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

doi:10.21203/rs.3.rs-28073/v1

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

https://doi.org/10.21203/rs.3.rs-28073/v1

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published 15 Sep, 2020

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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.

Translational Medicine

EPDR1

Hepatocellular carcinoma

Prognostic

Immune cell infiltration

Biomarker

Primary liver cancer (PLC) is one of the malignant tumors of the digestive system, which poses a huge threat towards human health; hepatocellular carcinoma (HCC) is the major histological type of PLC [1]. Globally, HCC ranks sixth in the number of incidences and second in the mortality rate among all malignancies [2, 3]. Moreover, the number of HCC incidences is rising, and it is expected that the annual incidences will be beyond 1 million by 2025 [4, 5]. Currently, the diagnosis of HCC is mainly based on the detection of serum alpha-fetoprotein (AFP), B-ultrasound, and computed tomography imaging. However, the misdiagnosis and missed diagnosis rates are very high [6–8]. Owing to the insidious onset, poor tumor biological behavior, and rapid progress of HCC, most patients reach advanced stage of the disease and miss the opportunity for radical treatment. Despite the advances in research related to HCC biomarkers, in recent years, lack of specific markers for tumor sub-types, disease stages, or prognosis remains an important gap in the understanding and treatment of HCC. Further, the prognosis of HCC patients is very poor, and the 5-year survival rate is as low as 30% [9, 10]. Therefore, identifying specific and sensitive biomarkers related to early diagnosis, treatment, and prognosis of HCC is of great significance.

The ependymin-related 1 (EPDR1) gene encodes for a protein that is similar to ependymins, which belong to a family of piscine brain glycoproteins [11]. Ependymins, encoded by Epd genes, are transmembrane proteins that play a crucial role in adhesion of neural cells [12]. For the first time, mammalian ependymin-related transcript was discovered in 2001 in two colorectal cancer (CRC) cell lines [13], and was designed as UCC1 (upregulated in colon cancer 1). Following this discovery, other studies identified and characterized the expression of MERP1 (mammalian ependymin-related protein 1) in hematopoietic cells, non-hematopoietic tissues, and in several malignant cell lines andtissues [14, 15], which was later confirmed to be UCC1, and currently known as EPDR1 gene. EPDR1 is highly expressed in the brain and also detected in other tissues, such as muscle, heart and in extracellular fluids [14–18].

The function of EPDR1 is not well known, although several studies have reported its differential expression and single-nucleotide polymorphisms associated with its locus in different pathological and developmental processes, which are known to affect the cell adhesion [19–24]. Furthermore, genetic variants in EPDR1 have been reported to be linked to several diseases, including Dupuytren’s disease [21, 25, 26] and primary angle closure glaucoma [23, 27], however these observations do not provide obvious insight into the molecular functions of the protein. In 2016 F. Valiente et al. reported that EPDR1 and its spliced isoforms are differentially expressed in human CRC cell lines, and the up-regulation of EPDR1 in human colorectal cancer was found to promote cell growth, proliferation, and invasiveness [28]. Genome-wide DNA methylation profiling studies revealed that methylation-mediated epigenetic silencing of EPDR1 may play an important role in preventing CRC progression [29]. In this context, exploring the role of EPDR1 in the onset and/or development of tumors is particularly applealing.

Our study is the first to report the association of EPDR1 with HCC growth and progression. Further, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses of EPDR1-coexpressed genes were performed to explore the associated processes and pathways. In addition, relationship between EPDR1 expression and tumor-infiltrating immune cells, as well as immune-related genes was explored through multi-dimensional analysis. The current study will provide novel insights into the underlying mechanisms associated with HCC development, and thus help in discovering novel potential targets and strategies for HCC diagnosis and treatment.

EPDR1 expression in HCC from different databases

The expression of EPDR1 in HCC was investigated using the datasets obtained from International Cancer Genome Consortium (ICGC) (https://icgc.org/daco) andThe Cancer Genome Atlas (TCGA) (https://cancergenome.nih.gov/), which were processed using limma and vioplot R software packages. The expression levels of EPDR1 gene in HCC was also explored using the Gene Expression Profiling Interactive Analysis (GEPIA) database (http://gepia.cancer-pku.cn/). Furthermore, we validated the expression of EPDR1 by using three independent Gene Expression Omnibus (GEO) microarray datasets (GSE76427, GSE64041 and GSE102079) obtained from NCBI-GEO database ( https://www.ncbi.nlm.nih.gov/gds).

