Exploring the potential mechanisms of PFAS exposure on colorectal cancer via combined bioinformatics analyses and experiments.

[BACKGROUND] Colorectal cancer (CRC) is a leading cause of cancer-related deaths influenced by both genetic and environmental factors. Per- and polyfluoroalkyl substances (PFAS) are widely recognized environment pollutants known for their high bioaccumulation potential and a long elimination half-life, which have been implicated in the development and progression of CRC. However, the underlying mechanism by which these substances cause CRC still remains unclear.

[METHODS] The PFAS-associated differentially expressed genes (DEGs) were identified by intersecting the DEGs in CRC with the interactive genes from the Comparative Toxicogenomics Database (CTD) database. Subsequently, the consensus genes were employed to develop a prognostic model using univariate Cox and LASSO analyses. Additionally, we examined the differences in clinicopathological characteristics, genetic variants, and potential drug sensitivity between the high-risk and low-risk groups. The effects of PRAME, one gene of the prognostic model, on CRC were further validated through both bioinformatics and experimental approaches.

[RESULTS] A total of 192 PFAS-related DEGs were screened and used to develop a prognostic model for CRC through univariate Cox and LASSO analyses. The feasibility of the model was validated using both an internal training set and an external validation set. The RiskScore was also identified as an independent prognostic factor for overall survival in CRC patients. Furthermore, CRC patients in high-risk group were suggested to possess a greater number of genetic variants and exhibit enhanced responses to a range of potential drugs and immunotherapies. We also observed that PRAME was highly expressed and correlated with poor prognosis in CRC. PFOS exposure induced the upregulation of PRAME in CRC cells, which subsequently enhanced cell proliferation and invasion capacity through PI3K/Akt/mTOR signalling pathway.

[CONCLUSIONS] We constructed a novel prognostic model based on 15 PFAS-related DEGs to predict the survival and responses to potential drugs and immunotherapy of CRC patients. Furthermore, we identified and assessed the feasibility of the critical gene PRAME in prognostic model as a vital marker for CRC. Our findings further suggested that PFOS exposure may increase the risk of CRC development via upregulation of PRAME-mediated PI3K/Akt/mTOR signalling pathway, indicating its potential as a novel therapeutic target for CRC in the future.