The ferroptosis-related gene GGTLC2 is identified as a novel biomarker for gastric cancer within the GGT family, with associations to immune infiltration and liver metastasis

Abstract

Gastric cancer (GC) has a high incidence and poor prognosis, often metastasizing to the liver. Gamma-glutamyl transferase (GGT) is a key indicator of liver damage, and its family members are associated with various cancers. However, their expression and prognostic significance in GC remain unclear. This study utilized R to analyze the expression and prognosis of GGT family members using RNA-seq and clinical data from the TCGA database, applying Lasso regression for key gene identification. We identified GGTLC2 as a significant gene related to GC prognosis. We examined the clinical relevance, methylation levels, and copy number variations of GGTLC2 using the MEXPRESS database and performed GSEA analysis to identify enriched pathways. Additionally, we explored the relationship between GGTLC2 and immune cell infiltration, as well as immune-related genes, and established GGTLC2 knockdown and overexpression cell lines. The results indicate that GGTLC2 is highly expressed in GC and is associated with DNA methylation, copy number variation, and liver metastasis. Functionally, GGTLC2 is primarily enriched in oxidative stress and immune-related pathways, affecting immune infiltration and the expression of inflammatory factors in the tumor microenvironment. In vivo and in vitro studies demonstrate that knocking down GGTLC2 inhibits GC proliferation, invasion, and migration while promoting apoptosis and ferroptosis. Conversely, overexpressing GGTLC2 significantly increases the number of metastatic tumors in the liver. Overall, GGTLC2 may influence the occurrence, development, and liver metastasis of GC by inhibiting ferroptosis, making it a promising novel biomarker for the diagnosis and treatment of GC and its metastasis.