A comprehensive prognostic and immunological analysis of ephrin family genes in hepatocellular carcinoma

Abstract

Background: Ephrins, a series of Eph-associated receptor tyrosine kinase ligands, play an important role in the tumorigenesis and progression of various cancers. However, their contributions to hepatocellular carcinoma (HCC) remain unclear. Thus, we aimed to explore their prognostic value and immune implications in HCC.Methods: Multiple public databases, such as TCGA, GTEx, and UCSC XENA, were used to analyze the expression of ephrin genes across cancers. Kaplan-Meier analysis and Cox regression were used to explore the prognostic role of ephrin genes in HCC. A logistic regression model was utilized to evaluate the association between ephrin gene expression and clinical characteristics. Gene set enrichment analysis (GSEA) was conducted to elucidate their potential biological mechanisms. Various immune algorithms were utilized to investigate the correlation between ephrin genes and tumor immunity. We also analyzed their association with drug sensitivity, and gene mutations. Finally, RT–qPCR was performed to validate the expression of ephrin family genes in HCC cells and clinical tissues.Results: The expression of EFNA1, EFNA2, EFNA3, EFNA4, EFNB1, and EFNB2 was upregulated in most cancer types, while EFNA5 and EFNB3 was downregulated in most cancers. In HCC, the expression levels of EFNA1, EFNA3, EFNA4, EFNB1, and EFNB2 were significantly higher in tumor tissues than in normal tissues. High expression of EFNA3, EFNA4, and EFNB1 was associated with tumor progression and worse prognosis in HCC patients. The expression of EFNA3 and EFNA4 was negatively associated with the stromal/ESTIMATE scores, while EFNB1 was positively correlated with the immune/stromal/ESTIMATE scores. Moreover, these ephrin genes were closely relevant to the infiltration of immune cells, such as B cells, CD4+ T cells, CD8+ T cells, neutrophil cells, macrophage cells, and dendritic cells. EFNB1 expression was positively associated with most immune-related genes, while EFNA3/EFNA4 was positively related to TMB and MSI. In addition, EFNA3, EFNA4, and EFNB1 were related to drug sensitivity and affected the mutation frequency of some genes in HCC.Conclusion: EFNA3, EFNA4, and EFNB1 are independent prognostic factors for HCC patients and are closely correlated with tumor immunity, which may provide a new direction for exploring novel therapeutic targets and biomarkers for immunotherapy.

Diversity of Intercellular Communication Modes: A Cancer Biology Perspective

“…Similarly, evidence has accumulated regarding the discriminatory role of Ephs/ephrins in metastasis [ 449 , 450 , 451 ]. The large number and combinatory nature of expression and interactions of Ephs/ephrins in various tissues and different tumor subtypes [ 438 , 452 , 453 , 454 , 455 ] is particularly favorable to a potential role in establishing and/or maintaining tumor heterogeneity. However, this can only be speculative at the moment, despite the publication of a finding of subtype-dependent frequency and exclusivity of mutations in Ephrins in gastric cancers [ 456 ].…”

Unraveling the Significance of EPH/Ephrin Signaling in Liver Cancer: Insights into Tumor Progression and Therapeutic Implications

“…By modulating cell–cell interactions and signaling pathways, they regulate tumor growth, invasion, and metastasis. Targeting EPH/ephrin signaling shows promise in enhancing immune responses against HCC, offering new avenues for therapeutic intervention and improved patient outcomes [ 95 ]. Huang et al [ 95 ] conducted a clinical study aimed to investigate the prognostic and immunological significance of ephrin family genes in HCC.…”

“…Targeting EPH/ephrin signaling shows promise in enhancing immune responses against HCC, offering new avenues for therapeutic intervention and improved patient outcomes [ 95 ]. Huang et al [ 95 ] conducted a clinical study aimed to investigate the prognostic and immunological significance of ephrin family genes in HCC. They investigated the association of ephrin family genes with prognosis and clinical characteristics HCC patients.…”

“…EFNB1 was correlated with larger tumor size and advanced TNM stage. Age, sex, N stages, M stages and Child–Pugh grades showed no significant association with EFNA3 , EFNA4 , and EFNB1 expression [ 95 ]. Furthermore, they investigated the relationship between ephrin gene expression and immune checkpoint inhibitors (ICIs) in HCC [ 95 ].…”

“…Age, sex, N stages, M stages and Child–Pugh grades showed no significant association with EFNA3 , EFNA4 , and EFNB1 expression [ 95 ]. Furthermore, they investigated the relationship between ephrin gene expression and immune checkpoint inhibitors (ICIs) in HCC [ 95 ]. They examined the correlation between EFNA3 , EFNA4 , and EFNB1 expression and immune-related biomarkers, including immune checkpoint-related genes, tumor mutational burden (TMB), and microsatellite instability (MSI).…”