5-Hydroxytryptamine promotes hepatocellular carcinoma proliferation by influencing β-catenin

• Published in: Molecular oncology Vol. 10; no. 2; pp. 195 - 212
• Main Authors: Fatima, Sarwat, Shi, Xiaoke, Lin, Zesi, Chen, Guo-qing, Pan, Xiao-hua, Wu, Justin Che-Yuen, Ho, John W., Lee, Nikki P., Gao, Hengjun, Zhang, Ge, Lu, Aiping, Bian, Zhao Xiang
• Format: Journal Article
• Language: English
• Published: United States Elsevier B.V 01.02.2016; John Wiley & Sons, Inc; John Wiley and Sons Inc
• Subjects: 5-HT; Animals; Axin Protein - metabolism; beta Catenin - chemistry; beta Catenin - metabolism; Biochemical analysis; Carcinogenesis - metabolism; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; Catenin; Cell cycle; Cell Proliferation; Colorectal cancer; Cyclin D1; Cyclin D1 - metabolism; Cytoplasm; Dkk1 protein; Female; Glutamate-ammonia ligase; Glutamate-Ammonia Ligase - metabolism; Glutamine; Hep G2 Cells; Hepatitis; Hepatocellular carcinoma; Humans; Intercellular Signaling Peptides and Proteins - metabolism; Intracellular signalling; Kinases; Liver - pathology; Liver cancer; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Male; Medical prognosis; Mice; Mice, Inbred BALB C; Mice, Nude; Middle Aged; Phosphorylation; Piperidines - pharmacology; Polymerase chain reaction; Real-Time Polymerase Chain Reaction; Receptors, Serotonin - metabolism; SB-258719; Serotonin - metabolism; Serotonin Antagonists - pharmacology; Sulfonamides - pharmacology; Therapeutic applications; Tumors; Vasoactive agents; Wnt protein; Wnt Signaling Pathway; Wnt/β-catenin signalling; Hong Kong China; United States > US; SB-258719; HCC; qPCR; HCV; SFM; 5-HT; GS; DKK1; HBV; Wnt/β-catenin signalling
• ISSN: 1574-7891; 1878-0261
• DOI: 10.1016/j.molonc.2015.09.008

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. •5-HT increases β-catenin protein levels in serum deprived HuH-7 and HepG2 cells.•Receptor 5-HT7 is overexpressed in 45.4% of HCC tissues.•Antagonist of receptor 5-HT7 attenuates β-catenin protein levels in vitro and in vivo.