Cargando…
Direct inhibition of the TLR4/MyD88 pathway by geniposide suppresses HIF‐1α‐independent VEGF expression and angiogenesis in hepatocellular carcinoma
BACKGROUND AND PURPOSE: 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. EXPERIMENTAL APPROACH:...
Autores principales: | , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2020
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7312435/ https://www.ncbi.nlm.nih.gov/pubmed/32144747 http://dx.doi.org/10.1111/bph.15046 |
_version_ | 1783549725687939072 |
---|---|
author | Zhang, Cheng Wang, Ning Tan, Hor‐Yue Guo, Wei Chen, Feiyu Zhong, Zhangfeng Man, Kwan Tsao, Sai Wah Lao, Lixing Feng, Yibin |
author_facet | Zhang, Cheng Wang, Ning Tan, Hor‐Yue Guo, Wei Chen, Feiyu Zhong, Zhangfeng Man, Kwan Tsao, Sai Wah Lao, Lixing Feng, Yibin |
author_sort | Zhang, Cheng |
collection | PubMed |
description | BACKGROUND AND PURPOSE: 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. EXPERIMENTAL APPROACH: 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. KEY RESULTS: 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. CONCLUSION 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. 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. |
format | Online Article Text |
id | pubmed-7312435 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-73124352020-06-25 Direct inhibition of the TLR4/MyD88 pathway by geniposide suppresses HIF‐1α‐independent VEGF expression and angiogenesis in hepatocellular carcinoma Zhang, Cheng Wang, Ning Tan, Hor‐Yue Guo, Wei Chen, Feiyu Zhong, Zhangfeng Man, Kwan Tsao, Sai Wah Lao, Lixing Feng, Yibin Br J Pharmacol Research Papers BACKGROUND AND PURPOSE: 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. EXPERIMENTAL APPROACH: 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. KEY RESULTS: 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. CONCLUSION 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. 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. John Wiley and Sons Inc. 2020-04-12 2020-07 /pmc/articles/PMC7312435/ /pubmed/32144747 http://dx.doi.org/10.1111/bph.15046 Text en © 2020 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Papers Zhang, Cheng Wang, Ning Tan, Hor‐Yue Guo, Wei Chen, Feiyu Zhong, Zhangfeng Man, Kwan Tsao, Sai Wah Lao, Lixing Feng, Yibin Direct inhibition of the TLR4/MyD88 pathway by geniposide suppresses HIF‐1α‐independent VEGF expression and angiogenesis in hepatocellular carcinoma |
title | Direct inhibition of the TLR4/MyD88 pathway by geniposide suppresses HIF‐1α‐independent VEGF expression and angiogenesis in hepatocellular carcinoma |
title_full | Direct inhibition of the TLR4/MyD88 pathway by geniposide suppresses HIF‐1α‐independent VEGF expression and angiogenesis in hepatocellular carcinoma |
title_fullStr | Direct inhibition of the TLR4/MyD88 pathway by geniposide suppresses HIF‐1α‐independent VEGF expression and angiogenesis in hepatocellular carcinoma |
title_full_unstemmed | Direct inhibition of the TLR4/MyD88 pathway by geniposide suppresses HIF‐1α‐independent VEGF expression and angiogenesis in hepatocellular carcinoma |
title_short | Direct inhibition of the TLR4/MyD88 pathway by geniposide suppresses HIF‐1α‐independent VEGF expression and angiogenesis in hepatocellular carcinoma |
title_sort | direct inhibition of the tlr4/myd88 pathway by geniposide suppresses hif‐1α‐independent vegf expression and angiogenesis in hepatocellular carcinoma |
topic | Research Papers |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7312435/ https://www.ncbi.nlm.nih.gov/pubmed/32144747 http://dx.doi.org/10.1111/bph.15046 |
work_keys_str_mv | AT zhangcheng directinhibitionofthetlr4myd88pathwaybygeniposidesuppresseshif1aindependentvegfexpressionandangiogenesisinhepatocellularcarcinoma AT wangning directinhibitionofthetlr4myd88pathwaybygeniposidesuppresseshif1aindependentvegfexpressionandangiogenesisinhepatocellularcarcinoma AT tanhoryue directinhibitionofthetlr4myd88pathwaybygeniposidesuppresseshif1aindependentvegfexpressionandangiogenesisinhepatocellularcarcinoma AT guowei directinhibitionofthetlr4myd88pathwaybygeniposidesuppresseshif1aindependentvegfexpressionandangiogenesisinhepatocellularcarcinoma AT chenfeiyu directinhibitionofthetlr4myd88pathwaybygeniposidesuppresseshif1aindependentvegfexpressionandangiogenesisinhepatocellularcarcinoma AT zhongzhangfeng directinhibitionofthetlr4myd88pathwaybygeniposidesuppresseshif1aindependentvegfexpressionandangiogenesisinhepatocellularcarcinoma AT mankwan directinhibitionofthetlr4myd88pathwaybygeniposidesuppresseshif1aindependentvegfexpressionandangiogenesisinhepatocellularcarcinoma AT tsaosaiwah directinhibitionofthetlr4myd88pathwaybygeniposidesuppresseshif1aindependentvegfexpressionandangiogenesisinhepatocellularcarcinoma AT laolixing directinhibitionofthetlr4myd88pathwaybygeniposidesuppresseshif1aindependentvegfexpressionandangiogenesisinhepatocellularcarcinoma AT fengyibin directinhibitionofthetlr4myd88pathwaybygeniposidesuppresseshif1aindependentvegfexpressionandangiogenesisinhepatocellularcarcinoma |