Pan-cancer prognostic value of TGFBR1: Bioinformatics and experimental validation with a focus on gastric cancer

Abstract

TGF-β receptor 1 (TGFBR1) is a key component of TGF-β signaling and has been implicated in tumor progression. However, its expression patterns, prognostic relevance and associated molecular contexts vary among malignancies and remain incompletely characterized within a consistent pan-cancer framework. In the present study, TGFBR1 expression, clinicopathological associations, survival outcomes, immune and stromal infiltration, genomic features, co-expression profiles and transcriptional programs were systematically evaluated using The Cancer Genome Atlas (TCGA), TCGA-Genotype-Tissue Expression and complementary public datasets. Multivariable Cox regression was performed with adjustment for age, sex and pathological stage and the independent GSE15459 gastric cancer (GC) cohort was used for external prognostic validation and gene-set enrichment analysis. TGFBR1 exhibited cancer type-dependent expression alterations rather than uniform upregulation across malignancies. Higher TGFBR1 expression remained associated with poorer overall survival (OS) in mesothelioma (MESO), adrenocortical carcinoma (ACC) and kidney renal papillary cell carcinoma and with poorer disease-specific survival in ACC, esophageal carcinoma, MESO, lung squamous cell carcinoma, stomach adenocarcinoma and bladder urothelial carcinoma after multivariable adjustment. In GSE15459, elevated TGFBR1 expression was associated with shorter OS and remained significant after adjustment for age, sex, pathological stage and Lauren classification. TGFBR1 expression was also associated with distinct immune, stromal, genomic and transcriptional contexts across cancer types. In GC, enrichment analyses revealed an association between higher TGFBR1 expression and apoptosis- and stress-response-associated programs, epithelial cell proliferation, focal-adhesion assembly and actin-cytoskeleton organization. In vitro, TGFBR1 knockdown reduced the proliferation and migration of GC cells, altered epithelial-mesenchymal transition-associated protein expression and promoted apoptosis. Collectively, these findings define the cancer-type-specific clinical and biological relevance of TGFBR1 and support its prognostic importance in selected malignancies, particularly GC, while further mechanistic and prospective validation remains necessary.