Comprehensive Analysis of the Expression and Prognosis for ITGBs: Identification of ITGB5 as a Biomarker of Poor Prognosis and Correlated with Immune Infiltrates in Gastric Cancer

Abstract

Background: Integrin β superfamily members (ITGBs) are documented to play important roles in various biological processes, and accumulating evidence suggests that ITGBs are associated with carcinogenic effects in several malignancies. Gastric cancer (GC) is a complicated and highly heterogeneous disease; however, the expression and prognostic values of eight ITGBs and potential mechanism in GC remain largely unclear. Methods: The expression and prognostic significance of ITGBs in GC were systematically analyzed through Gene Expression Profiling Interactive Analysis, Human Protein Atlas, Kaplan-Meier Plotter, and cBioPortal databases. Then, the mRNA transcription data and corresponding clinical data of GC were downloaded from the Gene Expression Omnibus database as a testing cohort, and differentially expressed and prognostic genes were identified. The correlation between ITGB5 expression and overall survival and various clinical parameters were found by using univariate/multivariable Cox regression and Kaplan-Meier survival analysis. Additionally, differential analysis of gene expression profiles in low- and high-ITGB5 expression groups and pathway enrichment analysis was performed. Finally, the correlation of ITGB5 expression with immune infiltrates in GC was clarified. Results: Compared with adjacent normal tissue, the results reveal that the mRNA levels of ITGB1-2 and ITGB4-8 are significantly higher in GC, and immunohistochemistry results show the consistency between RNA and protein expression levels. Cox regression and Kaplan-Meier survival analysis indicate that high ITGB5 expression contributes to a poor prognosis and could be an independent prognostic factor in GC patients. Besides this, gene functional enrichment analysis indicates that ITGB5 expression is significantly associated with extracellular matrix organization, cell-substrate adhesion, and ossification. The KEGG pathway analysis of ITGB5 shows a close association between ITGB5 and focal adhesion, ECM-receptor interaction, phagosome, and PI3K-Akt signaling pathway. Last, the infiltrating level of CD4⁺ T cells, macrophages, and dendritic cells are positively related to the expression of ITGB5, especially macrophages, and lower levels of macrophages predict a better prognosis in GC in our study. Conclusion: Our findings investigate that ITGB5 may function as a valid biomarker of prognosis, and high expression of ITGB5 predicts poor prognosis for patients with GC. Besides this, it might be a potential target of precision therapy against GC.

Keywords: ITGB5; ITGBs; gastric cancer; immune infiltrate; prognosis.

FIGURE 1

The expression of ITGBs in GC [(A) scatter diagram; (B) box plot] (GEPIA).

FIGURE 2

Correlation between mRNA expression of ITGBs and tumor stages in patients with GC (GEPIA).

FIGURE 3

Survival analysis and prognostic values of ITGBs in patients with GC (GEPIA).

FIGURE 4

IHC analysis of ITGBs in GC (the HPA database).

FIGURE 5

The heatmap (A) and volcano plot (B) of mRNA expression changes based on ITGB5 in GC samples from the GEO database.

FIGURE 6

Basic characteristic of ITGB5. (A) Expression of ITGB5 in different types of cancer. (B) Subcellular location and immunofluorescence images of ITGB5 expression in GC cells from HPA. (C–E) Detailed mutation information of ITGB5 in GC.

FIGURE 7

The results in the GEO test cohort. (A) The K-M curves for the two groups (high vs. low expression). (B,C) The forest maps of univariate and multivariate Cox regression analysis in the GEO data set. (D,G) The expression of ITGB5 assigned by clinical factors, comprising age, gender, T stage, and N stage.

FIGURE 8

The prognostic value of ITGB5 in GC (Kaplan–Meier Plotter).

FIGURE 9

The gene set enrichment analysis. (A) Bar plot of GO enrichment. (B) Bar plot of KEGG enriched terms.

FIGURE 10

Significant KEGG pathway determined by circos plot.

FIGURE 11

PI3K-Akt signaling pathway (A) and focal adhesion procedure (B) regulated by ITGBs.

FIGURE 12

Immune correlation analysis of ITGB5 based on immune infiltration in GC. (A) Correlation of ITGB5 expression with immune cell infiltration. (B) Prognostic value of immune cell infiltration in GC.

FIGURE 13

Correlation between ITGB5 expression and gene markers of macrophage in GC. (A) ITGB5 and M1 macrophages. (B) ITGB5 and M2 macrophages. (C) ITGB5 and tumor-associated macrophages.

FIGURE 14

Phagosome pathway regulated by ITGB5.