Identification of GINS2 prognostic potential and involvement in immune cell infiltration in hepatocellular carcinoma.
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ABSTRACT:
SUBMITTER: Li Z
PROVIDER: S-EPMC8771526 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundProtein phosphatase magnesium-dependent 1 delta (PPM1D), also referred to as wild-type p53-induced phosphatase 1 (Wip1) or protein phosphatase 2C delta (PP2Cδ), is an oncogenic nuclear serine/threonine phosphatase belonging to the PP2C family. However, the knowledge regarding PPM1D mRNA expression, tumor immunity, and the prognosis in hepatocellular carcinoma (HCC) is scanty.MethodsWe analyzed PPM1D, including its expression in both the normal and tumor tissue using the Sangerbox database and Tumor Immune Estimation Resource (TIMER). We evaluated its correlation with prognosis in different tumor types by the Kaplan-Meier plotter and Gene Expression Profiling Interactive Analysis (GEPIA). The correlations between PPM1D and the cancer immune infiltrates were determined using TIMER. The correlations between PPM1D expression and gene marker sets of the immune infiltrates were established by both the TIMER and GEPIA. Immunohistochemistry was performed to detect the expression of Wip1 protein encoded by PPM1D in HCC, and the relationship between Wip1 expression and the prognosis of HCC were analyzed.ResultsWe found out that PPM1D mRNA expression was significantly higher in several human cancers, including HCC, than in the corresponding normal human tissues. The PPM1D mRNA high expression in HCC was significantly correlated with poor prognosis. The expression was associated with progression-free survival (PFS) in multiple HCC patients' cohorts (PFS HR = 1.5, P = 0.0066). This was especially in early stage (stage 1) and AJCC_T 1 of HCC. Besides, PPM1D mRNA expression indicated a positive correlation with tumor-infiltrating Monocytes, tumor-associated macrophages (TAMs), M1 Macrophage, M2 Macrophage, dendritic cells (DCs), T-helper (Th) and Treg. Wip1 was higher in HCC than paracancerous tissue. High expression of Wip1 was associated with poor prognosis of HCC.ConclusionOur findings suggested that PPM1D mRNA is critical in activating tumor immunity. Besides, they implied that PPM1D could be a potential prognostic biomarker for cancer progression. Moreover, it correlated with tumor immune cell infiltration in HCC.
| S-EPMC8457582 | biostudies-literature
Project description:Rad51, a DNA-repair-related gene, has been reported to be involved in multiple cancers. However, its link with immune infiltration in liver cancer still unknown. Therefore, more research into the roles and activities of Rad51 in hepatocellular carcinoma (HCC) is required. The International Cancer Genome Consortium (ICGC) was used to identify the DNA repair gene Rad51, and has been proved to be overexpressed in HCC patients. We plotted the Kapan-Meier curve, demonstrating that patients with high expression of Rad51 have a poor prognosis. By analyzing the patient data, we discovered that high expression of Rad51 in HCC is linked to clinical stage, pathological T stage, grade, and age. Rad51 was found to be an independent prognostic factor for HCC patients using the multivariate cox model. Moreover, Rad51 expression was found to be associated with the infiltration of immune cells (B cells, CD4 + T cells, CD8 + T cells, neutrophils, macrophages, and dendritic cells) and was intimately linked to the expression of immune cell markers in HCC. Through the analysis of differentially coexpressed genes (DCGs) of Rad51, GO and KEGG enrichment analyses suggested that the expression level of Rad51 might be relevant to neuroactive ligand-receptor interactions, the cell cycle, DNA replication, homologous recombination, oocyte meiosis, and the Fanconi anemia pathway. These findings indicated that Rad51 is a valuable biomarker for the prognosis of patients with liver cancer and that its expression has a significant correlation with immune infiltrations.Abbreviations: HCC: hepatocellular carcinoma; ICGC: International Cancer Genome Consortium TCGA: The Cancer Genome Atlas; TIMER: Tumor Immune Estimation Resource; CAF: Cancer-associated fibroblast; GEPIA: Gene Expression Profiling Interactive Analysis; GSEA: Gene set enrichment analysis; OS: overall survival; PFS: progression-free survival; RFS: relapse-free survival; DSS: disease-specific survival. Partial cor: partial correlation coefficient; HPA: Human Protein Atlas; GO: Gene Ontology; KEGG: Kyoto Encyclopedia of Genes and Genomes; CAF: Cancer-associated fibroblast; DCGs: differentially co-expressed genes.
