Fatty Acid Metabolism is Associated with Immune Microenvironment Variation in Bladder Cancer, and FN1 May Mediate PD-L1 Expression through the IL6-STAT3 Pathway

Abstract

Background: Fatty acid metabolism plays an important role in many biological activities, such as cell membrane formation, energy storage, and signal molecule generation in tumorigenesis. Lipid metabolism affects the progression and treatment of Bladder Cancer (BLCA). Therefore, it is imperative to explore the function and prognostic value of lipid metabolism-related genes in BLCA patients. Methods: In this study, we collected gene expression profiles and clinical information in The Cancer Genome Map (TCGA) database and two independent Group on Earth Observations (GEO) datasets. Gene interaction information was obtained from ENCORI database. Based on these databases, we analyzed the expression patterns of genes and proteins involved in fatty acid metabolism and their matching clinicopathological features. Further, the gene for fatty acid metabolism, FN1, was screened for cellular function science experiments to validate our findings. Results: Analysis in the TCGA database identified 310 fatty acid metabolism-related mRNAs, 91 of which were differentially expressed in BLCA patients. Based on the correlation of Differentially Expressed Genes (DGEs) with patient characteristics, we developed a clinical prognostic correlation model and validated the accuracy of the model based on information from the GEO database. Survival analysis and clinical correlation analysis showed that elevated FN1 levels were highly correlated with shorter survival, higher staging, higher grading, and lower infiltration of immune cells in BLCA. Furthermore, we experimentally verified that FN1 can activate the IL6 -JAK - STAT3 pathway and further promote PD-L1 expression, which would serve as a potential factor for immune escape in bladder cancer. Finally, our experimental results were consistent with the bioinformatics analysis.