H4 receptor activation plays part in NSCLC progression

Feb 27 2014

By Laura Cowen, medwireNews Reporter

Histamine H₄ receptor activation decreases epithelial-to-mesenchymal transmission (EMT) in non-small-cell lung cancer (NSCLC), Chinese research shows.

The anti-EMT effect of H₄ receptor activation is likely to occur, at least in part, via sequential downregulation of cyclic adenosine monophosphate (cAMP), decreased transforming growth factor (TGF)- β1 signalling and downregulation of the EMT-inducing transcription factors ZEB1 and Snail and Slug.

This leads to increased expression of the epithelial marker E-cadherin and decreased expression of the mesenchymal marker Vimentin, report Gui-Li Xu (Kunming General Hospital of Chengdu Military Region) and colleagues in the European Journal of Cancer.

“These findings provide novel insight into the development mechanism of NSCLC; while H₄ receptors may be a new therapeutic target for NSCLC treatment,” they write.

The researchers conducted a series of in vitro and in vivo experiments to explore the effects of the H₄ receptor agonist 4-methylhistamine and antagonist JNJ7777120 on EMT progress.

They found that 4-methylhistamine dose-dependently decreased the proliferation of squamous carcinoma (H157), large cell carcinoma (H460), adenocarcinoma (A549) and bronchioalveolar (H322) cell lines.

At the minimum effective concentration of 1 μmol/L, 4-methylhistamine significantly increased both messenger (m)RNA and protein expression of E-cadherin and decreased that of Vimentin. The effects were most pronounced in the A549 adenocarcinoma cells, least pronounced in the H157 squamous carcinoma cells and were eliminated by treatment with JNJ7777120.

The results may partially be explained by the fact that A549 cells express larger amounts of expressed H₄ receptors than do H157 cells, say the researchers. They therefore suggest that “targeting H₄ receptors may be more effective in the treatment of lung adenocarcinoma that is more prevalent and generally believed to be more prone to metastasise than other kinds of NSCLC”.

Further studies into the downstream signalling pathways of histamine H₄ receptors showed that 4-methylhistamine treatment significantly decreased intracellular cAMP levels, TGF-β1 mRNA expression and TGF-β1 levels in cell culture. Pretreatment with JNJ7777120 blocked this effect.

For the in vivo studies, Xu and team injected nude mice with A549 cells and treated them intravenously with 4-methylhistamine or 0.9% sodium chloride (control group). Mice in the 4-methylhistamine group had a significantly lower tumour volume than those in the control group after 20 days of treatment. Furthermore, E-cadherin mRNA expression was significantly increased and Vimentin expression was significantly decreased after 4-methylhistamine administration.

“These findings confirmed our in vitro data and the anti-EMT effect of H₄ receptors in NSCLC,” say the researchers.

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