Identification of lncRNA FAM99A gene as a prognostic biomarker of hepatocellular carcinoma

Abstract Background The complicated pathogenesis of hepatic cancer involves multiple clinical prognosis-associated oncogenes. Methods We utilized the bioinformatics approach to analyze the data from hepatic cancer cases collected by TCGA repository. Results We first found that the FAM99A (Family With Sequence Similarity 99 Member A) gene, a long non-coding RNA (lncRNA), is lowly expressed in hepatocellular carcinoma and closely related to clinical prognosis. We further analyzed the underling molecular mechanism from the perspectives of copy number variation (CNV), DNA methylation, immune cell infiltration, and related cellular pathway. Even though we did not observe a strong correlation between the FAM99A expression and the CNV or immune cell infiltration, the high methylation levels of the five methylated probe sites (cg24218935, cg01745044, cg04353359, cg04938738, cg25356611) were found to be negatively correlated with low expression level of FAM99A. Besides, we performed the enrichment analysis to screen out a group of FAM99A-correlated genes and molecular pathways, such as complement cascade, RNA metabolism, drug metabolic process, PPAR signaling pathway, or cell cycle. Conclusions The liver-specific FAM99A gene was first identified as a prognosis marker of hepatocellular carcinoma, and the underlying molecular mechanism involves DNA methylation and a series of cellular pathways.

Download Full-text

Significant correlation between HSPA4 and prognosis and immune regulation in hepatocellular carcinoma

PeerJ ◽

10.7717/peerj.12315 ◽

2021 ◽

Vol 9 ◽

pp. e12315

Author(s):

Bing-Bing Shang ◽

Jun Chen ◽

Zhi-Guo Wang ◽

Hui Liu

Keyword(s):

Hepatocellular Carcinoma ◽

Dna Methylation ◽

Roc Curve ◽

Immune Regulation ◽

Immune Cell ◽

Genetic Alterations ◽

Cell Infiltration ◽

Immune Checkpoints ◽

Immune Cell Infiltration ◽

Cancer Stage

Background Hepatocellular carcinoma (HCC) is an inflammation-associated tumor involved in immune tolerance and evasion in the immune microenvironment. Heat shock proteins (HSPs) are involved in the occurrence, progression, and immune regulation of tumors. Therefore, HSPs have been considered potential therapeutic targets. Here, we aimed to elucidate the value of HSP family A (Hsp70) member 4 (HSPA4) in the diagnosis and predicting prognosis of HCC, and its relationship with immune cell infiltration, immune cell biomarkers, and immune checkpoints. Gene mutation, DNA methylation, and the pathway involved in HCC were also analyzed. Methods The gene expression omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases were used to compare HSPA4 expression, and the results were confirmed by immunohistochemical staining of clinical samples. R package was used to analyze the correlation between HSPA4 and cancer stage, and to establish receiver operating characteristic (ROC) curve of diagnosis, time-dependent survival ROC curve, and a nomogram model. cBioPortal and MethSurv were used to identify genetic alterations and DNA methylation, and their effect on prognosis. The Tumor Immune Estimation Resource (TIMER) was used to analyze immune cell infiltration, immune cell biomarkers, and immune checkpoints. The STRING database was used to analyze protein–protein interaction network information. Gene Ontology (GO) analysis and the Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to investigate the functions of HSPA4 and its functional partner genes. Results Overexpression of HSPA4 was identified in 25 cancers. Overexpression of HSPA4 considerably correlated with cancer stage and alpha-fetoprotein (AFP) level in HCC. Patients with higher HSPA4 expression showed poorer prognosis. HSPA4 expression can accurately identify tumor from normal tissue (AUC = 0.957). The area under 1-, 3-, and 5-year survival ROCs were above 0.6. The HSPA4 genetic alteration rate was 1.3%. Among the 14 DNA methylation CpG sites, seven were related to the prognosis of HCC. HSPA4 was positively related to immune cell infiltration and immune checkpoints (PD-1 and CTLA-4) in HCC. The KEGG pathway enrichment analysis revealed HSPA4 enrichment in antigen processing and presentation together with HSPA8 and HSP90AA1. We verified the value of HSPA4 in the diagnosis and predicting prognosis of HCC. HSPA4 may not only participate in the occurrence and progression but also the immune regulation of HCC. Therefore, HSPA4 can be a potential diagnostic and prognostic biomarker and a therapeutic target for HCC.