Survival analysis using R and Kaplan-Meier plotter

The prognostic significance of EPDR1 in HCC was explored using the Kaplan-Meier plotter (http://kmplot.com/analysis/) based on TCGA data and then validated using ICGC database using survival package in R software (version 3.5.2). The hazard ratio (HR) with 95% confidence intervals (CI) and log-rank p-value was also calculated.

Expression level of EPDR1 in human normal tissues

The gene expression and phenotype data corresponding to human normal tissues in GTEx were obtained from UCSC Xena project (http://xena.ucsc.edu/). The downloaded dataset included TOIL RSEM FPKM (n = 7,862) and phenotype (n = 9,783) data corresponding to different human normal tissues. The ensembl gene identifiers in the RNA-seq data were converted to official gene symbols using an in-house perl script. Further, the expression of EPDR1 in different organs of male and female were extracted based on GTEx RNA-seq and phenotype data using perl scripts and visualized using gganatogram and ggpubr R packages.

Correlation between EPDR1 expression and clinical characteristics of HCC patients

The correlation between EPDR1 expression and different clinicopathological characteristics of HCC patients, such as age, race, gender, survival, histopathological grade, AJCC stage, malignancy, cancer history, and stage was analyzed using R software and then validated using UALCAN (http://ualcan.path.uab.edu). T-test was used to estimate the significant differences in the gene expression levels between the groups.

Co-expression analysis using LinkedOmics database

The genes co-expressed with EPDR1 in HCC were identified using the LinkedOmics database (http://www.linkedomics.org/login.php), a third-party online tool containing TCGA data. Co-expressed genes were statistically analyzed and their expression patterns were shown using volcano plots and heatmaps. Heatmaps were generated using the heatmap R package. Pearson correlation coefficient was used to evaluate the significant correlation of the co-expressed genes with EPDR1 expression. FDR < 0.01 was considered for representing significant expression, whereas, p < 0.05 was considered for significantly related genes.

Relationship between EPDR1 expression and immune cell infiltration

The correlation between EPDR1 level and infiltration of immune cells in HCC was explored using Tumor Immune Estimation Resource (TIMER) database (http://cistrome.org/TIMER/). Correlation analysis of EPDR1 expression and infiltration levels of 22 immune cells was further performed based on TCGA HCC data using CIBERSORT. Further, the R package corrplot was used to investigate the correlations between the expression pattern of EPDR1 and known immune marker genes in HCC.

EPDR1 protein levels in HCC

The expression of EPDR1 protein in HCC was explored based on the immunohistochemistry (IHC) data from Human Protein Atlas (HPA) database (https://www.proteinatlas.org/), as well as the mass spectrometric data from Clinical Proteomic Tumor Analysis Consortium (CPTAC) database (https://cptac-data-portal.georgetown.edu/cptacPublic/).

Statistical Analysis

Statistical results for TCGA data were performed using different packages in R (version 3.6.1). The correlations between clinical characteristics and EPDR1 expression were analyzed using logistic regression. Univariate and multivariate Cox regression analyses were performed to reveal the relationship between EPDR1 and the clinical parameters and the immune cell infiltration with overall survival of HCC using survival package in R software. Time-dependent receiver operating characteristic (ROC) curves, with AUC values were quantified with the survival ROC package. The values with p < 0.05 were considered statistically significant.

EPDR1 expression is significantly elevated in HCC tissues

First we compared the expression of EPDR1 in HCC and normal liver tissues using multiple datasets obtained from TCGA, ICGC, GEPIA and GEO databases. Analysis of several HCC cohorts in the TCGA and ICGC databases revealed that EPDR1 mRNA expression was significantly higher in HCC tissues than in the adjacent normal tissues (Fig. 1A and 1B. Further, the expression data in the GEPIA database indicated up-regulation of EPDR1 in the HCC tissues compared to the normal tissues from TCGA (Fig. 1C) or GTEx database (Fig. 1D). Additionally, three independent microarray studies obtained from the GEO database validated the significant higher expression of EPDR1 in tumor tissues than in the normal tissue (Fig. 1E).

Finally, we verified the protein levels of EPDR1 in HCC tissues using HPA and CPTAC databases. The IHC data in HPA database revealed that the expression of EPDR1 was significantly higher in HCC tissue than the normal tissues (Fig. 1F). Further, EPDR1 level was found to be significantly increased in the HCC group compared to that in normal group (p = 9.938-e04) based on CPTAC data, as shown in Fig. 1G.

