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. 2022 Jan 27:11:781344.
doi: 10.3389/fonc.2021.781344. eCollection 2021.

GBE1 Is an Independent Prognostic Marker and Associated With CD163+ Tumor-Associated Macrophage Infiltration in Lung Adenocarcinoma

Yicheng Liang  1 , Yangyang Lei  2   3 , Mei Liang  1 , Minjun Du  1 , Zixu Liu  1 , Xingkai Li  1 , Xiangzhi Meng  1 , Boxuan Zhou  1 , Yushun Gao  1
Affiliations

GBE1 Is an Independent Prognostic Marker and Associated With CD163+ Tumor-Associated Macrophage Infiltration in Lung Adenocarcinoma

Yicheng Liang et al. Front Oncol. .

Abstract

Glycogen branching enzyme (GBE1) is a critical gene that participates in regulating glycogen metabolism. However, the correlations between GBE1 expression and the prognosis and tumor-associated macrophages in lung adenocarcinoma (LUAD) also remain unclear. Herein, we firstly analyzed the expression level of GBE1 in LUAD tissues and adjacent lung tissues via The Cancer Genome Atlas (TCGA) database. The effect of GBE1 on prognosis was estimated by utilizing TCGA database and the PrognoScan database. The relationships between the clinical characteristics and GBE1 expression were evaluated via TCGA database. We then investigated the relationships between GBE1 and infiltration of immune cells in LUAD by utilizing the CIBERSORT algorithm and Tumor Immune Estimation Resource (TIMER) database. In addition, we used a tissue microarray (TMA) containing 92 LUAD tissues and 88 adjacent lung tissues with immunohistochemistry staining to verify the association between GBE1 expression and clinical characteristics, as well as the immune cell infiltrations. We found the expression level of GBE1 was significantly higher in LUAD tissues. High expression of GBE1 was associated with poorer overall survival (OS) in LUAD. In addition, high expression of GBE1 was correlated with advanced T classification, N classification, M classification, TNM stage, and lower grade. Moreover, GBE1 was positively correlated with infiltrating levels of CD163+ tumor-associated macrophages in LUAD. In conclusion, the expression of GBE1 is associated with the prognosis and CD163+ tumor-associated macrophage infiltration in LUAD, suggesting that it has potential to be prognostic and immunological biomarkers in LUAD.

Keywords: CD163+ tumor-associated macrophage infiltration; GBE1; LUAD; clinical characteristics; immunohistochemistry (IHC); prognosis; tissue microarray (TMA).

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
The immunohistochemistry staining of GBE1 in LUAD tissue samples and corresponding noncancer tissue samples. GBE1 protein levels were upregulated in most LUAD tissues compared with the corresponding noncancer tissues in the TMA‐IHC results. The representative TMA‐IHC images of different staining intensities of GBE1 were as follows (A–H). (A) Strong intensity of GBE1 in LUAD tissue. (B) Moderate intensity of GBE1 in LUAD tissue. (C) Weak intensity of GBE1 in LUAD tissue. (D) Negative intensity of GBE1 in LUAD tissue. (E) Strong intensity of GBE1 in corresponding noncancer tissue. (F) Moderate intensity of GBE1 in tissue. (G) Weak intensity of GBE1 in corresponding noncancer tissue. (H) Negative intensity of GBE1 in corresponding noncancer tissue.
Figure 2
Figure 2
The relationship between GBE1 expression and prognosis in LUAD analyzed by PrognoScan database (A–D). (A) In the HARVARD-LC cohort, high expression of GBE1 predicted a poor OS in LUAD (HR = 1.80, p = 0.035). (B) In the jacob-00182-UM cohort, high expression of GBE1 predicted a poor OS in LUAD (HR = 1.54, p = 0.046). (C) In the GSE31210 cohort, high expression of GBE1 predicted a poor OS in LUAD (HR = 3.44, p = 0.005). (D) In the GSE31210 cohort, high expression of GBE1 predicted a poor RFS in LUAD (HR = 2.56, p = 0.006). OS, overall survival; RFS, recurrence-free survival.
Figure 3
Figure 3
The correlations between GBE1 expression and prognosis in LUAD and the multivariable Cox regression analysis by utilizing the TCGA cohort and TMA cohort (A–D). (A) The Kaplan-Meier survival curve comparing the high and low expression of GBE1 in TCGA cohort. (B) The Kaplan-Meier survival curve comparing the high and low expression of GBE1 in the TMA cohort. (C) The multivariable Cox regression analysis of different expression of GBE1 in TCGA cohort. (D) The multivariable Cox regression analysis of different expression of GBE1 in the TMA cohort.
Figure 4
Figure 4
TThe correlation analysis between GBE1 expression and different clinical characteristics in LUAD via TCGA cohort. (A) The correlation analysis between GBE1 expression and T stage. (B) The correlation analysis between GBE1 expression and N stage. (C) The correlation analysis between GBE1 expression and M stage. (D) The correlation analysis between GBE1 expression and TNM stage. (E) The correlation analysis between GBE1 expression and gender. (F) The correlation analysis between GBE1 expression and age.
Figure 5
Figure 5
(A) The relationship between GBE1 expression and immune-infiltrating cells by utilizing CIBERSORT algorithm: GBE1 expression was positively correlated with M2 macrophage infiltration of M2 macrophages, CD4+ memory-activated T cells, and resting dendritic cells. (B) The relationship between GBE1 expression and immune-infiltrating cells by utilizing the TIMER database: GBE1 expression was positively correlated with macrophage infiltration, CD8+ T-cell infiltration, and dendritic cell infiltration.
Figure 6
Figure 6
The correlation analysis between GBE1 and gene markers of tumor-associated immune cells in the TIMER database. (A–C) Gene markers of M1 macrophage; (D–F) gene markers of M2 macrophage; (G) gene marker of CD4+ T cell; (H–I) gene markers of CD8+ T cell; (J–K) gene markers of dendritic cell.
Figure 7
Figure 7
The relationship between GBE1 expression and M2 macrophage infiltrations in LUAD. (A, B) The correlations between GBE1 expression and CD163+ tumor-associated macrophage infiltration in TCGA and TMA cohorts (r 2 = 0.04, p < 0.01; r 2 = 0.09, p < 0.01). (C) The correlation between GBE1 expression and CD163 expression in TCGA cohort (p < 0.01). (D) The correlation between GBE1 expression and CD163 expression in the TMA cohort (p = 0.02).
Figure 8
Figure 8
The immunohistochemistry staining of GBE1 and CD163 in the same LUAD tissue samples. Strong intensity of GBE1 in LUAD tissue (A) low magnification and (B) high magnification. Strong intensity of CD163 in LUAD tissue (C) low magnification and (D) high magnification. Weak intensity of GBE1 in LUAD tissue (E) low magnification and (F) high magnification. Weak intensity of CD163 in LUAD tissue (G) low magnification and (H) high magnification.
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