Exposure to trichloromethane via drinking water promotes progression of colorectal cancer by activating IRE1α/XBP1 pathway of endoplasmic reticulum stress

Trichloromethane (TCM), a commonly recognized disinfection by-product formed during the chlorination of water, has been associated with the onset of colorectal cancer (CRC) in humans. Despite this, the impact of TCM on the progression of CRC remains uncertain. In this investigation, it was observed that exposure to TCM could augment the migratory capabilities of CRC cells and facilitate the advancement of colorectal tumors. To delve deeper into the mechanism responsible for TCM-induced CRC progression, we performed RNA-Seq analysis at cellular and animal levels after TCM exposure. Both the KEGG and GO enrichment analyses indicated the activation of endoplasmic reticulum stress (ERS) and the regulation of the cytoskeleton. Subsequently, we confirmed the activation of the IRE1α/XBP1 pathway of ERS through western blot and RT-qPCR. Additionally, we observed the aggregation of cytoskeletal proteins F-actin and β-tubulin at the cell membrane periphery and the development of cellular pseudopods using immunofluorescence following exposure to TCM in vitro. The downregulation of IRE1α and XBP1 through siRNA interference resulted in the disruption of cell cytoskeleton rearrangement and impaired cell migration capability. Conversely, treatment with TCM mitigated this inhibitory effect. Moreover, chronic exposure to low concentration of TCM also triggered CRC cell migration by causing cytoskeletal reorganization, a process controlled by the IRE1α/XBP1 axis. Our study concludes that TCM exposure induces cell migration through the activation of ERS, which in turn regulates cytoskeleton rearrangement. This study offers novel insights into the mechanism through which TCM facilitates the progression of CRC.