Download Full-text

ARID1A Is a Prognostic Biomarker and Associated with Immune Infiltrates in Hepatocellular Carcinoma

Canadian Journal of Gastroenterology and Hepatology ◽

10.1155/2022/3163955 ◽

2022 ◽

Vol 2022 ◽

pp. 1-14

Author(s):

Yuanyuan Feng ◽

Xinfang Tang ◽

Changcheng Li ◽

Ying Su ◽

Xiaoyu Wang ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Overall Survival ◽

Immune Cell ◽

Enrichment Analysis ◽

Gene Set Enrichment Analysis ◽

Cell Infiltration ◽

Migration And Invasion ◽

Risk Indicator ◽

Immune Cell Infiltration

Objective. ARID1A has been discovered as a potential cancer biomarker. But its role in hepatocellular carcinoma (HCC) is subject to considerable dispute. Methods. The relationship between ARID1A and clinical factors was investigated. Clinicopathological variables related to overall survival in HCC subjects were identified using Cox and Kaplan–Meier studies. The connection between immune infiltrating cells and ARID1A expression was investigated using the tumor Genome Atlas (TCGA) dataset for gene set enrichment analysis (GSEA). Finally, a cell experiment was used to confirm it. Results. The gender and cancer topography (T) categorization of HCC were linked to increased ARID1A expression. Participants with advanced levels of ARID1A expression had a worse prognosis than someone with lower levels. ARID1A was shown to be a risk indicator of overall survival on its own. ARID1A expression is inversely proportional to immune cell infiltration. In vitro, decreasing ARID1A expression substantially slowed the cell cycle and decreased HCC cell proliferation, migration, and invasion. Conclusion. The expression of ARID1A could be used to predict the outcome of HCC. It is closely related to tumor immune cell infiltration.

Download Full-text

RNA N6-Methyladenosine Regulator-Mediated Methylation Modifications Pattern and Immune Infiltration Features in Glioblastoma

Frontiers in Oncology ◽

10.3389/fonc.2021.632934 ◽

2021 ◽

Vol 11 ◽

Author(s):

Yimin Pan ◽

Kai Xiao ◽

Yue Li ◽

Yuzhe Li ◽

Qing Liu

Keyword(s):

Immune Cell ◽

Enrichment Analysis ◽

Gene Set Enrichment Analysis ◽

Cell Infiltration ◽

Immune Cell Infiltration ◽

Lasso Regression ◽

Gene Set Enrichment ◽

Clinical Prognosis ◽

Prognostic Assessment ◽

The Relationship

Glioblastoma (GBM) is a group of intracranial neoplasms with intra-tumoral heterogeneity. RNA N6-methyladenosine (m6A) methylation modification reportedly plays roles in immune response. The relationship between the m6A modification pattern and immune cell infiltration in GBM remains unknown. Utilizing expression data of GBM patients, we thoroughly explored the potential m6A modification pattern and m6A-related signatures based on 21 regulators. Thereafter, the m6A methylation modification-based prognostic assessment pipeline (MPAP) was constructed to quantitatively assess GBM patients’ clinical prognosis combining the Robustness and LASSO regression. Single-sample gene-set enrichment analysis (ssGSEA) was used to estimate the specific immune cell infiltration level. We identified two diverse clusters with diverse m6A modification characteristics. Based on differentially expressed genes (DEGs) within two clusters, m6A-related signatures were identified to establish the MPAP, which can be used to quantitatively forecast the prognosis of GBM patients. In addition, the relationship between 21 m6A regulators and specific immune cell infiltration was demonstrated in our study and the m6A regulator ELAVL1 was determined to play an important role in the anticancer response to PD-L1 therapy. Our findings indicated the relationship between m6A methylation modification patterns and tumor microenvironment immune cell infiltration, through which we could comprehensively understand resistance to multiple therapies in GBM, as well as accomplish precise risk stratification according to m6A-related signatures.

