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. 2022 Jul 28:12:968547.
doi: 10.3389/fonc.2022.968547. eCollection 2022.

Comprehensive analysis of the glutathione S-transferase Mu (GSTM) gene family in ovarian cancer identifies prognostic and expression significance

Juan Zhang  1 , Yan Li  1 , Juan Zou  2 , Chun-Tian Lai  1 , Tian Zeng  2 , Juan Peng  1 , Wen-da Zou  1 , Bei Cao  1 , Dan Liu  1 , Li-Yu Zhu  1 , Hui Li  1 , Yu-Kun Li  1   2
Affiliations

Comprehensive analysis of the glutathione S-transferase Mu (GSTM) gene family in ovarian cancer identifies prognostic and expression significance

Juan Zhang et al. Front Oncol. .

Abstract

Background: Ovarian cancer (OC) is one of the most common types of gynecologic tumor over the world. The Glutathione S-transferase Mu (GSTM) has five members, including GSTM1-5. These GSTMs is involved in cell metabolism and detoxification, but their role in OC remains unknown.

Methods: Data from multiple public databases associated with OC and GSTMs were collected. Expression, prognosis, function enrichment, immune infiltration, stemness index, and drug sensitivity analysis was utilized to identify the roles of GSTMs in OC progression. RT-qPCR analysis confirmed the effect of AICAR, AT-7519, PHA-793887 and PI-103 on the mRNA levels of GSTM3/4.

Results: GSTM1-5 were decreased in OC samples compared to normal ovary samples. GSTM1/5 were positively correlated with OC prognosis, but GSTM3 was negatively correlated with OC prognosis. Function enrichment analysis indicated GSTMs were involved in glutathione metabolism, drug metabolism, and drug resistance. Immune infiltration analysis indicated GSTM2/3/4 promoted immune escape in OC. GSTM5 was significantly correlated with OC stemness index. GSTM3/4 were remarkedly associated with OC chemoresistance, especially in AICAR, AT-7519, PHA-793887 and PI-103.

Conclusion: GSTM3 was negatively correlated with OC prognosis, and associated with OC chemoresistance and immune escape. This gene may serve as potential prognostic biomarkers and therapeutic target for OC patients.

Keywords: GSTM family; bioinformatic analysis; drug sensitivity; ovarian cancer; prognostic marker.

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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
Work flow of the study.
Figure 2
Figure 2
The GSTMs mRNA level in multiple cancer types. The red color cell indicates that GSTMs is enhanced in tumor samples compared to correspond normal samples, whereas blue color cell presents GSTMs is reduced in tumor samples compared to correspond normal samples.
Figure 3
Figure 3
The GSTMs expression in OC. (A) The mRNA level of GSTMs in OC samples and normal ovary samples based on TCGA and GETx database. (B) The mRNA level of GSTMs in different FIGO stage OC samples. (C) The protein level of GSTMs in OC samples and normal ovary samples based on CPTAC database. (D) The GSTM protein expression in OC samples and normal ovary samples based on HPA database. ***p < 0.001 ns, means No statistical significance.
Figure 4
Figure 4
The potential molecular function of GSTMs in OC. (A) The PPI network associated with GSTM1-5 based on GeneMANIA database. (B) Correlation heat map of PPI network based on TCGA database. (C) The GO enrichment of PPI network genes. (D) The KEGG enrichment of PPI network genes.
Figure 5
Figure 5
The prognosis significance of GSTM1-5 in OC. (A) The OS analysis of GSTM1/2/3/4/5 in OC dataset based on the Kaplan–Meier Plotter database. (B) The PFS analysis of GSTM1/2/3/4/5 in OC dataset based on the Kaplan–Meier Plotter database. (C) The PPS analysis of GSTM1/2/3/4/5 in OC dataset based on the Kaplan–Meier Plotter database.
Figure 6
Figure 6
The correlation of immune infiltration and GSTMs alteration in OC. (A) The DNA alteration rate of GSTM1, GSTM2, GSTM3, GSTM4 and GSTM5 was more than 2% in OC. (B) The overall survival rate based on OC patients with and without these genes alteration based on the cBioPortal dabtase. (C) The effect of GSTM1-5 CNV on the immune cell distribution based on the TIMER database. *p < 0.05.
Figure 7
Figure 7
The correlation of immune infiltration and GSTMs expression in OC. (A) The expression profiles of GSTM1, GSTM2, GSTM3, GSTM4 and GSTM5 in multiple immune cell types based on TCGA database. (B) The effect of GSTMs on the components of cellular immunity. (C) The correlation analysis between GSTMs expression and immune checkpoints gene expression in TCGA database via the Wilcox test. (G1 is the group of the OC patients with high expression of GSTMs. G2 is the group of the OC patients with low expression of GSTMs.) *p < 0.05; **p < 0.01; ***p < 0.001.
Figure 8
Figure 8
The association of stemness features and GSTMs in OC. (A) The stemness score heatmap of GSTM expression and clinical information. The top figure is the stemness score from low to high, and the bottom figure is the distribution of GSTMs expression and clinical information features after sorting. (B) Correlation analysis of stemness score and GSTMs gene expression. (C) The distribution of stemness scores in high expression of GSTMs OC groups, low expression of GSTMs OC groups, and normal ovary groups. (G1 is the group of the OC patients with high expression of GSTMs. G2 is the group of the OC patients with low expression of GSTMs.) ****p < 0.0001.
Figure 9
Figure 9
The Drug Sensitivity of GSTMs in OC. (A) The effect of multiple drugs on mRNA expression of GSTMs. (B) The mRNA expression of GSTM3/4 in multiple OC cell lines based on CCLE database. (C) The effects of AICAR, AT-7519, PHA-793887 and PI-103 on GSTM3/4 expression level in Hey-A8 cell lines. **p < 0.01; ***p < 0.001.
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