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Human Gastric Cancer Stem Cell (GCSC) Markers Are Prognostic Factors Correlated With Immune Infiltration of Gastric Cancer.

ABSTRACT: The prognosis of patients with gastric cancer (GC) is still unsatisfying. Numerous markers of gastric cancer stem cells (GCSCs) have been identified and were thought to be related to cancer aggressiveness. However, the roles of GCSC markers in GC patients' prognosis and immune infiltration remain unknown. Expression of GCSC markers was analyzed using Oncomine and Gene Expression Profiling Interactive Analysis (GEPIA). Their associations with clinicopathological parameters were analyzed using UALCAN and LinkedOmics. Alternations and protein expression of GCSC markers were analyzed by cBioPortal and the Human Protein Atlas databases, respectively. The prognostic significance of GCSC markers was evaluated using Kaplan-Meier plotter. Correlations between the expression of GCSC markers and immune infiltration along with biomarkers of tumor-infiltrating immune cells (TIICs) were assessed combined Tumor Immune Estimation Resource and GEPIA. GeneMANIA was used to discover the interactive genes of GCSC markers, and enrichment analysis was performed using Database for Annotation, Visualization, and Integrated Discovery server. We identified six GCSC markers significantly up-expressed in GC, compared with normal stomach tissues. Among them, the overexpression of ICAM1, THY1, and CXCR4 significantly indicated adverse, while EPCAM indicated beneficial clinicopathological features of GC patients. The up-regulation of CXCR4 showed unfavorable prognostic significance, whereas EPCAM and TFRC showed the opposite. The six GCSC markers were all correlated with the infiltration and activation of distinct TIICs. Especially, ICAM1, THY1, and CXCR4 showed strongly positive correlations with tumor-associated macrophages. Besides, chemokine, Toll-like receptor, NF-kappa B, and HIF-1 signaling pathways might be involved in the regulation of GCSC markers on cancer development. This study proposed that GCSC markers might be promising targets of GC treatment to weaken cancer stem-like properties and strengthen anticancer immunity.

SUBMITTER: Lin T

PROVIDER: S-EPMC8185345 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundHsa_circ_0072309 has been identified as a tumor suppressor in several carcinomas. However, its precise role in gastric cancer (GC) remains largely unknown. This study was aimed to explore the precise role of Hsa_circ_0072309 in GC.MethodsThe transcriptional and clinical data of stomach adenocarcinoma were downloaded using the University of California SantaCruz (UCSC) Xena browser. The circular RNA (circRNA) datasets were obtained from the Gene Expression Omnibus (GEO) database. The expression profile and survival analysis of differentially expressed micro RNAs (DEMIs) and differentially expressed messenger RNAs (DEMs) were performed. Correlations between the expression and immune infiltration of the DEMS were studied. Additionally, the expression of hsa_circ_0072309 in GC tissues and cell lines were validated, and the relationship between its expression and clinical features was investigated. Gain- and loss-of function experiments and molecular interaction experiments were also conducted.ResultsOverall, 7 differentially expressed circRNAs, 13 DEMIs, and 17 DEMs were screened. Two DEMIs (hsa_miR-34a-3p and hsa_miR-326) and five DEMs (C7, MARCKSL1, UBE2T, OLR1, and HOXC11) showed significant differences in the high- and low-risk groups. The most significantly enriched Gene Ontology terms were the circadian regulation of gene expression and protein binding. The most significantly enriched Kyoto Encyclopedia of Genes and Genomes pathways were the PI3K-Akt and Ras signal pathways. Additionally, six genes were significantly correlated with immune infiltration. The real-time quantitative PCR (RT-qPCR) results revealed a significant downregulation of hsa_circ_0072309 in GC tissues related to tumor size, vascular invasion, and lymph node metastasis. A hsa_circ_0072309 overexpression suppressed whereas a hsa_circ_0072309 knockdown promoted GC cells proliferation and migration in vitro; in addition, hsa_circ_0072309 could directly bind to has-miR-34a-3p and has-miR-330-5p.ConclusionsHsa_circ_0072309 is a potential diagnostic biomarker for GC, and complement component 7 may be a tumor suppressor. These may potentially predict the prognosis of patients with GC and may become new therapeutic targets.

