Bisphenol S exacerbates CRC progression through dual mechanisms of immune microenvironment reprogramming and SLC4A2-mediated EMT activation

Abstract

Bisphenol S (BPS) is frequently utilized in the domain of food packaging materials as well as in the sphere of industrial plastic manufacturing. Although existing studies suggest potential associations between BPS exposure and the development of various malignancies, the exact biological function of BPS in colorectal cancer (CRC) advancement is still not fully understood. This research intends to thoroughly explore how BPS influences the malignant characteristics of CRC at the molecular level, particularly its impact on the epithelial-mesenchymal transition (EMT) in tumor cells. This study employed a LASSO regression model to screen key genes associated with BPS exposure in CRC progression and constructed a prognostic prediction model. The ESTIMATE algorithm was employed to evaluate the stromal and immune scores within the tumor microenvironment, while the CIBERSORT technique was applied to examine the infiltration profiles of 22 distinct immune cell subsets. The impact of BPS on HCT8 cell proliferation, migratory ability, and EMT progression were systematically evaluated through Western blot, CCK-8 proliferation assays, scratch wound healing experiments, and Transwell assays for migration and invasion. BPS exposure within the concentration range of 10⁻¹ ⁰ to 10⁻⁶ M did not significantly inhibit HCT8 cell viability but markedly enhanced migration and invasion capabilities, accompanied by EMT progression. A prognostic model constructed from nine key genes linked to BPS and determined via LASSO regression exhibited robust predictive efficacy. Tumor microenvironment analysis indicated a substantial association between SLC4A2 gene expression and activated memory CD4 + T lymphocyte infiltration. Notably, BPS exposure specifically induced SLC4A2 upregulation, while siRNA-mediated SLC4A2 knockdown significantly suppressed BPS-induced cell migrationand reversed EMT phenotypes. This study first demonstrates that BPS promotes CRC cell migration by activating the EMT signaling pathway via SLC4A2 upregulation. SLC4A2, being a key player in BPS-induced tumorigenesis, could function as a promising biomarker and therapeutic target for CRC. These findings not only elucidate the molecular mechanisms underlying environmental pollutant-induced carcinogenesis but also provide experimental evidence for developing prevention strategies targeting BPS-associated CRC risks.