| S-EPMC8806544 | biostudies-literature
Project description:BackgroundHepatocellular carcinoma (HCC) is one of the most prevalent malignancies and is associated with high mortality. Transmembrane protein 147 (TMEM147) is a seven-transmembrane protein that may mediate immune regulation. However, the relevance of TMEM147 to immune regulation in HCC and the prognosis of HCC patients are unclear.MethodsWe analyzed TMEM147 expression in HCC by using the Wilcoxon rank-sum test. Real time quantitative PCR (RT-qPCR) and Western blot analysis of tumor tissues and cell lines were used to verify TMEM147 expression in HCC. The influence of TMEM147 on HCC prognosis was assessed using Kaplan-Meier analysis, Cox regression analysis, and a prognostic nomogram. The functions of the TMEM147-related differentially expressed genes (DEGs) were identified by Gene Ontology (GO)/Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses and gene set enrichment analysis (GSEA). In addition, we examined the associations between TMEM147 expression and immune infiltration using single-sample gene set enrichment analysis (ssGSEA) and immunofluorescence staining of HCC tissues.ResultsOur results showed that the expression of TMEM147 was significantly higher in human HCC tissues than in adjacent normal liver tissues, with similar findings in human HCC cell lines. High TMEM147 expression was correlated with T stage, pathological stage, histological grade, race, alpha-fetoprotein level, and vascular invasion in HCC. Moreover, we revealed that high TMEM147 expression was associated with shorter survival times and that TMEM147 could be a risk factor for overall survival, along with T stage, M stage, pathological stage, and tumor status. Mechanistic studies revealed that high TMEM147 expression was linked to the B lymphocyte, antigen response, IL6 signaling pathway, cell cycle, Kirsten rat sarcoma viral oncogene homolog (KRAS) signaling pathway, and myelocytomatosis oncogene (MYC) targets. Correspondingly, TMEM147 expression was positively associated with the infiltration of immune cells, including Th2 cells, follicular helper T cells, macrophages, and NK CD56 bright cells in HCC.ConclusionsTMEM147 might be a biomarker for poor prognosis and is related to immune cell infiltration in HCC.
| S-EPMC10257544 | biostudies-literature
Project description:Liver cancer is the fourth leading cause of cancer-related mortality worldwide and hepatocellular carcinoma (HCC) is the most common primary liver cancer. In the present study, it was demonstrated that translocated promoter region (TPR) was upregulated in tumor tissues and associated with prognosis and immune infiltration in HCC. The clinical outcome of patients with HCC with aberrant expression of TPR was examined using multiple databases, including Gene Expression Omnibus, The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression, Kaplan-Meier (KM) Plotter and Xiantao tool. The clinicopathologic characteristics of patients from TCGA database that were associated with overall survival were assessed using Cox regression and KM analysis. The potential hallmarks associated with TPR expression were further predicted by Metascape and Gene Set Enrichment Analysis, and the relationship between TPR and immune infiltration was explored using the Tumor-Immune System Interactions Database and the Tumor Immune Estimation Resource. The results demonstrated that TPR expression was higher in HCC and its overexpression was associated with a worse prognosis, alongside a correlation with several clinical features. Furthermore, cell differentiation, a prospective new hallmark of cancer, was differentially enriched in the high TPR expression phenotype pathway. Moreover, TPR may also modulate the tumor immune microenvironment as it was significantly associated with immunoregulators and chemokines, as well as different tumor infiltration immune cells. According to the in vitro experiments, TPR silencing inhibited the phosphorylation of AKT and the proliferation of HCC cells. In summary, TPR may be a new marker and target for HCC therapy.
| S-EPMC10895467 | biostudies-literature
Project description:BackgroundImmune infiltrates in the tumor microenvironment have established roles in tumor growth, invasion, and metastasis. However, the diagnostic and prognostic potential of immune cell signature in esophageal squamous cell carcinoma (ESCC) remains unclear.ResultsThe proportions of 22 subsets of immune cells from 331 samples including 205 ESCC and 126 normal esophageal mucosa retrieved from TCGA, GEO, and GTEx databases were deciphered by CIBERSORT. Nine overlapping subsets of immune cells were identified as important features for discrimination of ESCC from normal tissue in the training cohort by LASSO and Boruta algorithms. A diagnostic immune score (DIS) developed by XGBoost showed high specificities and sensitivities in the training cohort, the internal validation cohort, and the external validation cohort (AUC: 0.999, 0.813, and 0.966, respectively). Furthermore, the prognostic immune score (PIS) was developed based on naive B cells and plasma cells using Cox proportional hazards model. The PIS, an independent prognostic predictor, classified patients with ESCC into low- and high-risk subgroups in the internal validation cohort (P = 0.038) and the external validation cohort (P = 0.022). In addition, a nomogram model comprising age, N stage, TNM stage, and PIS was constructed and performed excellent (HR = 4.17, 95% CI: 2.22-7.69, P < 0.0001) in all ESCC patients, with a time-dependent 5-year AUC of 0.745 (95% CI: 0.644 to 0.845), compared with PIS or TNM stage as a prognostic model alone.ConclusionOur DIS, PIS, and nomogram models based on infiltrated immune features may aid diagnosis and survival prediction for patients with ESCC.
