Activation of histamine H4 receptors decreases epithelial-to-mesenchymal transition progress by inhibiting transforming growth factor-β1 signalling pathway in non-small cell lung cancer

Eur J Cancer. 2014 Apr;50(6):1195-206. doi: 10.1016/j.ejca.2013.12.025. Epub 2014 Jan 18.

Abstract

Previous investigations found that epithelial-to-mesenchymal transition (EMT) was an important character of non-small cell lung cancer (NSCLC) and it was also suggested that histamine H4 receptors may have a role in preventing EMT progress in certain kind of tumours. However, the effect of H4 receptor activation on EMT progress of NSCLC and its potential mechanisms remain unclear. Therefore, we performed both in vitro and in vivo experiments to explore the effects of specific H4 receptor agonist 4-methylhistamine and antagonist JNJ7777120 on EMT progress. We showed the expression of H4 receptors in NSCLC and found that 4-methylhistamine increased the expression of the epithelial marker E-cadherin and decreased the expression of Vimentin, the mesenchymal marker, in both NSCLC cell lines and xenograft NSCLC tumours. Pretreatment with JNJ7777120 or H4 receptor gene silencing decreased while overexpression of H4 receptors facilitated this effect of 4-methylhistamine. Furthermore, we showed that down-regulation of cyclic adenosine monophosphate (cAMP) was the secondary signalling after H4 receptor activation, which in turn resulted in inactivation of transforming growth factor-β1 (TGF-β1) pathway and down-regulation of several important EMT inducing factors such as ZEB1, Snail and Slug. In conclusion, these findings revealed the anti-EMT effect of histamine H4 receptor activation in NSCLC, which provide novel insight into the development mechanism of NSCLC; and H4 receptors may be a new therapeutic target for NSCLC treatment.

Keywords: Epithelial-to-mesenchymal transition; Histamine H(4) receptors; Non-small cell lung cancer; TGF-β1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cadherins / genetics
  • Cadherins / metabolism
  • Carcinoma, Non-Small-Cell Lung / drug therapy
  • Carcinoma, Non-Small-Cell Lung / genetics*
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Cell Line, Tumor
  • Cyclic AMP / metabolism
  • Epithelial-Mesenchymal Transition / drug effects
  • Epithelial-Mesenchymal Transition / genetics*
  • Gene Expression Regulation, Neoplastic / drug effects
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism
  • Humans
  • Immunohistochemistry
  • Indoles / pharmacology
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / pathology
  • Methylhistamines / pharmacology
  • Mice
  • Mice, Nude
  • Piperazines / pharmacology
  • RNA Interference
  • Receptors, G-Protein-Coupled / agonists
  • Receptors, G-Protein-Coupled / antagonists & inhibitors
  • Receptors, G-Protein-Coupled / genetics*
  • Receptors, Histamine / genetics*
  • Receptors, Histamine H4
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / drug effects
  • Signal Transduction / genetics*
  • Snail Family Transcription Factors
  • Survival Analysis
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Transforming Growth Factor beta1 / genetics*
  • Transforming Growth Factor beta1 / metabolism
  • Vimentin / genetics
  • Vimentin / metabolism
  • Xenograft Model Antitumor Assays
  • Zinc Finger E-box-Binding Homeobox 1

Substances

  • Cadherins
  • HRH4 protein, human
  • Homeodomain Proteins
  • Indoles
  • Methylhistamines
  • Piperazines
  • Receptors, G-Protein-Coupled
  • Receptors, Histamine
  • Receptors, Histamine H4
  • SNAI1 protein, human
  • Snai2 protein, mouse
  • Snail Family Transcription Factors
  • Transcription Factors
  • Transforming Growth Factor beta1
  • Vimentin
  • ZEB1 protein, human
  • Zinc Finger E-box-Binding Homeobox 1
  • 1-((5-chloro-1H-indol-2-yl)carbonyl)-4-methylpiperazine
  • 4-methylhistamine
  • Cyclic AMP