<i>Plasmodium </i>infection downregulates hypoxia‑inducible factor 1α expression to suppress the vascularization and tumorigenesis of liver cancer

Liver cancer is characterized by hypervascularization. Anti-angiogenic agents may normalize the tumor vasculature and improve the efficacy of other treatments. The present study aims to investigate the anti-angiogenic effect of <i>Plasmodium</i> infection in a mouse model of implanted liver cancer cells. HepG2 cells were injected into the left liver lobe of nude mice as a model of <i>in situ</i> hepatic tumorigenesis. <i>Plasmodium yoelii</i> parasitized erythrocytes were administered in the animal model of liver cancer to introduce <i>Plasmodium</i> infection. The tumor growth and microvascular density were determined in the presence or absence of <i>Plasmodium</i> infection. The expression levels of hypoxia-inducible factor 1α (HIF-1α) and angiogenesis-related factors were evaluated using western blotting and reverse transcription-quantitative PCR analysis. The results demonstrated that <i>Plasmodium</i> infection suppressed tumor growth and vascularization in the mouse model of implanted HepG2 cells. <i>Plasmodium</i> parasites reduced the expression of pro-angiogenic factors (vascular endothelial growth factor A and angiopoietin 2), matrix metalloproteinases [(MMP)2 and MMP9] and inflammatory cytokines [tumor necrosis factor α, interleukin 6 (IL)-6) and IL-1β] in both hepatic and tumor tissues. HIF-1α was downregulated in both hepatic and tumor tissues upon <i>Plasmodium</i> infection, and HIF-1α overexpression rescued angiogenesis and tumor growth under the condition of <i>Plasmodium</i> infection. In conclusion, the results of the present study demonstrated the anti-angiogenic and anti-tumorigenic effects of <i>Plasmodium</i> infection on liver cancer through downregulating HIF-1α expression, indicating that <i>Plasmodium</i> parasites could be developed as an intervention strategy to restrain neo-angiogenesis in liver cancer.