High expression of the ferroptosis-associated MGST1 gene in relation to poor outcome and maladjusted immune cell infiltration in uterine corpus endometrial carcinoma

Abstract

Background: Uterine corpus endometrial carcinoma (UCEC) tightly correlates with dysregulated iron homeostasis. MGST1 (microsomal glutathione S-transferase 1) involves in the regulation of oxidative stress and plays a key role in inhibiting iron-mediated cell death in cancer cells. Hence, we aimed to illuminate the characteristics of MGST1 expression and prognosis in UCEC using bioinformatics prediction to provide novel perspectives for theoretical supplementation and ferroptosis-based immunotherapy.

Methods: We retrieved MGST1 expression data via several public data portals. The relationships between MGST1 expression and clinicopathologic characteristics as well as survival time were evaluated via multivariate methods and Kaplan-Meier survival curves. The MGST1-interacting protein-protein interaction was also established by the STRING website. The TIMER and GEPIA databases were used to illustrate the association between MGST1 expression and infiltrated immune cells. We used the MethSurv website and the UALCAN website to determine the relationship between MGST1 expression and DNA methylation.

Results: MGST1 overexpression in UCEC compared with normal tissues correlates with different histological types, a lack of hormone therapy and poor survival time. MGST1 interacts with several ferroptosis-related proteins. Overexpression of MGST1 was accompanied by lower levels of NK cell and CD8⁺ T cell infiltration, higher myeloid-derived suppressor cell infiltration and different immunocytes with corresponding markers. Hypermethylation and low promoter methylation cooperate to regulate MGST1 expression.

Conclusion: Elevated MGST1 expression is related to tumour development and poor prognosis, as well as dysregulated infiltration of immune cells in UCEC, which can be a potential prognostic indicator and ferroptosis-based immunotherapy target.

Keywords: MGST1; ferroptosis; immune cell infiltration; prognosis; uterine corpus endometrial carcinoma.

FIGURE 1

Microsomal glutathione S‐transferase 1 (MGST1) expression status in pan‐cancers and uterine corpus endometrial carcinoma (UCEC). (A) Human MGST1 expression levels in pan‐cancer tissues and corresponding normal tissues. (B) MGST1 expression was markedly increased in UCEC tissues compared with normal tissues (p = 6.6e–05). (C–F) There were statistically significant differences between MGST1 mRNA levels and hormone therapy (p = 0.03), histological type (p < 0.05), overall survival (p = 0.03) and DSS events (p = 1.5e–03). (G–N) There were no differences with age, BMI, histologic grade, clinical stage, tumour invasion, radiation therapy, PFI event and surgical approach

FIGURE 2

Analysis of microsomal glutathione S‐transferase 1 (MGST1) gene expression in Gene Expression Omnibus datasets and the Human Protein Atlas. (A) Validation of higher MGST1 mRNA expression in uterine corpus endometrial carcinoma (UCEC) tissue than in normal tissue in the GSE17025 dataset (p = 0.03). (B, C) The level of MGST1 protein in UCEC tissue (B) was higher than that in normal tissue (C) in the Human Protein Atlas (Antibody HPA044840, 10×)

FIGURE 3

Kaplan–Meier analysis of microsomal glutathione S‐transferase 1 (MGST1) expression levels and uterine corpus endometrial carcinoma (UCEC) patients. Kaplan–Meier survival curves of UCEC patients with high and low MGST1 expression levels. The majority of patients with higher MGST1 had poor overall survival (p = 0.003), DSS (p = 0.003) and PFS (p = 0.02) outcomes

FIGURE 4

Univariate and multivariate regression analyses between microsomal glutathione S‐transferase 1 (MGST1) and other clinicopathologic parameters and overall survival (OS) in uterine corpus endometrial carcinoma patients. MGST1 expression was an independent factor associated with OS in terms of clinical stage (TNM), primary therapy outcome, histological type, poor histologic grade and radiation therapy

FIGURE 5

Protein–protein interaction network of microsomal glutathione S‐transferase 1 (MGST1) in uterine corpus endometrial carcinoma (UCEC) tissue. We established our PPI network of MGST1's interrelated protein in UCEC. The top 10 proteins and associated gene names were CMTM6, LAMP1, LAMP2, LPCAT1, MGST2, MGST3, STOM, TMEM30A, VAMP8 and VNN1

FIGURE 6

Relationship of microsomal glutathione S‐transferase 1 (MGST1) expression with infiltrating immune cells in uterine corpus endometrial carcinoma (UCEC). MGST1 expression was negatively correlated with NK cells (p = 7.01e–04) and CD8⁺ T cells (p = 2.39e–02) and positively correlated with MDSCs (p = 2.30e–04)