Direct inhibition of TLR4/MyD88 pathway by geniposide suppresses HIF1α‐independent VEGF expression and hepatocellular carcinoma angiogenesis
2020
BACKGROUND AND PURPOSE: As a typical hypervascular tumor, hepatocellular carcinoma (HCC) is predominantly grown through angiogenesis. Geniposide is a promising anti-inflammatory substance derived from Gardenia jasminoides, but its role in HCC progression remains obscure. METHODS: The anti-HCC characteristic of geniposide was investigated by cellular models and orthotopic HCC mice (n=5/group). Transcriptional regulation of VEGF promoter was measured by dual-luciferase reporter assay. The anti-angiogenic action of geniposide was measured by tube formation assay. Both surface plasmon resonance technology and human phospho-kinase array analysis were utilized to validate the relationship between geniposide-mediated targets and hepato-carcinogenesis. KEY RESULTS: Geniposide exhibited significant disruption on HCC proliferation, invasion, angiogenesis, and lung metastasis in orthotopic HCC mouse. The inhibition of HCC-secreted VEGF by geniposide suppressed the migration of endothelial cells and the formation of intratumoral blood vessels in a nontoxic and HIF-1alpha independent manner. Direct inhibition of TLR4 by geniposide led to the shutdown of TLR4/MyD88 pathway and STAT3/Sp1-dependent VEGF production. However, a competitive agonist of TLR4, lipopolysaccharide (LPS), rescued STAT3/Sp1-related VEGF reduction in geniposide-inhibited HCC angiogenesis. CONCLUSIONS AND IMPLICATIONS: The direct inhibitory effect of geniposide on TLR4/MyD88 activation contributes to the suppression of STAT3/Sp1-dependent VEGF overexpression in HCC angiogenesis and pulmonary metastasis, which is independent of regulating HIF-1alpha stabilization. Our study offers a novel anti-VEGF mechanism for HCC therapy.
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