Project description:BackgroundSeveral markers have been reported to be specific for hepatic cancer stem cells (HCSCs), which is usually thought to be highly associated with poor clinical outcomes. Tumor-infiltrating immune cells act as an important factor for oncogenesis. Little is known about the correlation of HCSC markers to prognosis and immune infiltrates.MethodsExpression of HCSC markers was analyzed through Oncomine database, Gene Expression Profiling Interactive Analysis (GEPIA) and Integrative Molecular Database of Hepatocellular Carcinoma (HCCDB), respectively. The prognostic effect of HCSC markers was evaluated using Kaplan-Meier plotter in association with different tumor stages, risk factors, and gender. The correlation of HCSC markers to tumor-infiltrating immune cells was tested by Tumor Immune Estimation Resource (TIMER). HCSC markers related gene sets were investigated by GEPIA, with their biological functions being analyzed by Cytoscape software.ResultsThe expression level of 10 HCSC markers in HCC was higher than that in normal tissues in at least one database. Among them, high expression of CD24, SOX9, and SOX12 was positively correlated with poor prognosis (CD24: OS P = 0.0012, PFS P = 7.9E-05. SOX9: OS P = 0.012. SOX12: OS P = 0.0004, PFS P = 0.0013, respectively). However, the expression of CD13, CD34 and ALDH1A1 was associated with prolonged OS and PFS. SOX12 was significantly upregulated in poor prognosis of HCC patients with different conditions. Besides, total nine HCSC markers were identified to be positively associated with immune infiltration, including SOX12. Furthermore, Toll-like receptor signaling pathway was found to be one major pathway of these HCSC markers related gene networks.ConclusionOur results suggest that seven upregulated HCSC markers (CD90, EpCAM, CD133, CD24, SOX9, CK19, and SOX12) are related with poor prognosis and immune infiltration in HCC. In addition, we find that high SOX12 expression remarkably affect prognosis in male HCC patients but not in female. HCC patients under viral infection or alcohol intake with increased SOX12 expression had poorer prognosis. Therefore, HCSCs markers likely play an important role in tumor related immune infiltration and SOX12 might be a potential therapeutic target in patients with HCC.

Project description:Background: Gastric cancer (GC) has a high mortality rate and is particularly prevalent in China. The extracellular matrix protein, prolyl 4-hydroxylase subunit alpha 3 (P4HA3), has been implicated in various cancers. We aimed to assess the diagnostic and prognostic value of P4HA3 in GC and investigate its correlation with immune cell infiltration. Methods: The present study used microarray data from the Cancer Genome Atlas (TCGA) to analyze the association of P4HA3 expression with clinicopathological features. Data from the Gene Expression Omnibus (GEO) were used for validation. Receiver operating characteristic (ROC) and Kaplan-Meier curves were constructed to determine the diagnostic and prognostic value of P4HA3 in GC. Univariate and multivariate regression analyses were performed to assess the impact of P4HA3 on overall survival (OS) rates. A protein-protein interaction (PPI) network was generated and functional enrichment evaluated. Single-sample gene set enrichment analysis (ssGSEA) was conducted to correlate P4HA3 expression with immune cell infiltration. The correlation between P4HA3 and immune check point genes was studied. Results: P4HA3 was over-expressed in GC, along with 15 other types of cancer, including breast invasive carcinoma and cholangiocarcinoma. P4HA3 showed high diagnostic and prognostic value in GC and was an independent prognostic factor. P4HA3, TNM (tumor, node, metastases) stage, pathological stage and age all correlated with OS rates. Genes related to P4HA3 were enriched in the lumen of the endoplasmic reticulum and included procollagen-proline 3-dioxygenase activity. P4HA3 expression correlated with numbers of macrophages, natural killer (NK) cells, immature dendritic cells (iDC), mast cells, eosinophils, effective memory T cells (Tem), T-helper 1 (Th1) cells and dendritic cells (DC). P4HA3 was positively correlated with hepatitis A virus cellular receptor 2 (HAVCR2) and programmed cell death 1 ligand 2 (PDCD1LG2). Conclusion: P4HA3 is a potential independent biomarker for prognosis of GC and may be an immunotherapy target in the treatment of GC.

