Correlation Between Prognostic Biomarker SLC1A5 and Immune Infiltrates in Various Types of Cancers Including Hepatocellular Carcinoma

BackgroundSolute carrier family 1 member 5 (SLC1A5) is a major glutamine transporter and plays a key role in tumor growth. The main objectives of this study were to visualize the prognostic landscape of SLC1A5 in multiple cancers and determine the relations between SLC1A5 expression and tumor immunity.MethodsSLC1A5 expression and its effect on tumor prognosis were analyzed using multiple online tools Oncomine, Gene Expression Profiling Interactive Analysis, PrognoScan, and Kaplan-Meier plotter with their own datasets as well as the data from The Cancer Genome Atlas. The correlations between SLC1A5 and tumor immune infiltrates were determined via TIMER.ResultsSLC1A5 expression was significantly higher in several types of cancers, including hepatocellular carcinoma (HCC), compared with corresponding normal tissues. High SLC1A5 expression correlated with poor overall survival and with disease-free survival related to alcohol consumption. Moreover, SLC1A5 expression correlated positively with the numbers of tumor-infiltrating B cells, CD4+ T and CD8+ T cells, macrophages, neutrophils, and dendritic cells in HCC and in lower-grade glioma (LGG). Also, SLC1A5 expression showed strong correlations with diverse immune marker sets in HCC and LGG, indicating its role in regulating tumor immunity.ConclusionsSLC1A5 represents a useful prognostic biomarker in multiple cancers, and its expression correlates highly with tumor immune-cell infiltration, especially in HCC and LGG.

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CDCA3 Is a Novel Prognostic Biomarker Associated with Immune Infiltration in Hepatocellular Carcinoma

BioMed Research International ◽

10.1155/2021/6622437 ◽

2021 ◽

Vol 2021 ◽

pp. 1-19

Author(s):

Zhihuai Wang ◽

Shuai Chen ◽

Gaochao Wang ◽

Sun Li ◽

Xihu Qin

Keyword(s):

Hepatocellular Carcinoma ◽

T Cells ◽

Immune Cell ◽

Disease Free Survival ◽

In Silico Analysis ◽

Gene Markers ◽

Free Survival ◽

Immune Infiltration ◽

Normal Tissues ◽

Tumor Tissues

Cell division cycle-associated protein-3 (CDCA3) contributes to the regulation of the cell cycle. CDCA3 plays an important role in the carcinogenesis of various cancers; however, the association between CDCA3 expression, prognosis of patients, and immune infiltration in the tumor microenvironment is still unknown. Here, we demonstrated that CDCA3 was differentially expressed between the tumor tissues and corresponding normal tissues using in silico analysis in the ONCOMINE and Tumor Immune Estimation Resource (TIMER) databases. We analyzed the relationship between the expression of CDCA3 and prognosis of patients with hepatocellular carcinoma (HCC) using the Kaplan–Meier plotter database and Gene Expression Profiling Interactive Analysis (GEPIA). Furthermore, we determined the prognostic value of CDCA3 expression using univariate and multivariate analyses. We observed that CDCA3 expression closely correlated with immune infiltration and gene markers of infiltrating immune cells in the TIMER database. CDCA3 was highly expressed in the tumor tissues than in the adjacent normal tissues in various cancers, including HCC. Increased expression of CDCA3 was accompanied by poorer overall survival (OS), relapse-free survival (RFS), progression-free survival (PFS), and disease-specific survival (DSS). The correlation between CDCA3 expression and OS and disease-free survival (DFS) was also studied using GEPIA. CDCA3 expression was associated with the levels of immune cell infiltration and was positively correlated with tumor purity. Moreover, CDCA3 expression was associated with gene markers such as PD-1, CTLA4, LAG3, and TIM-3 from exhausted T cells, CD3D, CD3E, and CD2 from T cells, and TGFB1 and CCR8 located on the surface of Tregs. Thus, we demonstrated that CDCA3 may be a potential target and biomarker for the management and diagnosis of HCC.

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A Pan-Cancer Analysis of SMARCA4 Alterations in Human Cancers

Frontiers in Immunology ◽

10.3389/fimmu.2021.762598 ◽

2021 ◽

Vol 12 ◽

Author(s):

Ling Peng ◽

Jisheng Li ◽

Jie Wu ◽

Bin Xu ◽

Zhiqiang Wang ◽

...

