Perfluorodecanoic acid (PFDA) exposure, through stabilizing HIF-1α to induce VEGF/VEGFR2 autocrine signaling, promotes colorectal cancer cell proliferation

Perfluorodecanoic acid (PFDA) is a persistent organic pollutant widely present in the environment and resistant todegradation. In recent years, due to its extensive use in industrial production and consumer products, PFDA continuously accumulates in organisms and has become a global public health concern. Although epidemiological data suggest a possible association between PFDA and various cancer risks, its specific carcinogenic mechanism, particularly in colorectal cancer development, remains unclear. Therefore, this study aims to investigate the effects of environmentally relevant concentrations of PFDA on the biological behavior of colorectal cancer cells and to elucidate. the underlying molecular mechanisms. In vitro, human colorectal cancer cell lines HCT116 and HT-29 were used as models. Our results demonstrated that PFDA treatment significantly enhanced the malignant phenotype of cancer cells in a dose-dependent manner. Colony formation ability was enhanced. Meanwhile, cell invasion capacity was also significantly improved. Additionally, PFDA exposure induced glycolytic metabolic reprogramming in cancer cells, a metabolic feature closely associated with rapid tumor growth and malignant progression. To further elucidate the mechanism, our team conducted in-depth molecular biological investigations. The study found that PFDA does not affect gene transcription but instead directly binds to and stabilizes the VHL protein, preventing its degradation of HIF-1α. This consequently significantly upregulates its classic downstream target genes, VEGF and its receptor VEGFR2, thereby activating key downstream pro-survival and proliferation signaling pathways. Using a nude mouse subcutaneous xenograft model, our data also confirmed that in vivo PFDA exposure promotes tumor growth, with significant increases in both tumor volume and weight. In summary, this study lays a solid foundation for further in-depth toxicological research on PFDA.