Prognostic Implications and Therapeutic Potential of MXD Genes in Gastric Cancer.

Abstract

Background: MAX dimerization (MXD) genes play integral roles in various types of tumors. The expression patterns, prognostic value, potential mechanisms, and roles in immunotherapy of MXD genes in gastric cancer (GC) remain not fully elucidated.

Objective: We aimed to explore the role of MXDs in GC.

Methods: The Wilcoxon rank sum test and t-test were employed to evaluate the differential expression of the MXD gene family members in GC tissues compared to non-paired normal gastric tissues. cBioPortal was utilized for examining genetic alterations within the MXD gene family. R software, specifically version 3.6.3, was used to scrutinize the expression patterns of MXD genes in GC, their correlation with clinical parameters, and to generate a correlation heat map. The survival package (v3.2-10) and the Cox regression model were implemented to evaluate the prognostic significance of the MXD gene family. The pROC package (v1.17.0.1) was applied to assess the diagnostic potential of the MXD gene family. R software (v3.6.3) was also used to explore potential regulatory networks involving members of the MXD gene family and related genes. The GSVA package (v1.34.0) was leveraged to investigate the link between the expression of the MXD gene family and immune cell infiltration. Visualization was facilitated by the ggplot2 (v3.3.3), survminer (v0.4.9), and clusterProfiler (v3.14.3) packages. Gene Set Cancer Analysis (GSCA) was employed to determine the sensitivity of the MXD gene family's expression to drugs from the GDSC database. The expression levels of MXD genes were validated across various cell lines using quantitative real-time PCR (qRT-PCR).

Results: MXD1 was significantly upregulated in GC, while MXD3 and MXD4 were significantly downregulated. Significant correlations were identified between the expression levels of MXD3 and the T stage (p = 0.041) and age (p = 0.001) of GC patients. Additionally, a notable association was observed between MXD4 expression and the histologic grade (p = 0.006) in GC patients. Low MXD3 expression was associated with a poor prognosis in GC. Low MXD3 expression was an independent prognostic factor for poor outcomes in GC patients. MXD3 demonstrated some accuracy in predicting tumor and normal tissue outcomes (AUC = 0.884). MXDs mediate gastric carcinogenesis and progression by regulating immune cells and pathways, including endocytosis, cell cycle, and apoptosis. The expression of the MXD gene family was associated with immune cell infiltration and drug sensitivity. MXD3 and MXD4 expression levels were significantly downregulated in GC cell lines, while MXD1 expression was significantly upregulated.

Conclusion: The MXD gene family may serve as novel biomarkers of poor prognosis and as potential immunotherapeutic targets for GC.