AGPAT family members act as potential predictive biomarkers and therapeutic targets in cervical cancer

Cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) are the primary histological subtypes of cervical cancer. Although the AGPAT family of enzymes is implicated in various cancer types, the specific roles of its members in cervical cancer remain unclear. In the present study, we investigated the value of AGPAT1-5 as potential biomarkers and therapeutic targets in cervical cancer by assessing their impact on disease development and outcomes. AGPAT gene expression data and clinical information from 306 patients with CESC and three control subjects were collected from The Cancer Genome Atlas. Given the limited number of normal cervical samples in TCGA (n = 3), we utilized the GEPIA database to integrate GTEx normal cervical samples (n = 10) as controls for differential expression analysis. These data were analyzed for differential gene expression, gene-gene and protein-protein interactions, prognostic and diagnostic value, clinical correlations, functional enrichment, and various tumor-infiltrating immune cell types. Validation was performed using two independent Gene Expression Omnibus (GEO) datasets (GSE6791 and GSE63514). The study revealed that AGPAT4 mRNA expression was significantly downregulated in cervical cancer tissues compared to normal tissues in the GEPIA analysis, while AGPAT1, AGPAT2, AGPAT3, and AGPAT5 showed no significant differences. Validation in GEO datasets demonstrated that AGPAT1, AGPAT2, and AGPAT3 were consistently downregulated in tumor tissues, whereas AGPAT5 was upregulated, and AGPAT4 showed no significant change. High levels of AGPAT3 and AGPAT4 expression, in particular, were associated with a worse prognosis in CESC patients. Immune infiltration analysis restricted to CESC samples revealed that AGPAT3 expression was significantly correlated with multiple immune cell types, including positive correlations with Macrophages M1, T cells CD4 memory resting, and Monocytes. Furthermore, guided by functional enrichment analysis implicating immune-related pathways, we examined the correlation between AGPAT3 expression and key T cell regulatory molecules, including FOXP3, IL2RA, IKZF2, and CCR8, revealing significant positive associations. In vitro assays demonstrated that knocking out AGPAT3 expression significantly decreased the proliferation and migration of HeLa and C-33 A cervical cancer cell line. These results suggest that AGPAT3 could be a valuable biomarker and a promising therapeutic target in cervical cancer.