pan-cancer analyses also demonstrated that the RPM was capable of accurate risk stratification across multiple cancer types, and RPM score was significantly associated with TMB, microsatellite instability (MSI), CD8+ T-cell infiltration, and the expression of cytokines interferon-γ (IFN-γ), transforming growth factor-β (TGF-β) and tumor necrosis factor-α (TNF-α), which are key predictors of immunotherapy response. The IGSC strengthens our understanding of the diverse biological processes in tumor immune microenvironment, and the RPM can be a promising biomarker for predicting the prognosis and response in cancer immunotherapy.
| S-EPMC9046667 | biostudies-literature
Project description: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.
| S-EPMC7786136 | biostudies-literature
Project description:BackgroundThe tumor microenvironment (TME) involves infiltration of multiple immune cell subsets, which could influence the prognosis and clinical characteristics. The increasing evidence on the role of tumor-infiltrating lymphocytes (TILs) in primary and metastatic melanomas supports that the immune system is involved in the progression and outcomes of melanoma. However, the immune infiltration landscape in melanoma has not been systematically elucidated.MethodsIn this study, we used CIBERSORT and ESTIMATE algorithms to analyze immune infiltration pattern of 993 melanoma samples. Then we screened differential expression genes (DEGs) related to immune subtypes and survival. The immune cell infiltration (ICI) score was constructed by using principal-component analysis (PCA) based on immune signature genes from DGEs. Gene set enrichment analysis (GSEA) was applied to explore high and low ICI score related pathways. Finally, the predictive ability of ICI score was evaluated in survival prognosis and immunotherapy benefit.ResultWe identified three ICI clusters and three gene clusters associated with different immune subtypes and survival outcomes. Then the ICI score was constructed, and we found that high ICI score exhibited activated immune characteristics and better prognosis. High ICI score was significantly enriched in immune pathways and highly expressed immune signature genes. More importantly, we confirmed that melanoma patients with high ICI score had longer overall survival and rate of response to immunotherapy.ConclusionWe presented a comprehensive immune infiltration landscape in melanoma. Our results will facilitate understanding of the melanoma tumor microenvironment and provide a new immune therapy strategy.
| S-EPMC8134682 | biostudies-literature