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Endothelial Cell-Derived Interleukin-6 Facilitated Colorectal Cancer Cell Migration and Invasion by Regulating Osteopontin in a Paracrine Manner
Vol 38, Issue 1, 2024
Abstract
Background: Patients with metastatic colorectal cancer (CRC) generally suffer from poor prognosis. Therefore, there is an urgent need to further delineate the mechanism of metastasis in CRC, which is of clinical significance for the development of more targeted therapy. This study aimed to explore the potential role of endothelial cells-derived interleukin-6 (IL-6) in CRC metastasis. Methods: Human umbilical vein endothelial cell (HUVEC)-conditioned medium and CRC-conditioned medium were prepared, with the latter being the control. Enzyme-linked immunosorbent assay was employed to detect IL-6 levels in HUVEC-conditioned or CRC-conditioned culture media. CRC cells were separately cultured in both media to investigate the effect of HUVECs on CRC metastasis using cell counting kit-8 assay, scratch test and Transwell assay. The role of HUVEC-derived IL-6 in CRC cells was investigated using rescue assay. The expressions of the osteopontin protein and the proteins in glycogen synthase kinase-3β (GSK3β)-β-catenin signaling pathways were determined by Western blotting. To confirm the mediating role of osteopontin in the relationship between IL-6 and CRC, the expression of osteopontin in CRC cells was up-regulated. Results: IL-6 level was higher in HUVEC-conditioned medium than in CRC-conditioned medium (p < 0.001). CRC cells in the HUVEC-conditioned medium showed enhanced viability, migration and invasion (p < 0.05). HUVEC-secreted IL-6 facilitated malignant phenotypes and activated osteopontin and GSK3β-β-catenin signaling pathway of CRC cells in a dose-dependent manner (p < 0.05). Moreover, osteopontin overexpression contributed to CRC metastasis in vitro and activated GSK3β-β-catenin signaling pathway (p < 0.001), while such effect was abrogated by IL-6 silencing (p < 0.001). Conclusion: HUVEC-derived IL-6 facilitated the metastasis of CRC cells by regulating osteopontin in a paracrine manner.
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Medical Genetics, University of Torino Medical School, Italy

Department of Biomedical, Surgical and Dental Sciences, University of Milan, Italy