5-Hydroxytryptamine promotes hepatocellular carcinoma proliferation by influencing β-catenin
| Autor: | Ge Zhang, Sarwat Fatima, Guoqing Chen, Zesi Lin, Aiping Lu, John W. Ho, Xiao-Ke Shi, Hengjun Gao, Nikki P. Lee, Justin C.Y. Wu, Zhaoxiang Bian, Xiaohua Pan |
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| Rok vydání: | 2015 |
| Předmět: |
0301 basic medicine
Male Cancer Research Serotonin Carcinoma Hepatocellular Carcinogenesis Mice Nude Biology Real-Time Polymerase Chain Reaction 03 medical and health sciences Mice Cyclin D1 Axin Protein Piperidines Glutamate-Ammonia Ligase AXIN1 Genetics AXIN2 Animals Humans Phosphorylation Receptor Wnt Signaling Pathway beta Catenin Cell Proliferation Mice Inbred BALB C Sulfonamides Liver Neoplasms Wnt signaling pathway General Medicine Hep G2 Cells Articles Middle Aged 030104 developmental biology Oncology DKK1 Liver Cell culture Catenin Receptors Serotonin Immunology Cancer research Molecular Medicine Intercellular Signaling Peptides and Proteins Female Serotonin Antagonists |
| Zdroj: | Molecular oncology. 10(2) |
| ISSN: | 1878-0261 |
| Popis: | 5-Hydroxytryptamine (5-HT), a neurotransmitter and vasoactive factor, has been reported to promote proliferation of serum-deprived hepatocellular carcinoma (HCC) cells but the detailed intracellular mechanism is unknown. As Wnt/β-catenin signalling is highly dysregulated in a majority of HCC, this study explored the regulation of Wnt/β-catenin signalling by 5-HT. The expression of various 5-HT receptors was studied by quantitative real-time polymerase chain reaction (qPCR) in HCC cell lines as well as in 33 pairs of HCC tumours and corresponding adjacent non-tumour tissues. Receptors 5-HT1D (21/33, 63.6%), 5-HT2B (12/33, 36.4%) and 5-HT7 (15/33, 45.4%) were overexpressed whereas receptors 5-HT2A (17/33, 51.5%) and 5-HT5 (30/33, 90.1%) were reduced in HCC tumour tissues. In vitro data suggests 5-HT increased total β-catenin, active β-catenin and decreased phosphorylated β-catenin protein levels in serum deprived HuH-7 and HepG2 cells compared to control cells under serum free medium without 5-HT. Activation of Wnt/β-catenin signalling was evidenced by increased expression of β-catenin downstream target genes, Axin2, cyclin D1, dickoppf-1 (DKK1) and glutamine synthetase (GS) by qPCR in serum-deprived HCC cell lines treated with 5-HT. Additionally, biochemical analysis revealed 5-HT disrupted Axin1/β-catenin interaction, a critical step in β-catenin phosphorylation. Increased Wnt/β-catenin activity was attenuated by antagonist of receptor 5-HT7 (SB-258719) in HCC cell lines and patient-derived primary tumour tissues in the presence of 5-HT. SB-258719 also reduced tumour growth in vivo. This study provides evidence of Wnt/β-catenin signalling activation by 5-HT and may represent a potential therapeutic target for hepatocarcinogenesis. |
| Databáze: | OpenAIRE |
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