Download Full-text

A Critical Role of Peptidylprolyl Isomerase A Pseudogene 22/microRNA-197-3p/Peptidylprolyl Isomerase A Axis in Hepatocellular Carcinoma

Frontiers in Genetics ◽

10.3389/fgene.2021.604461 ◽

2021 ◽

Vol 12 ◽

Author(s):

Yuwei Gu ◽

Chao Wang ◽

Shengsen Chen ◽

Jia Tang ◽

Xiaoxiao Guo ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Immune Cell ◽

Critical Role ◽

Enrichment Analysis ◽

Vital Role ◽

Functional Enrichment ◽

Cell Infiltration ◽

Immune Cell Infiltration ◽

Chemokine Ligand ◽

Peptidylprolyl Isomerase

The burden of hepatocellular carcinoma (HCC) worldwide is increasing over time, while the underlying molecular mechanism of HCC development is still under exploration. Pseudogenes are classified as a special type of long non-coding RNAs (lncRNAs), and they played a vital role in regulating tumor-associated gene expression. Here, we report that a pseudogene peptidylprolyl isomerase A pseudogene 22 (PPIAP22) and its parental gene peptidylprolyl isomerase A (PPIA) were upregulated in HCC and were associated with the clinical outcomes of HCC. Further investigation revealed that PPIAP22 might upregulate the expression of PPIA through sponging microRNA (miR)-197-3p, behaving as competing endogenous RNA (ceRNA). PPIA could participate in the development of HCC by regulating mRNA metabolic process and tumor immunity based on the functional enrichment analysis. We also found a strong correlation between the expression levels of PPIA and the immune cell infiltration or the expression of chemokines, especially macrophage, C-C motif chemokine ligand 15 (CCL15), and C-X-C motif chemokine ligand 12 (CXCL12). Our findings demonstrate that the PPIAP22/miR-197-3p/PPIA axis plays a vital role in the progression of HCC by increasing the malignancy of tumor cells and regulating the immune cell infiltration, especially macrophage, through CCL15-CCR1 or CXCL12-CXCR4/CXCR7 pathways.

Download Full-text

HILPDA Is a Prognostic Biomarker and Correlates With Macrophage Infiltration in Pan-Cancer

Frontiers in Oncology ◽

10.3389/fonc.2021.597860 ◽

2021 ◽

Vol 11 ◽

Author(s):

Chengdong Liu ◽

Xiaohan Zhou ◽

Hanyi Zeng ◽

Dehua Wu ◽

Li Liu

Keyword(s):

Survival Data ◽

Immune Cell ◽

Enrichment Analysis ◽

The Cancer Genome Atlas ◽

Cell Infiltration ◽

Immune Cell Infiltration ◽

Clinical Prognosis ◽

Cancer Data ◽

Tumor Types ◽

Pan Cancer

Background: The protein hypoxia-inducible lipid droplet-associated (HILPDA) is differentially expressed in various tumors. However, its role and correlation with immune cell infiltration in most tumors remain unclear.Methods: HILPDA expression was analyzed in pan-cancer data from The Cancer Genome Atlas (TCGA) database. The influence of HILPDA in clinical prognosis was evaluated using clinical survival data from TCGA. Enrichment analysis of HILPDA was conducted using the R package “clusterProfiler.” We downloaded the immune cell infiltration score of TCGA samples from published articles and analyzed the correlation between the magnitude of immune cell infiltration and HILPDA expression.Results: HILPDA was highly expressed and associated with worse overall survival, disease-specific survival, and progression-free interval in most tumor types. In addition, HILPDA expression was significantly associated with the glycolysis pathway and infiltration of immune cells. Tumor-associated macrophage (TAM) infiltration increased in tissues with high HILPDA expression in most tumor types. Immunosuppressive genes, such as PD-L1, PD-1, TGFB1, and TGFBR1 were positively correlated with HILPDA.Conclusions: Our study suggests that HILPDA is a marker of poor prognosis. High HILPDA may contribute to TAM infiltration and be associated with tumor immunosuppression status.

Download Full-text

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.

Download Full-text

Identification of Prognostic Genes in the Tumor Microenvironment of Hepatocellular Carcinoma

Frontiers in Immunology ◽

10.3389/fimmu.2021.653836 ◽

2021 ◽

Vol 12 ◽

Author(s):

