Alleviatory effect of <em>Dictyophora duplicata</em> polysaccharide in colitis-associated colorectal cancer via HIF-1&amp;alpha;/VEGF axis

Colitis-associated colorectal cancer (CAC) is a common gastrointestinal tumor with high malignancy. Recent studies have demonstrated the anticancer properties of natural polysaccharides. Therefore, we investigated the anticancer effect and mechanisms of a water-soluble polysaccharide (DDP-A1) isolated from fruiting bodies of <em>Dictyophora duplicata</em> in mice with azoxymethane/dextran sodium sulfate (AOM/DSS)-induced CAC. <em>D. duplicata</em> were extracted using hot water and purified via ethanol precipitation, deproteinization, dialysis, and freeze-drying to obtain crude polysaccharides. Subsequently, these crude polysaccharides are further purified using anion exchange chromatography and gel filtration chromatography to yield the DDP-A1. Additionally, a murine model of CAC was established via three cycles of sequential treatments with AOM and DSS to examine the anticancer effect of DDP-A1. Notably, DDP-A1 had a molecular weight of 8.14 kDa and was mainly composed of glucose and mannose. DDP-A1 treatment reduced tumor number and restored the colorectal index in CAC mice. Gut microbiota analysis showed that DDP-A1 significantly enhanced the relative abundances of <em>Prevotella</em> and <em>Parabacteroides</em> and decreased the relative abundances of <em>Allobaculum</em> and <em>Desulfovibrio</em> in CAC mice. Proteomic and metabolomic analyses showed that DDP-A1 inhibited the expression levels of heparanase and succinate, implying that DDP-A1 played a protective role in part by regulating angiogenesis. Immunofluorescence assay, immunohistochemistry, and western blotting confirmed that DDP-A1 inhibited the phosphorylation of extracellular signal-regulated kinase (ERK) and downregulated the expression of succinate dehydrogenase subunit B, hypoxia-inducible factor-1 alpha (HIF-1α), and vascular endothelial growth factor (VEGF). Mechanistically, DDP-A1 effectively inhibited the progression of CAC through the HIF-1α/VEGF axis. Conclusively, these findings provide a scientific basis for the application of <em>D. duplicata</em> to regulate angiogenesis as an alternative therapeutic strategy for the clinical management of CAC.