Keyword(s):

Dna Methylation ◽

Tumor Immunity ◽

Immune Cell ◽

Gene Set Enrichment Analysis ◽

The Cancer Genome Atlas ◽

Cell Infiltration ◽

Poor Overall Survival ◽

Atpase Subunit ◽

Human Cancers ◽

Cancer Types

BackgroundSMARCA4, the essential ATPase subunit of SWI/SNF chromatin remodeling complex, regulates transcription through the control of chromatin structure and is increasingly thought to play significant roles in human cancers. This study aims to explore the potential role of SMARCA4 with a view to providing insights on pathologic mechanisms implicated here.MethodsThe potential roles of SMARCA4 in different tumors were explored based on The Cancer Genome Atlas (TCGA), Genotype-tissue expression (GTEx), Tumor Immune Estimation Resource (TIMER), and Gene Set Enrichment Analysis (GSEA) datasets. The expression difference, mutation and phosphorylation status, survival, pathological stage, DNA methylation, tumor mutation burden (TMB), microsatellite instability (MSI), mismatch repair (MMR), tumor microenvironment (TME), and immune cell infiltration related to SMARCA4 were analyzed.ResultsHigh expression levels of SMARCA4 were observed in most cancer types. SMARCA4 expression in tumor samples correlates with poor overall survival in several cancers. Lung adenocarcinoma cases with altered SMARCA4 showed a poorer prognosis. Enhanced phosphorylation levels of S613, S695, S699, and S1417 were observed in several tumors, including breast cancer. SMARCA4 correlated with tumor immunity and associated with different immune cells and genes in different cancer types. TMB, MSI, MMR, and DNA methylation correlated with SMARCA4 dysregulation in cancers. SMARCA4 expression was negatively associated with CD8+ T-cell infiltration in several tumors. Furthermore, the SWI/SNF superfamily-type complex and ATPase complex may be involved in the functional mechanisms of SMARCA4, albeit these data require further confirmation.ConclusionsOur study offers a comprehensive understanding of the oncogenic roles of SMARCA4 across different tumors. SMARCA4 may correlate with tumor immunity.

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CDKN2A is a Prognostic Biomarker and Correlated with Immune Infiltrates in Hepatocellular Carcinoma

Bioscience Reports ◽

10.1042/bsr20211103 ◽

2021 ◽

Author(s):

Jun-peng Luo ◽

Jing Wang ◽

Jin-hua Huang

Keyword(s):

Hepatocellular Carcinoma ◽

T Cell ◽

Immune Cell ◽

Kinase Inhibitor ◽

Prognostic Biomarker ◽

Disease Free Survival ◽

Cyclin Dependent Kinase ◽

Strong Correlations ◽

Immune Infiltration ◽

Cyclin Dependent Kinase Inhibitor

Cyclin Dependent Kinase Inhibitor 2A (CDKN2A) is an essential regulator of immune cell functionality, but the mechanisms whereby it drives immune infiltration in hepatocellular carcinoma (HCC) remain unclear. In the current study, we studied the association with CDKN2A expression and immune invasion with the risk of developing HCC. A totally of 2207 different genes were found between HCC and adjacent liver tissues from TCGA and GEO databases. CDKN2A was highly expressed in HCC and associated with poorer overall survival and disease-free survival. Notably, CDKN2A expression was positively correlated with infiltrating levels into purity, B cell, CD+8 T cell, CD+4 T cell, macrophage, neutrophil, and dendritic cells in HCC. CDKN2A expression showed strong correlations between diverse immune marker sets in HCC. These findings suggest that CDKN2A expression potentially contributes to regulation of tumor-associated macrophages and can be used as a prognostic biomarker for determining prognosis and immune infiltration in HCC.

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Prognostic roles of the transcriptional expression of exportins in hepatocellular carcinoma

Bioscience Reports ◽

10.1042/bsr20190827 ◽

2019 ◽

Vol 39 (8) ◽

Cited By ~ 2

Author(s):

Lubiao Chen ◽

Yanlin Huang ◽

Liang Zhou ◽

Yifan Lian ◽

Jialiang Wang ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Survival Data ◽