Prognostic Significance Of Epdr1 Expression In Hcc

Next, we sought to investigate the prognostic significance of EPDR1 expression in HCC. The association between EPDR1 level and the survival outcomes of HCC patients was assessed using Kaplan-Meier survival curves (Fig. 2). The results showed clustering of patients into two groups according to the median value of EPDR1 expression level in each cohort. The group with high EPDR1 expression had significantly shorter overall survival (OS), progression-free survival (PFS), recurrence free survival (RFS) and disease specific survival (DSS) compared to the group with low expression of EPDR1 based on TCGA data using GEPIA database (Fig. 2A). Figure 2B indicates significant correlation (p < 0.001) between high EPDR1 mRNA expression and worse OS for HCC patients based on the data obtained from ICGC database. As shown in Fig. 2C, univariate analysis using Cox regression revealed that EPDR1 expression and T stage are significantly associated with overall survival (p < 0.05). Multivariate analysis and ROC curve revealed that up-regulated expression of EPDR1 is an independent prognostic factor of poor prognosis based on TCGA data (p < 0.005). The prognostic significance of EPDR1 verified using the data obtained from ICGC database is shown in Fig. 2D.

Correlation between EPDR1 expression and clinical characteristics of HCC patients

The correlation between EPDR1 expression and various clinicopathological parameters in HCC patients based on TCGA and ICGC data are shown in Fig. 3a and Fig. 3B, respectively. We observed significantly higher levels of EPDR1 in male patients (p = 0.015), and in patients with advanced stage of the disease (p = 0.018) and bad prognosis (p = 0.012). Furthermore, the expression of EPDR1 was shown to be significantly increased gradually from stage I to stage IV (p = 0.001), and was found to be significantly higher in patients with follow-up death (p = 0.003). Thus, these results indicate that EPDR1 is overexpressed and positively associated with advanced tumor stage in HCC.

Expression Of Epdr1 In Human Normal Tissues

EPDR1 expression in normal human tissueswas determined using the data obtained from the GTEx database. Red represents high expression, black represents median expression, and green represents low expression (Fig. 4A). EPDR1 was found to be highly expressed in most tissues except in the liver, as shown in Fig. 4A and B,. Further, no significant gender based difference was observed in the expression of EPDR1 in most tissues or organs, except in case of blood and skeletal muscle (p < 0.05 and p < 0.01, respectively) (Fig. 4B).

Epdr1 Co-expressed Genes In Hcc

To gain insight into the biological importance of EPDR1 in HCC, the function module of LinkedOmics was used to examine the EPDR1 co-expression in liver HCC (LIHC) cohort. Figure 5A shows genes highly co-expressed with EPDR1 based on Pearson correlation; genes positively and negatively correlated with EPDR1 are marked in dark red and dark green dots, respectively (FDR < 0.01). Top 50 genes showing significant positive and negative correlation with EPDR1 are shown in heatmaps (Fig. 5B and C). The prognostic role of the top 50 genes positively and negatively correlated with EPDR1 in LIHC cohort are shown in Fig. 5D. Further, 24 of the top 50 positively correlated genes were shown to be high-risk genes; whereas 8 of the top 50 negatively correlated genes were low-risk genes (Fig. 5D). Gene Ontology (GO) enrichment analysis showed that EPDR1 co-expressed genes were significantly associated with the activation of integrin-mediated signaling pathway, antigen processing, and presentation and leukocyte apoptotic process, while the processes, such as fatty acid metabolism, protein activation cascade were inhibited (Fig. 5E). KEGG pathway analysis showed enrichment of pathways such as, hippo signaling, pathways related to various infections, small cell lung cancer, nucleotide excision repair, and DNA replication (Fig. 5F). These results suggest a widespread impact of EPDR1 expression on the global transcriptome of HCC tissues.

To further analyze the biological functions of EPDR1 in HCC, GSEA was performed on datasets with high and low expression of EPDR1. These results revealed significant differences (FDR q-value < 0.01) in the enrichment of MSigDB Collection (c2.cp.biocarta and h.all. v6.1. symbols). The most markedly enriched signaling pathways screened according to their NES are shown in Fig. 5G. As shown, pathways related to lysosome, NOD like receptor signaling, WNT signaling, ubiquitin mediated proteolysis, MAPK signaling, cancer and apoptosis were significantly represented by EPDR1 high expression phenotype, whereas, pathways associated with glycine, serine and threonine metabolism were represented by EPDR1 low expression phenotype.

