Abstract

Purpose: Recent reports indicate that histamine and its novel, high-affinity histamine H₄ receptor (H₄R) play a role in carcinogenesis, and thus H₄R signalling has become a focus of increasing interest in the pathogenesis of many cancers. The roles of H₄R in oral epithelial dysplasia (OED) and oral tongue squamous cell carcinoma (OTSCC) are unknown. The purpose of this study was to assess H₄R expression in OTSCC patients and in OTSCC-derived cell lines.

Methods: Biopsies taken from OED, OTSCC and healthy oral mucosa were studied by immunostaining. Primary human oral keratinocytes (HOKs) and two OTSCC-derived cell lines (HSC-3 and SCC-25) were used for the in vitro studies. Quantitative real-time PCR was used to measure oncogene expression in the stimulated HOKs.

Results: We found that H₄R-immunoreactivity was significantly reduced in the OED and OTSCC samples, especially in the samples with higher histopathological grades and noticeably increased mast cell counts. The presence of H₄R in HSC-3 cells had clearly waned, in contrast to the HOKs. Gene expression data indicated that histamine-relevant inflammatory and environmental elements may participate in the regulation of oncogenes.

Conclusions: Our results suggest an association between H₄R and oral carcinogenesis. Furthermore, our findings raise a potential implication of histamine-mediated factors in the regulation of oncogenes, possibly via mast cells, as crucial components of the tumor microenvironment. The identification of new elements that govern oral cancer development is highly relevant for the development of novel therapeutic approaches in OTSCC.