Open Access5‐Hydroxytryptamine promotes hepatocellular carcinoma proliferation by influencing β‐catenin
Author(s) -
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
Publication year - 2016
Publication title -
molecular oncology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.332
H-Index - 88
eISSN - 1878-0261
pISSN - 1574-7891
DOI - 10.1016/j.molonc.2015.09.008
Subject(s) - axin2 , wnt signaling pathway , cyclin d1 , dkk1 , receptor , cancer research , cell growth , biology , cell culture , catenin , hepatocellular carcinoma , medicine , endocrinology , signal transduction , cell , microbiology and biotechnology , cell cycle , biochemistry , genetics
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.