Project description:IntroductionGastric cancer is one of the common malignant tumors with a high incidence and mortality in China. Prognostic biomarkers and potential predictors of the treatment efficacy of gastric cancer urgently need to be identified. Integrin-β (ITGB) is a superfamily of integrins and is involved in cell adhesion, tissue repair, immune response, and tumor metastasis.MethodsWe analyzed ITGB1 expression in our hospital samples of the gastric cancer cohort. And the public data of The Cancer Genome Atlas stomach adenocarcinoma (TCGA-STAD), The Asian Cancer Research Group (ACRG)/GSE62254, and GSE15459 data sets were analyzed by using the bioinformatic methods. The relationships between ITGB1 expression and clinicopathological features, patient prognosis, activation of the Wnt/β-catenin signaling pathway, and tumor immunosuppressive factors were also explored.ResultsThe positive rate of ITGB1 expression in the Fudan University Shanghai Cancer Center gastric cancer tumor tissues was 61.4% (258/420) and correlated with deep invasion (p = 0.017), an advanced clinical stage (p = 0.011), and a poor prognosis (p < 0.05). The TCGA-STAD/ACRG/GSE15459 cohorts also showed similar results. ITGB1 is one of the upstream molecules of the Wnt/β-catenin signaling pathway and is correlated with tumor immune suppression. In gastric cancer, we found a correlation between ITGB1 expression and Wnt/β-catenin signaling pathway activity. In the TCGA-STAD/ACRG/GSE15459 cohorts, ITGB1 expression was positively associated with immunosuppressive factors and negatively associated with immunoactive factors. Patients with low ITGB1 expression exhibited a significantly high immunotherapy response ratio according to an analysis of tumor immune dysfunction and exclusion (TIDE), which may indicate that ITGB1 is a potential predictor of immunotherapy efficacy.ConclusionsITGB1 affects the prognosis in gastric cancer patients and plays a core role in immune suppression in gastric cancer.

Project description:BackgroundGastric cancer (GC) is the fifth most common cancer and the second leading cause of cancer-related deaths worldwide. Due to the lack of specific markers, the early diagnosis of gastric cancer is very low, and most patients with gastric cancer are diagnosed at advanced stages. The aim of this study was to identify key biomarkers of GC and to elucidate GC-associated immune cell infiltration and related pathways.MethodsGene microarray data associated with GC were downloaded from the Gene Expression Omnibus (GEO). Differentially expressed genes (DEGs) were analyzed using Gene Ontology (GO), Kyoto Gene and Genome Encyclopedia, Gene Set Enrichment Analysis (GSEA) and Protein-Protein Interaction (PPI) networks. Weighted gene coexpression network analysis (WGCNA) and the least absolute shrinkage and selection operator (LASSO) algorithm were used to identify pivotal genes for GC and to assess the diagnostic accuracy of GC hub markers using the subjects' working characteristic curves. In addition, the infiltration levels of 28 immune cells in GC and their interrelationship with hub markers were analyzed using ssGSEA. And further validated by RT-qPCR.ResultsA total of 133 DEGs were identified. The biological functions and signaling pathways closely associated with GC were inflammatory and immune processes. Nine expression modules were obtained by WGCNA, with the pink module having the highest correlation with GC; 13 crossover genes were obtained by combining DEGs. Subsequently, the LASSO algorithm and validation set verification analysis were used to finally identify three hub genes as potential biomarkers of GC. In the immune cell infiltration analysis, infiltration of activated CD4 T cell, macrophages, regulatory T cells and plasmacytoid dendritic cells was more significant in GC. The validation part demonstrated that three hub genes were expressed at lower levels in the gastric cancer cells.ConclusionThe use of WGCNA combined with the LASSO algorithm to identify hub biomarkers closely related to GC can help to elucidate the molecular mechanism of GC development and is important for finding new immunotherapeutic targets and disease prevention.

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Human Gastric Cancer Stem Cell (GCSC) Markers Are Prognostic Factors Correlated With Immune Infiltration of Gastric Cancer.

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