Wei Ao, Haoran Li, Yuhang Zhang, Zhenheng Wu, Hao Yang, Zhigang Chen
BPA-induced CXCL8 upregulation is associated with CRC malignant progression and enhanced p38 MAPK signaling. TEAD4 may function as an upstream transcriptional regulator of CXCL8, although its direct regulation by BPA remains unclear. Given the clinical correlation between CXCL8 upregulation and T2DM status, this pathway may represent a potential mechanistic link contributing to the frequently observed T2DM-CRC comorbidity.
BACKGROUND: Bisphenol A (BPA) is a common environmental endocrine disruptor linked to type 2 diabetes mellitus (T2DM) and colorectal cancer (CRC), but the exact mechanism connecting BPA exposure to their comorbidity is unclear.
METHODS: This study integrated network toxicology, single-cell transcriptomic data, molecular simulation, in vitro cell experiments, and patient-derived explant (PDE) models to systematically explore the potential molecular basis underlying the correlation between BPA exposure and T2DM-CRC comorbidity.
RESULTS: CXCL8 was identified as the sole overlapping gene shared among the 30 BPA-T2DM-CRC common targets, the PPI-derived hub genes, and the DEGs identified in GSE115313. It was upregulated in T2DM-CRC tissues, associated with obesity and T2DM, and showed strong diagnostic performance in CRC (AUC=0.895). Immune analysis indicated an increased proportion of Tregs in CRC samples from patients with T2DM, while CXCL8 expression correlated positively with M1 macrophage and activated mast cell infiltration. Single-cell transcriptomic data analysis of GSE188711 showed that CXCL8 expression varied along the inferred pseudotime trajectory and appeared enriched in the annotated B-cell population. Molecular simulations showed moderate binding between BPA and CXCL8 (binding energy: -5.7 kcal/mol). BPA treatment boosted CRC cell proliferation, migration, and invasion, while CXCL8 knockdown reduced these activities. The malignant effects of BPA were significantly reduced when CXCL8 was knocked down. Mechanistically, TEAD4 was identified as a potential upstream transcriptional regulator of CXCL8, while increased CXCL8 expression was accompanied by enhanced p38 MAPK pathway activation.
CONCLUSIONS: BPA-induced CXCL8 upregulation is associated with CRC malignant progression and enhanced p38 MAPK signaling. TEAD4 may function as an upstream transcriptional regulator of CXCL8, although its direct regulation by BPA remains unclear. Given the clinical correlation between CXCL8 upregulation and T2DM status, this pathway may represent a potential mechanistic link contributing to the frequently observed T2DM-CRC comorbidity.