Abstract
BACKGROUND: Fibronectin type III domain containing 1 (FNDC1) exhibits emerging roles in tumorigenesis, yet its pan-cancer implications and mechanistic contributions to stomach adenocarcinoma (STAD) remain underexplored. This study systematically evaluates FNDC1's prognostic relevance, immune interactions, and functional impact in STAD. METHODS: Multi-omics analyses integrated FNDC1 expression, mutation profiles, and immune associations across 33 cancers using The Cancer Genome Atlas (TCGA) data. Immunohistochemistry assessed FNDC1, mismatch repair (MMR) protein, and human epidermal growth factor receptor 2 (HER2), and clinicopathological information was collected for statistical analysis. Finally, we conducted in vitro experiments to assess the effects of FNDC1 knockdown on STAD. RESULTS: In various cancers, the main genetic alterations of FNDC1 are mutations and deep deletions, with a mutation frequency of 10% observed primarily in malignant melanoma and endometrial carcinoma. The expression levels of FNDC1 messenger RNA (mRNA) in breast invasive carcinoma (BRCA), cholangiocarcinoma (CHOL), colon adenocarcinoma (COAD), esophageal carcinoma (ESCA), head and neck squamous cell carcinoma (HNSC), kidney renal clear cell carcinoma (KIRC), and STAD are significantly higher than those in adjacent normal tissues (P<0.05). In STAD, FNDC1 shows significant correlations with cell infiltrations such as endothelial cells, eosinophils, granulocyte-monocyte progenitors, hematopoietic stem cells, macrophage M1, macrophage M2, monocytes, myeloid dendritic cells, and activated myeloid dendritic cells. In STAD, FNDC1 exhibits significant positive correlations with immune checkpoints HAVCR2 and PDCD1LG2. Proteins with similar expression patterns to FNDC1 and ranking in the top 100 include GNAS, GNB1, MXRA5, COL3A1, COL10A1, ASPN, SFRP2, SFRP4, FXYD2, and GNG2. Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment analysis shows that in STAD, FNDC1-related genes are involved in pathways such as neuroactive ligand-receptor interaction, calcium signaling, cAMP signaling, vascular smooth muscle contraction, and pancreatic secretion. Gene Ontology (GO) functional enrichment analysis in STAD shows that FNDC1-related genes are involved in pathways related to the muscle system process, collagen-containing extracellular matrix, and receptor ligand activity. Clinical sample analysis demonstrates that FNDC1 protein is upregulated in STAD compared to adjacent normal tissues (P<0.05). Age, tumor size, tumor differentiation, Lauren classification, lymphovascular invasion, neural invasion, tumor deposit, postoperative recurrence, T stage, N stage, M stage, tumor-node-metastasis (TNM) stage, HER2 expression, and MMR protein expression are relevant risk factors for poor prognosis in STAD patients, with age, tumor size, Lauren classification, lymphovascular invasion, neural invasion, and postoperative recurrence being independent risk factors affecting prognosis. Vitro experiments demonstrate that knocking down FNDC1 can decrease the proliferation, migration and invasion abilities of STAD. CONCLUSIONS: FNDC1 is highly expressed in various tumor tissues and may serve as a potential prognostic biomarker and immunotherapy target in cancer. It plays a crucial role in proliferation, migration and invasion of STAD.