Abstract
BackgroundErythropoietin receptor (EPOR), a member of the cytokine class I receptor family, mediates erythropoietin (EPO)-induced erythroblast proliferation and differentiation, but its significance goes beyond that. The expression and prognosis of EPOR in cancer remain unclear.MethodsThis study intended to perform a pan-cancer analysis of EPOR by bioinformatics methods. Several databases such as GTEx, TCGA, CCLE, and others were used to explore the overall situation of EPOR expression, and the correlation of EPOR expression with prognosis, microRNAs (miRNAs), immune infiltration, tumor microenvironment, immune checkpoint genes, chemokines, tumor mutation burden (TMB), microsatellite instability (MSI), methyltransferases, and DNA mismatch repair (MMR) genes in 33 tumors was analyzed. In addition, we compared the promoter methylation levels of EPOR in cancer tissues with those in normal tissues and performed protein–protein interaction network, gene–disease network, and genetic alteration analyses of EPOR, and finally enrichment analysis of EPOR-interacting proteins, co-expressed genes, and differentially expressed genes.ResultsThe TCGA database showed that EPOR expression was upregulated in BLCA, CHOL, HNSC, KIRC, LIHC, STAD, and THCA and downregulated in LUAD and LUSC. After combining the GTEx database, EPOR expression was found to be downregulated in 18 cancer tissues and upregulated in 6 cancer tissues. The CCLE database showed that EPOR expression was highest in LAML cell lines and lowest in HNSC cell lines. Survival analysis showed that high EPOR expression was positively correlated with OS in LUAD and PAAD and negatively correlated with OS in COAD, KIRC, and MESO. Moreover, EPOR had a good prognostic ability for COAD, LUAD, MESO, and PAAD and also influenced progression-free survival, disease-specific survival, disease-free survival, and progression-free interval in specific tumors. Further, EPOR was found to play a non-negligible role in tumor immunity, and a correlation of EPOR with miRNAs, TMB, MSI, and MMR genes and methyltransferases was confirmed to some extent. In addition, the enrichment analysis revealed that EPOR is involved in multiple cancer-related pathways.ConclusionThe general situation of EPOR expression in cancer provided a valuable clinical reference. EPOR may be target gene of hsa-miR-575, etc. A pan-cancer analysis of panoramic schema revealed that EPOR not only may play an important role in mediating EPO-induced erythroblast proliferation and differentiation but also has potential value in tumor immunity and is expected to be a prognostic marker for specific cancers.
Highlights
Cancer is a key public health issue worldwide, and the “COVID19” epidemic that continues from 2019 to the present hinders cancer diagnosis and treatment, which may lead to higher cancer mortality rates [1]
Analysis of The Cancer Genome Atlas (TCGA) dataset showed that the expression levels of Erythropoietin receptor (EPOR) in bladder urothelial carcinoma (BLCA), CHOL, head and neck squamous cell carcinoma (HNSC), kidney renal clear cell carcinoma (KIRC), liver hepatocellular carcinoma (LIHC), stomach adenocarcinoma (STAD), and thyroid carcinoma (THCA) were higher than normal tissues but those in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) were lower than normal tissues (Figure 1A), as detailed in Supplementary Table 1
Because TCGA database has lesser normal tissue data (n = 727), we combined the normal tissue data of Genotype-Tissue Expression (GTEx) database (n = 7,568), compared with the tumor data of TCGA database (n = 9,807), and the results showed that the expression levels of EPOR were lower than normal tissues in 18 cancer tissues including breast invasive carcinoma (BRCA), cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), and colon adenocarcinoma (COAD), and higher than normal tissues in CHOL, glioblastoma multiforme (GBM), HNSC, brain lower grade glioma (LGG), skin cutaneous melanoma (SKCM), and testicular germ cell tumor (TGCT) (Figure 1B); the details are shown in Supplementary Table 2
Summary
Cancer is a key public health issue worldwide, and the “COVID19” epidemic that continues from 2019 to the present hinders cancer diagnosis and treatment, which may lead to higher cancer mortality rates [1]. Erythropoietin receptor (EPOR) is a member of the cytokine class I receptor family that mediates erythropoietin (EPO)-induced proliferation and differentiation of erythroblasts, with a structural motif consisting of two extracellular immunoglobulin-like domains, four spaced cysteine residues, and the sequence WSXWS, lacking tyrosine kinase activity and binding to JAK kinase, forming homodimer, heterodimer, or heterotrimer complexes [2]. Våtsveen et al [30] found high levels of EPOR mRNA in myeloma cells to be associated with a better survival prognosis and suggested that EPOR expression may be a novel prognostic marker in primary myeloma. The impact of EPOR expression on the prognosis of cancer patients cannot be determined, and whether it can be a valid prognostic marker for cancer remains to be explored, as well as the lack of studies on EPOR in pan-cancer. The expression and prognosis of EPOR in cancer remain unclear
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