Shixin Xiang ◽

Jing Li ◽

Jing Shen ◽

Yueshui Zhao ◽

Xu Wu ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Regression Analysis ◽

Tumor Microenvironment ◽

Immune Cell ◽

Enrichment Analysis ◽

Gene Set Enrichment Analysis ◽

Functional Enrichment ◽

Cell Infiltration ◽

Immune Cell Infiltration ◽

Tumor Purity

Background: Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in the world. The efficacy of immunotherapy usually depends on the interaction of immunomodulation in the tumor microenvironment (TME). This study aimed to explore the potential stromal-immune score-based prognostic genes related to immunotherapy in HCC through bioinformatics analysis.Methods: ESTIMATE algorithm was applied to calculate the immune/stromal/Estimate scores and tumor purity of HCC using the Cancer Genome Atlas (TCGA) transcriptome data. Functional enrichment analysis of differentially expressed genes (DEGs) was analyzed by the Database for Annotation, Visualization, and Integrated Discovery database (DAVID). Univariate and multivariate Cox regression analysis and least absolute shrinkage and selection operator (LASSO) regression analysis were performed for prognostic gene screening. The expression and prognostic value of these genes were further verified by KM-plotter database and the Human Protein Atlas (HPA) database. The correlation of the selected genes and the immune cell infiltration were analyzed by single sample gene set enrichment analysis (ssGSEA) algorithm and Tumor Immune Estimation Resource (TIMER).Results: Data analysis revealed that higher immune/stromal/Estimate scores were significantly associated with better survival benefits in HCC within 7 years, while the tumor purity showed a reverse trend. DEGs based on both immune and stromal scores primarily affected the cytokine–cytokine receptor interaction signaling pathway. Among the DEGs, three genes (CASKIN1, EMR3, and GBP5) were found most significantly associated with survival. Moreover, the expression levels of CASKIN1, EMR3, and GBP5 genes were significantly correlated with immune/stromal/Estimate scores or tumor purity and multiple immune cell infiltration. Among them, GBP5 genes were highly related to immune infiltration.Conclusion: This study identified three key genes which were related to the TME and had prognostic significance in HCC, which may be promising markers for predicting immunotherapy outcomes.

Download Full-text

Integrated Transcriptional Profiling Analysis and Immune-Related Risk Model Construction for Intracranial Aneurysm Rupture

Frontiers in Neuroscience ◽

10.3389/fnins.2021.613329 ◽

2021 ◽

Vol 15 ◽

Author(s):

Dezhi Shan ◽

Xing Guo ◽

Guozheng Yang ◽

Zheng He ◽

Rongrong Zhao ◽

...

Keyword(s):

Immune Response ◽

Inflammatory Response ◽

Signaling Pathway ◽

Immune Cell ◽

Risk Model ◽

Enrichment Analysis ◽

Cell Infiltration ◽

Enzyme Linked Immunosorbent Assay ◽

Immune Cell Infiltration ◽

Related Risk

Intracranial aneurysms (IAs) may cause lethal subarachnoid hemorrhage upon rupture, but the molecular mechanisms are poorly understood. The aims of this study were to analyze the transcriptional profiles to explore the functions and regulatory networks of differentially expressed genes (DEGs) in IA rupture by bioinformatics methods and to identify the underlying mechanisms. In this study, 1,471 DEGs were obtained, of which 619 were upregulated and 852 were downregulated. Gene enrichment analysis showed that the DEGs were mainly enriched in the inflammatory response, immune response, neutrophil chemotaxis, and macrophage differentiation. Related pathways include the regulation of actin cytoskeleton, leukocyte transendothelial migration, nuclear factor κB signaling pathway, Toll-like receptor signaling pathway, tumor necrosis factor signaling pathway, and chemokine signaling pathway. The enrichment analysis of 20 hub genes, subnetworks, and significant enrichment modules of weighted gene coexpression network analysis showed that the inflammatory response and immune response had a causal relationship with the rupture of unruptured IAs (UIAs). Next, the CIBERSORT method was used to analyze immune cell infiltration into ruptured IAs (RIAs) and UIAs. Macrophage infiltration into RIAs increased significantly compared with that into UIAs. The result of principal component analysis revealed that there was a difference between RIAs and UIAs in immune cell infiltration. A 4-gene immune-related risk model for IA rupture (IRMIR), containing CXCR4, CXCL3, CX3CL1, and CXCL16, was established using the glmnet package in R software. The receiver operating characteristic value revealed that the model represented an excellent clinical situation for potential application. Enzyme-linked immunosorbent assay was performed and showed that the concentrations of CXCR4 and CXCL3 in serum from RIA patients were significantly higher than those in serum from UIA patients. Finally, a competing endogenous RNA network was constructed to provide a potential explanation for the mechanism of immune cell infiltration into IAs. Our findings highlighted the importance of immune cell infiltration into RIAs, providing a direction for further research.

