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. 2023 Dec 4;15(23):13840-13853.
doi: 10.18632/aging.205265. Epub 2023 Dec 4.

Prognostic significance and immune characteristics of APOE in gastric cancer

Xiulan Peng  1 , Zhen Cai  2 , Duansi Chen  3 , Fei Ye  4 , Lifeng Hong  5
Affiliations

Prognostic significance and immune characteristics of APOE in gastric cancer

Xiulan Peng et al. Aging (Albany NY). .

Abstract

Gastric cancer (GC) is a prevalent malignancy affecting the digestive system, and it is the second leading cause of cancer-related mortality worldwide. Immunotherapy presents a potential lifeline for patients with advanced gastric cancer, emphasizing the need to find new molecular targets that improve the response to immunotherapy. In our research, we conducted a comprehensive bioinformatic analysis to investigate the expression profiles of apolipoprotein E (APOE) transcription. Subsequently, we examined the correlation between APOE transcription and the prognosis of GC patients. Additionally, we evaluated the connection between APOE transcription and immune cells abundance. To validate our findings, we conducted immunohistochemistry experiment to ascertain the level of APOE protein in GC patients and assessed its prognostic role in a cohort of 97 GC individuals. Our results revealed that APOE is increased in GC tissues, and APOE displays diagnostic potential in distinguishing GC from normal tissues. Notably, upregulated APOE expression in GC patients is associated with unfavorable overall survival. Differential APOE expression was further observed across different immune subtypes of GC, indicating its involvement in immune cell activation and infiltration. Moreover, we detected increased APOE protein expression in GC tissues, which exhibited a strong correlation with poor survival outcomes. In light of these findings, APOE has become a crucial prognostic molecular with immunomodulatory function in GC. These results underscore the significance of APOE across various cancer types, including GC, and provide valuable insights into its role from both a bioinformatics and clinical perspective.

Keywords: APOE; biomarker; gastric cancer; immunotherapy; prognostic; survival.

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Conflict of interest statement

CONFLICTS OF INTEREST: The authors declare no conflicts of interest related to this study.

Figures

Figure 1
Figure 1
The transcription levels of APOE in human cancers. APOE mRNA expression in pan-cancer (A, B) and gastric cancer (C, D).
Figure 2
Figure 2
Analysis of APOE mRNA expression in normal and gastric cancer (GC) tissues from 2 public databases. APOE mRNA levels are significantly lower (P < 0.0001) in normal gastric mucosal than that in gastric cancer tissue samples in the (A) Chen (Normal = 29; Tumor = 83), (B) Cui (Normal = 80; Tumor = 80), (C) Derric (Normal = 31; Tumor = 38), and (D) Wang (Normal = 15; Tumor = 12) Gastric datasets from the Oncomine database; and (E) GSE29272 (Normal = 134; Tumor = 134) and (F) GSE54129 (Normal = 21; Tumor = 111) datasets from the GEO databases.
Figure 3
Figure 3
Receiver operating characteristic (ROC) curve analysis to determine diagnostic relevance of APOE mRNA levels in GC patients. ROC curve analysis of APOE mRNA levels in the (A) Chen (AUC = 0.9477), (B) Cui (AUC = 0.7466), (C) Derric (AUC = 0.8141) and (D) Wang (AUC = 0.9333) Gastric datasets from the Oncomine database; (E) GSE29272 (AUC = 0.9270) and (F) GSE54129 (AUC = 0.9661) datasets from the GEO databases; and (G) STAD dataset (AUC = 0.7897) from the TCGA database; The receiver operating characteristic (ROC) curve analysis to determine diagnostic relevance of APOE mRNA levels in GC patients.
Figure 4
Figure 4
Survival analysis of APOE mRNA in gastric cancer. Low levels of APOE are correlated with longer overall time (A) and disease-free survival time (B) based on TCGA dataset. Low levels of APOE are related to longer overall time (C) and disease-free survival time (D) based on GEO database.
Figure 5
Figure 5
APOE is associated with immune infiltration and immune activation in GC. (A) Heatmap displayed APOE mRNA level associated relative abundance of 28 immune cells in GC. (B) The relationship between the mRNA level of APOE and 28 immune cells in GC. (C) Heatmap showing relative association between APOE and 25 immunity-related gene sets. (D) The relationship between 25 immunity-related gene sets and APOE in GC. (E) Heatmap showing relative association between APOE and steps of the cancer immunity cycle. (F) The relationship between steps of the cancer immunity cycle and APOE in GC.
Figure 6
Figure 6
APOE is associated with immune cell infiltration in GC. (A) The comparison of TILCs in APOE low and high subgroups. (B) The association between APOE and immune cells.
Figure 7
Figure 7
Relationship between immune cell markers and APOE transcription in GC. (A) Levels of ITGAX (P < 0.0001), NRP1 (P < 0.0001), ITGAM (P < 0.0001), CCR7 (P < 0.0001), CD8A (P < 0.0001) and CD8B (P < 0.0001) were significantly higher in APOE higher group. (B) Levels of ITGAX (r = 0.6098, P < 0.0001), NRP1 (r = 0.3538, P < 0.0001), ITGAM (r = 0.5375, P < 0.0001), CCR7 (r = 0.3775, P < 0.0001), CD8A (r = 0.5568, P < 0.0001) and CD8B (r = 0.457, P < 0.0001) are positively correlated with APOE expression in GC.
Figure 8
Figure 8
APOE is upregulated in GC clinical samples and correlated with shorter survival in GC patients. (A) Immunohistochemical staining of normal and gastric cancer tissues with anti-APOE antibody. (B) Quantitative analysis of APOE staining shows significantly H-score in gastric tumor samples compared with adjacent normal tissues (83 normal tissues and 97 tumor samples). (C) GC patients with APOE over-expression displayed less favorable overall survival than those with low APOE expression.
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