| S-EPMC9251101 | biostudies-literature
Project description:Background: Increasing evidence supports that competing endogenous RNAs (ceRNAs) and tumor immune infiltration act as pivotal players in tumor progression of hepatocellular carcinoma (HCC). Nonetheless, comprehensive analysis focusing on ceRNAs and immune infiltration in HCC is lacking. Methods: RNA and miRNA sequencing information, corresponding clinical annotation, and mutation data of HCC downloaded from The Cancer Genome Atlas Liver Hepatocellular Carcinoma (TCGA-LIHC) project were employed to identify significant differentially expressed mRNAs (DEMs), miRNAs (DEMis), and lncRNAs (DELs) to establish a ceRNA regulatory network. The Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene ontology (GO) enrichment pathways were analyzed to functionally annotate these DEMs. A multigene-based risk signature was developed utilizing least absolute shrinkage and selection operator method (LASSO) algorithm. Moreover, survival analysis and receiver operating characteristic (ROC) analysis were applied for prognostic value validation. Seven algorithms (TIMER, XCELL, MCPcounter, QUANTISEQ, CIBERSORT, EPIC, and CIBERSORT-ABS) were utilized to characterize tumor immune microenvironment (TIME). Finally, the mutation data were analyzed by employing "maftools" package. Results: In total, 136 DELs, 128 DEMis, and 2,028 DEMs were recognized in HCC. A specific lncRNA-miRNA-mRNA network consisting of 3 lncRNAs, 12 miRNAs, and 21 mRNAs was established. A ceRNA-based prognostic signature was established to classify samples into two risk subgroups, which presented excellent prognostic performance. In additional, prognostic risk-clinical nomogram was delineated to assess risk of individual sample quantitatively. Besides, risk score was significantly associated with contexture of TIME and immunotherapeutic targets. Finally, potential interaction between risk score with tumor mutation burden (TMB) was revealed. Conclusion: In this work, comprehensive analyses of ceRNAs coexpression network will facilitate prognostic prediction, delineate complexity of TIME, and contribute insight into precision therapy for HCC.
| S-EPMC8473911 | biostudies-literature
Project description:Background: BTBD10 serves as an activator of Akt family members through decreasing the protein phosphatase 2A-mediated dephosphorylation. The present study attempted to investigate the prognostic value of BTBD10 in hepatocellular carcinoma (HCC), specially, its relationship with tumor-infiltrating lymphocytes (TILs). Methods: BTBD10 expression was evaluated in HCC using The Cancer Genome Atlas (TCGA) and Xijing Hospital database, and verified in HCC cell lines. Cox analyses were performed to analyze independent prognostic risk factors for HCC. The optimal cut-off value of BTBD10 was calculated, by which all patients were divided into two groups to compare the overall survival (OS). The signaling pathways were predicted, by which BTBD10 may affect the progression of HCC. To investigate the impact of BTBD10 on HCC immunotherapy, correlations between BTBD10 and TILs, immune checkpoints, m6A methylation-related genes and ferroptosis-related genes were assessed. The distribution of half-maximal inhibitory concentration (IC50) of diverse targeted drugs was observed based on the differential expression of BTBD10. Results: BTBD10 expression was higher in HCC tissues and cell lines than that of normal liver tissues and cells. The patients with high expression of BTBD10 showed a worse OS, as compared to that of BTBD10 low-expressing group. Cox analyses indicated that BTBD10 was an independent prognostic risk factor for HCC. Several molecular pathways of immune responses were activated in HCC patients with high-expressing of BTBD10. Furthermore, BTBD10 expression was demonstrated to be positively correlated with tumor-infiltrating B cells, T cells, macrophages, neutrophils and dendritic cells. Meanwhile, the expression of BTBD10 was synchronized with that of several m6A methylation-related genes, ferroptosis-related genes and immune checkpoints. The IC50 scores of Sorafenib, Navitoclax, Veliparib, Luminespib, and Imatinib were found to be lower in BTBD10 high-expressing HCC group. Conclusion: BTBD10 negatively regulates tumor immunity in HCC and exhibits adverse effect on the prognosis of HCC, which could be a potential target for immunotherapy.
