In the present study, we attempted to identify DEGs associated with OS and the classification of TNM stages in GC patients from the TCGA database. MCEMP1 was identified to be involved in immune activities. Importantly, in this study, a series of bioinformatics analyses indicated that MCEMP1 might be an indicator of the status of the TME in GC patients. Furthermore, many studies have demonstrated that the TME is significantly correlated with the initiation, progression and metastasis of GC[14, 15] and that TICs are closely related to the clinical prognosis of GC patients[16].
A large number of studies have shown that specific genes and transcription factors play an important role in the TME of GC[15, 17]. In recent years, many drugs targeting various components of the TME have been approved for clinical use, including aromatase, vascular endothelial growth factor (VEGF) and immune checkpoint inhibitors (ICIs)[18]. They have made great achievements in the treatment of GC. Inhibition of the programmed death-1 (PD-1)/programmed death ligand 1 (PD-L1) axis by ICIs, including nivolumab and pembrolizumab, has become a new therapeutic strategy for advanced GC[19]. Immunotherapies targeting PD-1 and PD-L1 have been approved for GC patients[20]. However, ICIs have shown limited survival benefits to GC patients. Most patients with GC either do not respond to ICIs, develop primary and acquired treatment resistance[21], or experience immune-related adverse events[22]. For advanced GC, tumor mutation load can also be used as a prognostic biomarker independent of PD-L1 expression[23]. Although both PD-L1 and tumor mutational burden (TMB) are widely used as biomarkers to judge the prognosis of patients, it is not suitable to use these two markers alone in many patients, so it is urgent to explore more biomarkers to meet the clinical requirements of immunotherapy. In our present research, we forested the correlation between TICs in the TME and prognosis and incorporated the clinical stage, survival rate and TNM stage of GC patients by analyzing data from the TCGA database. Among the DEGs identified, we found that the expression of MCEMP1 was closely related to the survival rate and advanced clinicopathological status (clinical stage and distant metastasis). These results indicate that MCEMP1 is a potential prognostic biomarker and a target for the treatment of GC.
MCEMP1 was identified as a high-risk gene for GC. MCEMP1 encodes a unidirectional transmembrane protein and participates in the regulation of mast cell differentiation or the immune response[12]. It is expressed mainly by monocytes and mast cells[24]. MCEMP1 is closely related to the innate immune system and plays an important role in regulating the immune response. Deletion of MCEMP1 can increase the activity of T lymphocytes, the expression of immunoglobulin and the activity of NK cells, inhibit the release of inflammatory factors and induce T lymphocyte apoptosis[25]. A clinical study of bladder cancer confirmed that MCEMP1 expression is related to the occurrence and prognosis of bladder cancer[24]. Another study established a risk score model to predict the prognosis of GC patients, which also included the MCEMP1 gene[26]. These results suggest that MCEMP1 is closely related to the prognosis of GC. In addition, the GSEA results showed that many immune-related signaling pathways, such as antigen processing and presentation, galactose metabolism, glycosaminoglycan degradation, NK cell-mediated cytotoxicity, the NOD-like receptor signaling pathway, the proteasome, and the Toll-like receptor signaling pathway, were downregulated in the MCEMP1 high expression group. These results indicate that MCEMP1 plays promotes the development of GC.
To further demonstrate the role of MCEMP1 in the prognosis of GC, we predicted the relationship between MCEMP1 and infiltrating immune cells. In this study, we found that MCEMP1 expression was related to 14 kinds of TICs and positively correlated with neutrophils (|R| = 0.68). It has been reported that tumor cells use neutrophils to enhance the metastatic ability of cancer. Neutrophils are the main kind of TIC in the TME of GC according to many reports, and neutrophil extracellular traps (Nets) are related to the biological behavior of many kinds of malignant tumors. It has been reported that tumor-educated neutrophils (TENS) can significantly promote the growth and metastasis of GC by inducing mesenchymal stem cells (MSCs) to transform into cancer-associated fibroblasts (CAFs)[27]. This result suggests that with the upregulation of MCEMP1 expression, the main response in the microenvironment of GC changes from an antitumor immune response to promoting tumor cell metabolism.