School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong S.A.R., China.
Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong S.A.R., China.
Br J Pharmacol. 2020 Jul;177(14):3240-3257. doi: 10.1111/bph.15046. Epub 2020 Apr 12.
As a typical hypervascular tumour, hepatocellular carcinoma (HCC) is predominantly grown through angiogenesis. Geniposide is a promising anti-inflammatory compound found in Gardenia jasminoides, but its effects on the progression of HCC remain untested.
The anti-HCC effects of geniposide was investigated in cellular models and orthotopic HCC mice. Transcriptional regulation of the 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 techniques and human phospho-kinase array analysis were utilized to validate the relationship between targets of geniposide and hepatocarcinogenesis.
Geniposide exhibited significant disruption of HCC proliferation, invasion, angiogenesis and lung metastasis in orthotopic HCC mice. Geniposide inhibited secretion of VEGF by HCC and suppressed the migration of endothelial cells and the formation of intra-tumour blood vessels, without cytotoxicity and independently of the transcription factor HIF-1α. Direct inhibition of TLR4 by geniposide led to the shutdown of the TLR4/MyD88 pathway and STAT3/Sp1-dependent VEGF production. However, LPS, an agonist of TLR4, restored STAT3/Sp1-related VEGF production in geniposide-inhibited HCC angiogenesis.
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. This action of geniposide was not affected by stabilization of HIF-1α. Our study offers a novel anti-VEGF mechanism for the inhibition of HCC.
作为一种典型的富血管肿瘤，肝细胞癌（HCC）主要通过血管生成生长。栀子苷是栀子中的一种有前途的抗炎化合物，但它对 HCC 进展的影响尚未得到检验。
在细胞模型和原位 HCC 小鼠中研究了栀子苷的抗 HCC 作用。通过双荧光素酶报告基因检测测定 VEGF 启动子的转录调控。通过管形成测定法测定栀子苷的抗血管生成作用。利用表面等离子体共振技术和人磷酸激酶阵列分析来验证栀子苷的靶标与肝癌发生之间的关系。
栀子苷在原位 HCC 小鼠中显著破坏 HCC 的增殖、侵袭、血管生成和肺转移。栀子苷抑制 HCC 分泌 VEGF，并抑制内皮细胞迁移和肿瘤内血管形成，无细胞毒性，且独立于转录因子 HIF-1α。栀子苷直接抑制 TLR4 导致 TLR4/MyD88 途径失活和 STAT3/Sp1 依赖性 VEGF 产生。然而，TLR4 的激动剂 LPS 在栀子苷抑制的 HCC 血管生成中恢复了 STAT3/Sp1 相关的 VEGF 产生。
栀子苷对 TLR4/MyD88 激活的直接抑制作用有助于抑制 HCC 血管生成和肺转移中 STAT3/Sp1 依赖性 VEGF 过表达。栀子苷的这种作用不受 HIF-1α 稳定的影响。我们的研究为抑制 HCC 提供了一种新的抗 VEGF 机制。