Epdr1 Expression And Tumor-infiltrating Immune Cells (tiics)

The survival of patients in several cancers is determined by the number and activity of tumor-infiltrating lymphocytes [30]. Therefore, we explored the relationship between EPDR1 expression and immune cell infiltration in HCC using the TIMER database. Figure 6A shows that EPDR1 expression significantly correlates with purity, and infiltration of B cells, CD8 + T cells, CD4 + T cells, macrophages, neutrophils and dendritic cells in HCC tissues. Moreover, copy number variation of EPDR1 was shown to affect the infiltration of B cells, CD4 + T cells, neutrophils, and dendritic cells in HCC (Fig. 6B). Further, the association between EPDR1 expression and level of infiltration of 22 immune cells in TCGA HCC datasets using CIBERSORT indicated clear infiltration of the immune cell subpopulations. The correlation heatmap (Fig. 6C) revealed the proportions of different TIIC subpopulations that were weakly to moderately correlated with the expression of EPDR1.

To better broaden the understanding of EPDR1 crosstalk with immune related genes, we analyzed the association between EPDR1 expression and various immune signatures from TCGA and ICGC datasets. The signatures include immune marker genes of common tumor-infiltrating lymphocytes (TILs), T cell exhaustion, immune inhibitory or stimulatory genes (including immune checkpoint gene sets), cytokine-related genes, major histocompatibility complex genes, and mast cells (Fig. 6D). The results showed that expression of KIR2DL4 (natural killer cell), ITGAM (neutrophil), GATA3 (TH2), STAT6 (TH2), STAT5A (TH2), BCL6 (Tfh), STAT3 (Th17) and HAVCR2 (T cell exhaustion) were significantly correlated with EPDR1 expression levels based on TCGA database (p < 0.05), while KIR2DL2 (natural killer cell), KIRDS4 (natural killer cell), ITGAM (neutrophil), STAT4 (Th1), STAT5A (Th2), STAT6 (Th2), LAG3 (T cell exhaustion), HAVCR2 (T cell exhaustion) and HDC (mast cells) were significantly correlated with EPDR1 expression levels based on ICGC database (p < 0.05).

HCC is the most common type of liver cancer. Most HCC patients are diagnosed at an advanced stage, which lacks effective treatment [31, 32]. Therefore, early screening and diagnosis of HCC patients is beneficial for the treatment and prognosis of patients. However, currently there are no effective biomarkers for the early diagnosis of HCC, and the molecular mechanisms underlying HCC metastasis remains unclear [33, 34]. EPDR1, a member of piscine brain glycoproteins, plays a role in cell adhesion. To gain detailed insights into the potential functions of EPDR1 and its regulatory network in HCC, we performed bioinformatics analysis using publicly available data, which we hope will benefit future research related to HCC.

In the current study, we explored the expression of EPDR1 in HCC patient data obtained from various database to assess its prognostic value. High expression of EPDR1 was significantly correlated with worse RFS, PFS, OS, and DSS of HCC patients. Further, the relationship between EPDR1 expression and various clinicopathological characteristics of HCC patients highlights the role of elevated EPDR1 as an independent prognostic factor for poor OS. The HCC patients with high EPDR1 expression are more likely to present advanced grade, stage, and poor prognosis than those with low EPDR1 expression. Therefore, our findings suggest that EPDR1 overexpression occurs in most HCC cases and deserves further clinical validation as a potential diagnostic and prognostic marker.

To probe the signaling pathways associated with EPDR1 expression, we constructed the EPDR1 co-expression network and performed functional analysis of the co-expressed genes. GO and KEGG pathway analysis revealed that the co-expressed genes were mainly related to processes and pathways associated with different signaling, DNA replication and metabolism. To further analyze the biological role of EPDR1 in HCC, GSEA was performed, which revealed that EPDR1 overexpression was implicated in multiple signaling pathways, such as WNT, MAPK, NOD like receptor, and cancer, and apoptosis.. These signaling pathways and processes have been reported to be associated with HCC carcinogenesis [35]. However, in vivo studies are needed to further validate the association of these processes and pathways in regulating EPDR1 functions in HCC.

