Glycer-AGEs-RAGE signaling enhances the angiogenic potential of hepatocellular carcinoma by upregulating VEGF expression
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AIM: To investigate the effect of glyceraldehyde-derived advanced glycation end-products (Glycer-AGEs) on hepatocellular carcinoma (HCC) cells. METHODS: Two HCC cell lines (Hep3B and HepG2 cells) and human umbilical vein endothelial cells (HUVEC) were used. Cell viability was determined using the WST-8 assay. Western blotting, enzyme linked immunosorbent assay, and real-time reverse transcription-polymerase chain reactions were used to detect protein and mRNA. Angiogenesis was evaluated by assessing the proliferation, migration, and tube formation of HUVEC. RESULTS: The receptor for AGEs (RAGE) protein was detected in Hep3B and HepG2 cells. HepG2 cells were not affected by the addition of Glycer-AGEs. Glycer-AGEs markedly increased vascular endothelial growth factor (VEGF) mRNA and protein expression, which is one of the most potent angiogenic factors. Compared with the control unglycated bovine serum albumin (BSA) treatment, VEGF mRNA expression levels induced by the Glycer-AGEs treatment were 1.00 ± 0.10 vs 1.92 ± 0.09 (P < 0.01). Similarly, protein expression levels induced by the Glycer-AGEs treatment were 1.63 ± 0.04 ng/mL vs 2.28 ± 0.17 ng/mL for the 24 h treatment and 3.36 ± 0.10 ng/mL vs 4.79 ± 0.31 ng/mL for the 48 h treatment, respectively (P < 0.01). Furthermore, compared with the effect of the control unglycated BSA-treated conditioned medium, the Glycer-AGEs-treated conditioned medium significantly increased the proliferation, migration, and tube formation of HUVEC, with values of 122.4% ± 9.0% vs 144.5% ± 11.3% for cell viability, 4.29 ± 1.53 vs 6.78 ± 1.84 for migration indices, and 71.0 ± 7.5 vs 112.4 ± 8.0 for the number of branching points, respectively (P < 0.01). CONCLUSION: These results suggest that Glycer-AGEs-RAGE signaling enhances the angiogenic potential of HCC cells by upregulating VEGF expression.
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RAGE amounts are increased in HCC liver compared with hepatitis and healthy liver, and serum AGE amounts are higher in HCC than in NASH and healthy liver specimens.
“Increased amounts of RAGE are also observed in the liver of hepatocellular carcinoma (HCC), and its level is significantly greater than it is liver affected by hepatitis and healthy liver specimens.”
From Advanced glycation end products (AGEs) and other adducts in aging-related diseases and alcohol-mediated tissue injury (2021) · cites this paper as [130]
AGEs and RAGE play an important role in promoting NAFLD, NASH, fibrosis/cirrhosis, and HCC pathogenesis.
“These results suggest an important role for AGEs and RAGE in promoting NAFLD, NASH, fibrosis/cirrhosis, and HCC pathogenesis129–131.”
From Advanced glycation end products (AGEs) and other adducts in aging-related diseases and alcohol-mediated tissue injury (2021) · cites this paper as [130]
In HCC, AGE-RAGE interaction is associated with angiogenesis and tumor proliferation and invasion, which are ameliorated by RAGE inhibition.
“In HCC, the AGE-RAGE interaction is associated with angiogenesis and tumor proliferation and invasion, which are ameliorated by RAGE inhibition.”
From Advanced glycation end products (AGEs) and other adducts in aging-related diseases and alcohol-mediated tissue injury (2021) · cites this paper as [130]
Soluble RAGE, inhibitors of the RAGE signaling pathway, neutralizing antibodies against RAGE or AA-AGE adduct, and other AGE-degrading compounds have been reported to decrease AGE adduct formation.
“Furthermore, soluble RAGE119,200, inhibitors of the RAGE signaling pathway130,131, neutralizing antibodies against RAGE57 or AA-AGE adduct199, and other AGE-degrading compound(s), such as pyridoxamine and ALT-711200, lipoic acid291, synthetic compounds OPB-9195292, and nitrothiadiazolo[3,2-α]pyrimidines293, have been reported to decrease AGE adduct formation.”
From Advanced glycation end products (AGEs) and other adducts in aging-related diseases and alcohol-mediated tissue injury (2021) · cites this paper as [130]
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References 40 · Cited by 64
Research works printed but not linked: 1
- Mayoral R, Fernández-Martínez A, Boscá L, Martín-Sanz P. Prostaglandin E2 promotes migration and adhesion in hepa- tocellular carcinoma cells. Carcinogenesis 2005; 26: 753-761
- Authors
- Takino, J.
- Venue
- World Journal of Gastroenterology
- Publisher
- Baishideng Publishing Group Inc.
- Published
- 2012
- Volume
- 18
- Issue
- 15
- Pages
- 1781
- ISSN
- 1007-9327 (ISSN-L)
- PMC
- PMC3332291
- OpenAlex
- W2144513682
- Cited by
- 64
- References
- 40
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 1 · 2023: 6 · 2022: 3 · 2021: 8 · 2020: 6 · 2019: 3 · 2017: 7 · 2016: 5 · 2015: 8 · 2014: 8 · 2013: 5
- FWCI
- 4.31
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc
- Locations
- World Journal of Gastroenterology (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Japan Society for the Promotion of Science (22300264)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Advanced Glycation End Products research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
- Keywords
- advanced glycation end products, glyceraldehyde, receptor for advanced glycation end products, hepatocellular carcinoma, angiogenesis, vascular endothelial growth factor, VEGF expression, endothelial cell proliferation and migration, tube formation, tumor microenvironment, oxidative stress, hepatocellular carcinoma progression
- MeSH terms
- Receptor for Advanced Glycation End Products, Cell Movement, Glyceraldehyde, Carcinoma, Hepatocellular, Humans, Liver Neoplasms, Neovascularization, Pathologic, Receptors, Immunologic, Signal Transduction, Up-Regulation, Glycation End Products, Advanced, Vascular Endothelial Growth Factor A, Hep G2 Cells
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