Sphingosine-1-phosphate induces angiogenesis via the activating STAT3 signaling pathway to drive colorectal cancer progression.

BACKGROUND: Tumor angiogenesis is a characteristic hallmark of carcinogenesis. Sphingosine-1-phosphate (S1P), a key bioactive lipid produced in vivo, drives the progression of multiple malignant tumors. This study aimed to investigate the function of S1P-mediated angiogenesis in the progression of colorectal cancer (CRC). METHODS: CD31 expression was detected by immunohistochemistry, while serum levels of S1P and CD31 were measured by enzyme-linked immunosorbent assay (ELISA). The regulatory network linking S1P to STAT3/VEGFA was analyzed via the Search Tool for Interacting Chemicals (STITCH) database. Protein and messenger RNA levels were examined via Western blotting and quantitative real-time polymerase chain reaction. Cell Counting Kit-8 (CCK-8), colony formation, wound-healing, Transwell, and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assays were applied to assess the phenotypic effects of S1P on CRC cells and human umbilical vein endothelial cells (HUVECs). A tube formation assay was conducted to assess angiogenesis in vitro, and a mouse xenograft model was created for in vivo studies. RESULTS: CD31 and VEGFA were upregulated in CRC tissues. Serum S1P and CD31 concentrations were elevated and positively correlated with one another in patients with CRC. In terms of mechanism, S1P aggravated the malignant behaviors of CRC cells, activated the phosphorylated STAT3-VEGFA axis, and promoted tube formation in HUVECs. Knockdown of VEGFA significantly attenuated the S1P-induced promotion of malignant phenotypes in CRC cells. Inhibition of the STAT3 pathway abolished the S1P-mediated enhancement of HUVEC phenotypes and angiogenesis. Mouse xenograft experiments verified that S1P facilitates tumor growth by activating the STAT3/VEGFA pathway. CONCLUSIONS: S1P facilitates the emergence of malignant phenotypes of CRC cells, the angiogenesis of HUVECs in vitro, and tumor growth in vivo via the modulation of the STAT3-VEGFA signaling axis. These findings suggest that S1P may be a valuable diagnostic and prognostic marker for CRC progression.