Role of lipid-associated fibroblasts and their signature genes FABP4, CD36 and ABCA8 in gastric cancer progression.

Cancer-associated fibroblasts (CAFs) serve key roles in gastric cancer progression, however, the role of specific CAF subsets, particularly lipid-rich CAFs (lipo-CAFs), remains unclear. Therefore, the present study aimed to investigate whether lipo-CAFs are associated with gastric cancer progression. A total of 28 lipo-CAF-associated genes was used to classify patients with gastric cancer in The Cancer Genome Atlas Stomach Adenocarcinoma dataset. Differential expression analysis was subsequently performed to identify biological processes and pathways associated with the lipo-CAF phenotype. Validation analyses were conducted using the GSE84437 dataset and expression and survival analyses of the signature genes were performed using data from the Human Protein Atlas database and Tumor-Immune System Interaction Database. Finally, NIH-3T3 cells were transduced with lentiviral vectors to knock down the candidate genes and were co-cultured with mouse gastric cancer MFC cells to evaluate the fibroblast-mediated effects of these genes on gastric cancer cell behavior in vitro. The majority of lipo-CAF-associated genes were highly expressed in gastric cancer. Patients were stratified into high- and low-risk groups based on gene expression patterns and these groups exhibited differences in prognosis, energy metabolism-associated pathways and immune infiltration. A prognostic model was constructed using these genes and externally validated. Findings indicated that fatty acid-binding protein 4 (FABP4), CD36 and ATP-binding cassette subfamily A member 8 (ABCA8) may exert tumor-promoting roles in gastric cancer. In fibroblast-based co-culture experiments, knockdown of these three genes in NIH-3T3 cells inhibited the proliferation of co-cultured gastric cancer cells. Lipo-CAF-associated genes were found to be coupled with gastric cancer progression and with distinct immune and stromal features of the tumor microenvironment. Among these genes, FABP4, CD36 and ABCA8 demonstrated tumor-promoting effects in fibroblast-based co-culture experiments, highlighting their potential relevance for prognostic stratification and future therapeutic investigation in gastric cancer.