Download Full-text

Glucose-6-Phosphate Dehydrogenase is a Prognostic Biomarker and Correlated with Immune Infiltrates in Hepatocellular Carcinoma

10.21203/rs.3.rs-1232206/v1 ◽

2022 ◽

Author(s):

Yang Bu ◽

Kejun Liu ◽

Yiming Niu ◽

Ji Hao ◽

Lei Cui ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Tumor Microenvironment ◽

Liver Cancer ◽

Immune Cell ◽

Cox Regression ◽

Functional Enrichment ◽

Cell Infiltration ◽

Immune Cell Infiltration ◽

Potential Biomarker ◽

Glucose 6 Phosphate Dehydrogenase

Abstract Background: Glucose-6-phosphate dehydrogenase (G6PD) plays an important role in the metabolic and immunological aspects of tumors. In hepatocellular carcinoma (HCC), the alteration of tumor microenvironment influences recurrence and metastasis. We extracted G6PD-related data from public databases of HCC tissues and used a bioinformatics approach to explore the correlation between G6PD expression and clinicopathological features and prognosis of immune cell infiltration in HCC.Methods: We extract G6PD expression information from TCGA and GEO databases in liver cancer tissues and normal tissues, validated by immunohistochemistry, and the correlation between G6PD expression and clinical features is analyzed, and the clinical significance of G6PD in liver cancer is assessed by Kaplan-Meier, Cox regression and prognostic line graph models. Functional enrichment analysis is performed by protein-protein interaction (PPI) network, GO/KEGG, GSEA and G6PD-associated differentially expressed genes (DEGs). TIMER and ssGSEA packages are used to assess the correlation between expression and the level of immune cell infiltration.Results: Our results show that G6PD expression is significantly upregulated in hepatocellular carcinoma tissues (P < 0.001). G6PD expression is associated with histological grade, pathological stage, T-stage, vascular infiltration and AFP level (P < 0.05); HCC patients in the low G6PD expression group had longer overall survival and better prognosis compared with the high G6PD expression group (P < 0.05). The level of G6PD expression also affects the levels of macrophages, unactivated dendritic cells, B cells, and follicular helper T cells in the tumor microenvironment.Conclusion: High expression of G6PD is a potential biomarker for poor prognosis of hepatocellular carcinoma, and G6PD may be a target for immunotherapy of HCC.

Download Full-text

Identification of Potential Therapeutic Targets and Molecular Regulatory Mechanisms for Osteoporosis by Bioinformatics Methods

BioMed Research International ◽

10.1155/2021/8851421 ◽

2021 ◽

Vol 2021 ◽

pp. 1-10

Author(s):

Li Zhang ◽

Yunlong Yang ◽

Dechun Geng ◽

Yonghua Wu

Keyword(s):

Immune Cell ◽

Therapeutic Targets ◽

Enrichment Analysis ◽

Differentially Expressed ◽

Cell Infiltration ◽

Immune Cell Infiltration ◽

Differential Analysis ◽

Ppi Network ◽

The Difference ◽

And Control

Background. Osteoporosis is characterized by low bone mass, deterioration of bone tissue structure, and susceptibility to fracture. New and more suitable therapeutic targets need to be discovered. Methods. We collected osteoporosis-related datasets (GSE56815, GSE99624, and GSE63446). The methylation markers were obtained by differential analysis. Degree, DMNC, MCC, and MNC plug-ins were used to screen the important methylation markers in PPI network, then enrichment analysis was performed. ROC curve was used to evaluate the diagnostic effect of osteoporosis. In addition, we evaluated the difference in immune cell infiltration between osteoporotic patients and control by ssGSEA. Finally, differential miRNAs in osteoporosis were used to predict the regulators of key methylation markers. Results. A total of 2351 differentially expressed genes and 5246 differentially methylated positions were obtained between osteoporotic patients and controls. We identified 19 methylation markers by PPI network. They were mainly involved in biological functions and signaling pathways such as apoptosis and immune inflammation. HIST1H3G, MAP3K5, NOP2, OXA1L, and ZFPM2 with higher AUC values were considered key methylation markers. There were significant differences in immune cell infiltration between osteoporotic patients and controls, especially dendritic cells and natural killer cells. The correlation between MAP3K5 and immune cells was high, and its differential expression was also validated by other two datasets. In addition, NOP2 was predicted to be regulated by differentially expressed hsa-miR-3130-5p. Conclusion. Our efforts aim to provide new methylation markers as therapeutic targets for osteoporosis to better treat osteoporosis in the future.

Download Full-text