IL‑17A promotes CXCR2‑dependent angiogenesis in a mouse model of liver cancer.

Serum interleukin (IL)-17A level is associated with higher microvessel density and poor prognosis in liver cancer. However, the specific mechanism underlying the role of IL-17A in liver cancer remains controversial. In the present study, the effect of IL-17A on liver cancer cells was examined. IL-17A had no evident impact on vascular endothelial growth factor A (VEGFA) production in HepG2 and Huh7.5 cells as determined by reverse transcription-quantitative PCR and ELISA, but it did stimulate angiogenic CXC chemokine secretion, including chemokine (C-X-C motif) ligand 1 (CXCL1), CXCL2, CXCL3, CXCL5, CXCL6 and CXCL8 in Huh7.5 cells and CXCL2 in HepG2 cells. In addition, the production of angiostatic chemokines such as CXCL10 was not affected. The supernatant of Huh7.5-IL17A cells promoted endothelial cell chemotaxis, which was attenuated by the C-X-C chemokine receptor type 2 (CXCR2) inhibitor SB225002. Although there was no role of IL-17A in promoting in vitro cell proliferation, IL-17A markedly increased the tumor growth of Huh7.5 cells in both subcutaneous and orthotopic xenograft models with increased vascularization. Taken together, these results demonstrated that IL-17A may stimulate chemokine-induced angiogenesis and promote tumor progression, independent of VEGF signaling. The CXCL-CXCR2 axis may be a novel target for the anti-angiogenesis treatment of liver cancer.