2. Academic Validation
  3. 5-Hydroxytryptamine promotes hepatocellular carcinoma proliferation by influencing β-catenin

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

  • Mol Oncol. 2016 Feb;10(2):195-212. doi: 10.1016/j.molonc.2015.09.008.
Sarwat Fatima 1,  Xiaoke Shi 2,  Zesi Lin 3,  Guo-qing Chen 4,  Xiao-hua Pan 5,  Justin Che-Yuen Wu 6,  John W Ho 7,  Nikki P Lee 8,  Hengjun Gao 9,  Ge Zhang 10,  Aiping Lu 11,  Zhao Xiang Bian 12
Affiliations

Affiliations

  • 1 Lab of Brain and Gut Research, Centre of Clinical Research for Chinese Medicine, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong Special Administrative Region; Centre for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong Special Administrative Region.
  • 2 Lab of Brain and Gut Research, Centre of Clinical Research for Chinese Medicine, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong Special Administrative Region.
  • 3 Lab of Brain and Gut Research, Centre of Clinical Research for Chinese Medicine, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong Special Administrative Region; School of Fundamental Medical Science, University of Chinese Medicine, Guangzhou, China.
  • 4 Lab of Brain and Gut Research, Centre of Clinical Research for Chinese Medicine, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong Special Administrative Region; Chongqing Academy of Chinese Materia Medica, Chongqing, 400065, China.
  • 5 Shen Zhen People's Hospital, Shenzhen, 518020, China.
  • 6 Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Shatin, Hong Kong Special Administrative Region.
  • 7 School of Life Sciences, The Chinese University of Hong Kong, Hong Kong Special Administrative Region.
  • 8 Department of Surgery, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region.
  • 9 Institute of Digestive Disease, Department of Gastroenterology, Tongji Hospital, Tongji University, Shanghai, 200065, China; Shanghai Engineering Center for Molecular Medicine, National Engineering Center for Biochip at Shanghai, Shanghai, 201203, China.
  • 10 Institute for Advancing Translational Medicine in Bone and Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong Special Administrative Region.
  • 11 Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, 100700, China; School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong Special Administrative Region.
  • 12 Lab of Brain and Gut Research, Centre of Clinical Research for Chinese Medicine, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong Special Administrative Region; Centre for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong Special Administrative Region. Electronic address: [email protected].
PMID: 26474915 DOI: 10.1016/j.molonc.2015.09.008
Abstract

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.

Keywords

5-HT; SB-258719; Wnt/β-catenin signalling.

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