Disease Free Survival ◽

Dna Amplification ◽

Genetic Alterations ◽

The Cancer Genome Atlas ◽

Functional Enrichment ◽

High Expression ◽

Poor Overall Survival ◽

Cancer Tissues

Abstract Aims: A large number of studies have suggested that exportins (XPOs) play a pivotal role in human cancers. In the present study, we analyzed XPO mRNA expression in cancer tissues and explored their prognostic value in hepatocellular carcinoma (HCC). Methods: Transcriptional and survival data related to XPO expression in HCC patients were obtained through the ONCOMINE and UALCAN databases. Survival analysis plots were drawn with Gene Expression Profiling Interactive Analysis (GEPIA). Sequence alteration data for XPOs were obtained from The Cancer Genome Atlas (TCGA) database and c-BioPortal. Gene functional enrichment analyses were performed with Database for Annotation, Visualization and Integrated Discovery (DAVID). Results: Compared with normal liver tissues, significant XPO mRNA overexpression was observed in HCC cancer tissues. There was a trend of higher XPO expression in more advanced clinical stages and lower differentiated pathological grades of HCC. In HCC patients, high expression of XPO1, CSE1L, XPOT, XPO4/5/6 was related to poor overall survival (OS), and XPO1, CSE1L and XPO5/6 were correlated with poor disease-free survival (DFS). The main genetic alterations in XPOs involved mRNA up-regulation, DNA amplification and deletion. General XPO mutations were remarkably associated with worse OS and mostly affected the pathways of RNA transport and oocyte meiosis. Conclusion: High expression of XPOs was associated with a poor prognosis in HCC patients. XPOs may be exploited as good prognostic biomarkers for survival in HCC patients.

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Uncovering of the Association Between m5C Regulator-Mediated Methylation Modification Patterns and Tumor Microenvironment Infiltration Characteristics in Hepatocellular Carcinoma

10.21203/rs.3.rs-580707/v1 ◽

2021 ◽

Author(s):

Xinyu Gu ◽

Haibo Zhou ◽

Qingfei Chu ◽

Qiuxian Zheng ◽

Jing Wang ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Immune Cells ◽

Immune Cell ◽

Enrichment Analysis ◽

Tumour Microenvironment ◽

Gene Set Enrichment Analysis ◽

The Cancer Genome Atlas ◽

Cell Infiltration ◽

Gene Set ◽

Normal Tissues

Abstract Background: 5-Methylcytosine (m5C) plays essential roles in hepatocellular carcinoma (HCC), but the association between m5C regulation and immune cell infiltration in HCC has not yet been clarified.Methods: In this study, we analysed 371 patients with HCC from The Cancer Genome Atlas (TCGA) database, and the expression of 13 m5C regulators was investigated. Additionally, gene set variation analysis (GSVA), unsupervised clustering analysis, single-sample gene set enrichment analysis (ssGSEA), correlation analysis, and immunohistochemical (IHC) staining were performed.Results: Among the 371 patients, 41 had mutations in m5C regulators, the frequency of which was 11.26%. Then, we identified three m5C modification patterns that had obvious tumour microenvironment (TME) cell infiltration characteristics. Cluster-1 had an immune rejection phenotype; Cluster-2 had an immunoinflammatory phenotype; and Cluster-3 had an immune desert phenotype. In addition, we found that DNMT1 was highly expressed in tumour tissues compared with normal tissues in a tissue microarray (TMA) and that it was positively correlated with many TME-infiltrating immune cells. High expression of the m5C regulator DNMT1 was related to a poor prognosis in patients with HCC. Furthermore, we developed three Immu-clusters that were consistent with the immune characteristics of the m5C methylation modification patterns. We also discovered differences in the levels of immune cells and expression of chemokines and cytokines among the three Immu-clusters.Conclusions: Our work revealed the association between m5C modification and immune regulators in the TME. These findings also suggest that DNMT1 has great potential as a prognostic biomarker and therapeutic target for HCC.

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Upregulated Seizure-Related 6 Homolog-Like 2 Is a Prognostic Predictor of Hepatocellular Carcinoma

Disease Markers ◽

10.1155/2020/7318703 ◽

2020 ◽

Vol 2020 ◽

pp. 1-8

Author(s):

Linhe Wang ◽

Xiangchao Ling ◽

Caihui Zhu ◽

Zhiheng Zhang ◽

Ziming Wang ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Cancer Progression ◽

Disease Free Survival ◽

Gene Expression Omnibus ◽

The Cancer Genome Atlas ◽

Poor Overall Survival ◽

Tissue Samples ◽

Prognostic Predictor ◽

Qrt Pcr ◽

Cancer Genome Atlas

Seizure-related 6 homolog-like 2 (SEZ6L2), which is localized on the cell surface, has been found to be associated with tumor angiogenesis and lung cancer progression. However, the role of SEZ6L2 in hepatocellular carcinoma (HCC) is still unclear. We obtained data from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) to investigate SEZ6L2 expression and regulation in HCC. Then, HCC tissue samples were collected to verify SEZ6L2 by quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemical staining (IHC). Patient information was collected for survival and prognosis analysis. qRT-PCR, IHC, and bioinformatics analysis showed that the SEZ6L2 protein was highly expressed in HCC samples. Clinical data showed that high SEZ6L2 protein expression was correlated with tumor-node-metastasis (TNM) stages (P=0.046), tumor number (P=0.016), and tumor size (P=0.029). Meanwhile, SEZ6L2 overexpression was closely associated with poor overall survival and disease-free survival in HCC patients. Moreover, SEZ6L2 is an independent prognostic predictor for the survival of HCC patients. This study suggests a significant correlation between SEZ6L2 and HCC, which means that SEZ6L2 may potentially serve as a useful prognostic biomarker for HCC patients.