The liver is the largest immune organ of the body and harbors various immune cells. HCC is a typical inflammatory related tumor, and immune tolerance and escape plays a key role in the carcinogenesis process [36]. Previous studies have mainly focused on tumor proliferation and invasion, whereas, recently the concept of tumor immune microenvironment has emerged as one of the important factor. In tumor microenvironment (TME), cancer cells, non-cancerous cells, and extracellular matrix form a dynamic system that interacts with each other. A number of growth factors, cytokines and chemokines are produced in the TME that facilitate immune tolerance, and promote progression of cancer [37]. Therefore, we explored the potential role EPDR1 in immune regulation in HCC using the various databases. Our study indicated that EPDR1 expression significantly correlates with the infiltration levels of various immune cells in the TME of HCC, suggesting a role of EPDR1 in modulating cancer immunity. Further, our results indicated a possible mechanism, where EPDR1 regulates the functions of different immune cells in HCC. The analysis revealed significant correlation of several immune signatures with EPDR1 level. Most cancers evade immune supervision by impairing the functions of immune cells, such as tumor associated neutrophils, regulatory T cells, marrow-derived suppressor cells, tumor-associated macrophages and/or by releasing inhibitory cytokines, such as GM-CSF, VEGF, IL-1β and chemokines [16, 37–39]. These immune cells and cytokines are vital players of TME and are associated with immune regulation in HCC. Hence exploring these factors might provide novel targets for immunotherapy of HCC. To summarize, our results indicate that EPDR1 plays a crucial role in the modulation and recruitment of immune cells as well as in affecting the expression of immune signatures in HCC. However, further research, including in vivo and in vitro validation, as well as clinical trials with optimum numbers of samples, are needed to evaluate the correlation between EPDR1 more accurately and immune regulation in HCC.

In conclusion, this is the first study to identify EPDR1 as a novel biomarker with prognostic significance in HCC patients. Our results indicated an association between EPDR1 expression and immune cell infiltration, as well as revealed the potential molecular mechanism underlying the carcinogenesis of HCC. Thus, we conclude that EPDR1 can be used as an effective target for the diagnosis and treatment of HCC in the future.

PLC: Primary liver cancer; HCC: Hepatocellular carcinoma; AFP: Alpha-fetoprotein; CRC: Colorectal cancer; GO: Gene Ontology; KEGG: Kyoto Encyclopedia of Genes and Genomes. GO: Gene Ontology; TCGA: The Cancer Genome Atlas; ICGC: International Cancer Genome Consortium; GEPIA: Gene Expression Profiling Interactive Analysis; GTEx: Genotype-Tissue Expression; GEO: Gene Expression Omnibus; HR: Hazard ratio; CI: Confidence interval; GSEA: Gene set enrichment analysis; NES: normalized enrichment score; TIMER: Tumor Immune Estimation Resource; IHC: Immunohistochemistry; HPA: Human Protein Atlas; CPTAC: Clinical Proteomic Tumor Analysis Consortium; ROC: Receiver operating characteristic; OS: overall survival; PFS: Progression-free survival; RFS: Recurrence free survival; DSS: Disease specific survival; LIHC: Liver HCC; TIICs: Tumor infiltrating immune cells; TILs: Tumor-infiltrating lymphocytes; TME: Tumor microenvironment.

Ethics approval and consent to participate

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Consent for publication

Not applicable

Availability of data and materials

All data generated or analyzed during this study are included in this published article.

Competing interests

The authors declare that there are no conflicts of interest.

Funding

This work was supported by the National Natural Science Foundation of China (81703149), National Natural Sciences Foundation of Hunan province (NO. 2019JJ30041) and Innovation-Driven Project of Central South University (NO.2020CX044).

Authors' contributions

RC Chen and Yiya Zhang designed the study. Yiya Zhang analyzed the data. RC Chen and Yiya Zhang wrote the manuscript. All authors read and approved the final manuscript.

Acknowledgements

We would like to thank Editage (www.editage.cn) for English language editing.

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

Status:

Journal Publication

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Abstract

Figures

Background

Methods

EPDR1 expression in HCC from different databases

Survival analysis using R and Kaplan-Meier plotter

Expression level of EPDR1 in human normal tissues

Correlation between EPDR1 expression and clinical characteristics of HCC patients

Co-expression analysis using LinkedOmics database

Relationship between EPDR1 expression and immune cell infiltration

EPDR1 protein levels in HCC

Statistical Analysis

Results

EPDR1 expression is significantly elevated in HCC tissues

Prognostic Significance Of Epdr1 Expression In Hcc

Correlation between EPDR1 expression and clinical characteristics of HCC patients

Expression Of Epdr1 In Human Normal Tissues

Epdr1 Co-expressed Genes In Hcc

Epdr1 Expression And Tumor-infiltrating Immune Cells (tiics)

Discussion

Conclusions

Abbreviations

Declarations

References

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