| S-EPMC8764259 | biostudies-literature
Project description:BackgroundA preliminary study by our group revealed that the deficiency of EGF domain-specific O-linked N-acetylglucosamine transferase (EOGT) impaired regulatory T-cell differentiation in autoimmune hepatitis. Nevertheless, the prognostic value of EOGT in advanced hepatocellular carcinoma (HCC) and its relationship with immune infiltration remain obscured.MethodsInitially, EOGT expression was evaluated by Oncomine, TIMER, GEO, and UALCAN databases. Besides, the prognostic potential of EOGT expression was analyzed using GEPIA, Kaplan-Meier plotter, CPTAC, Cox regression, and nomogram in HCC samples. Furthermore, we investigated the association between EOGT expression and tumor mutation burden, DNA methylation, and immune infiltration in addition to its possible mechanism via cBioPortal, TIMER, GEPIA, ESTIMATE, CIBERSORT, GSEA, STRING, and Cytoscape.ResultsThe expression of EOGT in HCC was significantly higher than that in normal tissues. Additionally, elevated EOGT expression was correlated with advanced tumor staging and linked to poor overall survival and relapse-free survival, serving as a significant unfavorable prognostic indicator in HCC patients. Remarkably, our results revealed that high-EOGT expression subgroups with elevated TP53 or low CTNNB1 mutations have worse clinical outcomes than the others. Regarding immune infiltration, immunofluorescent staining showed that immune cells in HCC were positive for EOGT. Besides, elevated EOGT expression was linked to exhausted T cells and immune suppressor cells in HCC samples. More importantly, the proportion of CD8+ T cells was reduced in HCC samples with a high level of EOGT expression, but EOGT did not exhibit prognostic potential in HCC samples with increased CD8+ T cells.ConclusionsEOGT may hold great potential as a novel biomarker to distinguish prognosis and immune profiles of HCC patients.
| S-EPMC8766744 | biostudies-literature
Project description:BackgroundThe enzyme L-asparaginase (ASRGL1) catalyzes the hydrolysis of L-asparagine (Asn) to L-aspartic acid (Asp) and ammonia. Numerous studies have shown a strong correlation between ASRGL1 expression and tumorigenesis. However, the expression and biological function of ASRGL1 in hepatocellular carcinoma (HCC) are still unclear.MethodsWe explored the mRNA expression of ASRGL1 in HCC using the HCCDB, Oncomine, and TIMER 2.0 databases. Western blotting and immunohistochemical analyses were also used to determine the mRNA expression of ASRGL1 in HCC. LinkedOmics was used to analyze the genes co-expressed with ASRGL1 and regulators including kinases, miRNAs, and transcription factors. The Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways of the co-expressed genes were also investigated using LinkedOmics. The correlation between ASRGL1 expression and immune infiltrates was analyzed using the TIMER 2.0 and Gene Expression Profiling Interactive Analysis (GEPIA) databases. The effects of ASRGL1 expression on patient outcome were investigated using the UALCAN and GEPIA databases, and the Kaplan-Meier plotter. c-Bioportal was used to explore the mutations of ASRGL1 in HCC.ResultsCompared with the adjacent tissues, ASRGL1 was upregulated in HCC. High ASRGL1 expression in HCC indicated poor relapse-free survival, progression-free survival, disease-specific survival, and overall survival. The expression of ASRGL1 was significantly correlated with infiltrating levels of B cells, CD4+ T cells, macrophages, neutrophils, and dendritic cells in HCC.ConclusionOur findings suggest that ASRGL1 is overexpressed in HCC and that ASRGL1 expression was significantly correlated with immune infiltration in HCC and prognosis. Therefore, ASRGL1 may serve as a biomarker for the early diagnosis and treatment of HCC.
| S-EPMC8267417 | biostudies-literature
Project description:BackgroundImmunotherapeutic approaches have recently emerged as effective treatment regimens against various types of cancer. However, the immune-mediated mechanisms surrounding papillary renal cell carcinoma (pRCC) remain unclear. This study aimed to investigate the tumor microenvironment (TME) and identify the potential immune-related biomarkers for pRCC.MethodsThe CIBERSORT algorithm was used to calculate the abundance ratio of immune cells in each pRCC samples. Univariate Cox analysis was used to select the prognostic-related tumor-infiltrating immune cells (TIICs). Multivariate Cox regression analysis was performed to develop a signature based on the selected prognostic-related TIICs. Then, these pRCC samples were divided into low- and high-risk groups according to the obtained signature. Analyses using Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA) were performed to investigate the biological function of the DEGs (differentially expressed genes) between the high- and low-risk groups. The hub genes were identified using a weighted gene co-expression network analysis (WGCNA) and a protein-protein interaction (PPI) analysis. The hub genes were subsequently validated by multiple clinical traits and databases.ResultsAccording to our analyses, nine immune cells play a vital role in the TME of pRCC. Our analyses also obtained nine potential immune-related biomarkers for pRCC, including TOP2A, BUB1B, BUB1, TPX2, PBK, CEP55, ASPM, RRM2, and CENPF.ConclusionIn this study, our data revealed the crucial TIICs and potential immune-related biomarkers for pRCC and provided compelling insights into the pathogenesis and potential therapeutic targets for pRCC.
| S-EPMC8605132 | biostudies-literature