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CLEC3B as a Potential Prognostic Biomarker in Hepatocellular Carcinoma

Frontiers in Molecular Biosciences ◽

10.3389/fmolb.2020.614034 ◽

2021 ◽

Vol 7 ◽

Author(s):

Xing-Wei Xie ◽

Shan-Shan Jiang ◽

Xiang Li

Keyword(s):

Hepatocellular Carcinoma ◽

Tumor Immunity ◽

Immune Cell ◽

Prognostic Biomarker ◽

Cell Infiltration ◽

Immune Cell Infiltration ◽

Lectin Domain ◽

Kaplan Meier ◽

Immune Biomarkers ◽

The Relationship

C-Type Lectin Domain Family 3 Member B (CLEC3B) encodes proteins associated with tumor invasion and metastasis. However, the interrelation between CLEC3B gene expression, tumor immunity, and prognosis of patients with hepatocellular carcinoma (HCC) is unclear. This study was conducted to investigate the prognostic potential of CLEC3B and its association with tumor tissue infiltration markers. CLEC3B expression was examined using the TIMER and Oncomine databases, with its prognostic potential assessed using the GEPIA and Kaplan–Meier plotter databases. The relationship between CLEC3B and tumor immune cell infiltration biomarkers was analyzed using TIMER. Here, we revealed that CLEC3B expression was decreased in HCC and was correlated with a poor survival rate in patients with HCC. Additionally, the expression of CLEC3B was negatively correlated with differential immune cell infiltration and various immune biomarkers. These results indicate a potential mechanism by which the expression of CLEC3B might adjust tumor immunity by modulating the infiltration of HCC immune cells. Our study demonstrated that CLEC3B could be a potential prognostic biomarker and might be involved in tumor immune cell infiltration in HCC.

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Glutamyl-Prolyl tRNA Synthetase mRNA is Highly Expressed in Hepatocellular Carcinoma and May be Associated with Poor Prognosis

10.21203/rs.3.rs-817259/v1 ◽

2021 ◽

Author(s):

Jinyong Shu ◽

Yi Gao ◽

Guifeng Zhang ◽

Pan Luo

Keyword(s):

Hepatocellular Carcinoma ◽

Histological Grade ◽

Mrna Level ◽

Trna Synthetase ◽

Cancer Genome ◽

The Cancer Genome Atlas ◽

Poor Overall Survival ◽

Normal Tissues ◽

Cancer Genome Atlas ◽

Genome Atlas

Abstract BackgroundAlthough glutamyl-prolyl tRNA synthetase (EPRS) mRNA is overexpressed and plays an important role in most tumors, its role in the development and progression of hepatocellular carcinoma (HCC) remains unclear. MethodsThe expression of EPRS in tumor and adjacent tissues was queried using TIMER and The Cancer Genome Atlas. The results were validated using the real-time reverse transcription polymerase chain reaction on RNA extracted from tumor and adjacent non-tumor samples from 10 HCC patients.ResultsUsing bioinformatics analysis, we found that EPRS mRNA was overexpressed in HCC tumor tissues, and the expression level of EPRS mRNA in The Cancer Genome Atlas database was significantly correlated with tumor size (p = 0.0010), histological grade (p = 0.0002), TNM stage (p = 0.0001), and vascular invasion (p = 0.0123) of HCC. The Kaplan-Meier survival analysis demonstrated that the expression of EPRS mRNA was associated with poor overall survival (p = 0.0004). Ten pairs of tumor and adjacent normal tissues were collected from patients with HCC, and the expression of EPRS mRNA was verified. The results showed that the EPRS mRNA level in HCC tissues was higher than that in paracancerous tissues (p = 0.0401). ConclusionOverexpression of EPRS mRNA may be associated with tumorigenesis and the progression of HCC.

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EPDR1 correlates with immune cell infiltration in hepatocellular carcinoma and can be used as a prognostic biomarker

10.21203/rs.3.rs-28073/v1 ◽

2020 ◽

Author(s):

Ruochan Chen ◽

Yiya Zhang

Keyword(s):

Hepatocellular Carcinoma ◽

Functional Analysis ◽

Immune Cell ◽

Prognostic Biomarker ◽

Prognostic Significance ◽

Enrichment Analysis ◽

Gene Set Enrichment Analysis ◽

Cell Infiltration ◽

Immune Cell Infiltration ◽

Normal Tissues

Abstract Background: Hepatocellular carcinoma (HCC) has high mortality rate and is a serious disease burden globally. Hence, identification and characterization of novel biomarkers for the diagnosis and prognosis of HCC are critically important. The protein EPDR1 (ependymin related 1) is a member of piscine brain glycoproteins and is involved in cell adhesion. This is the first study to report the expression of EPDR1 and its prognostic significance, pathological role, and association with cancer immunity in HCC.Methods: The gene expression, prognostic, and clinicopathological analyses were performed based on the data obtained from multiple transcriptome databases. Protein expression of EPDR1 in HCC was verified using human protein atlas and CPTAC databases. Co-expression network analysis using the LinkedOmics database was performed to identify genes co-expressed with EPDR1 expression. Functional analysis of the co-expressed genes, including gene set enrichment analysis was performed to identify the functional role of EPDR1. The statistical analysis was conducted in R, and the relationship between EPDR1 expression and immune cell infiltration was analyzed using TIMER and CIBERSORT resources. Results: The expression of EPDR1 was found to be significantly higher in HCC tissues than in the normal tissues and is an independent prognostic factor for the overall survival of HCC patients. Further, a high level of EPDR1 was shown to be correlated with advanced stage of HCC. Functional analysis revealed that EPDR1 is associated with multiple signaling pathways as well as pathways related to cancer and apoptosis. Notably, EPDR1 expression significantly correlated with purity and the infiltration levels of B cells, CD8+ and CD4+ T cells, macrophages, neutrophils, and dendritic cells in HCC. Further, the EPDR1 expression significantly correlated with the expression of immune signatures, such as KIR2DL4, ITGAM, GATA3, STAT6, STAT5A, BCL6, STAT3, and HAVCR2.Conclusions: Our study identified EPDR1 as a novel prognostic biomarker in HCC. The expression of EPDR1 was shown to be associated with immune cell infiltration as well as the signature molecules that potentially regulate these processes during the carcinogenesis of HCC. With better understanding of its biological function, EPDR1 could become an effective target for HCC diagnosis and treatment in the future.

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The bioinformatics and experimental analysis of AlkB family for prognosis and immune cell infiltration in hepatocellular carcinoma

PeerJ ◽

10.7717/peerj.12123 ◽

2021 ◽

Vol 9 ◽

pp. e12123

Author(s):

Bi Peng ◽

Yuanliang Yan ◽

Zhijie Xu

Keyword(s):

Hepatocellular Carcinoma ◽

T Cells ◽

Metal Ion ◽

Immune Cell ◽

Disease Free Survival ◽

Normal Liver ◽

Expression Levels ◽

Normal Tissues ◽

Molecular Profiles

Background Serving as N6-methyladenosine demethylases, the AlkB family is involved in the tumorigenesis of hepatocellular carcinoma (HCC). However, the molecular profiles and clinical values of the AlkB family in HCC are not well known. Methods Several bioinformatics tools and in vitro experiments were used to identify the immune-related profiles and prognostic values of AlkB family in HCC. Results In this study expression levels of ALKBH1/2/3/4/7 were all remarkably increased in HCC tissues when compared with normal tissues. Quantitative PCR (qPCR) and immunohistochemistry were used to validate the expression of AlkB family members in HCC tissues and normal liver tissues. In addition, high expression levels of ALKBH4 were negatively correlated with overall survival (OS) and disease-free survival (DFS) in patients with HCC. Increased ALKBH4 was also associated with pathological stage in HCC patients. The molecular profiles of AlkB family in HCC were mainly associated with peptidyl-serine modification, peptidyl-tyrosine modification, regulation of metal ion transport, etc. Furthermore, tumor-infiltrating immune cell analysis indicated that ALKBH1/2/3/4/5/6/7/8 and FTO were related to the infiltration of different immune cell, such as CD8+ T cells, macrophages, neutrophils, dendritic cells and CD4+ T cells. We also discovered that the methylation levels of ALKBH1/2/4/5/6/8 and FTO were remarkably reduced in HCC tissues. Conclusions Collectively, our findings may deepen the understanding of specific molecular profiles of the AlkB family in HCC pathology. In particular, ALKBH4 could serve as a promising prognostic candidate for treating HCC, and these results might potentiate the development of more reliable therapeutic strategies for patients with HCC.

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