University of Oulu

Salem, A., Almahmoudi, R., Listyarifah, D. et al. Cell Oncol. (2017) 40: 621.

Histamine H₄ receptor signalling in tongue cancer and its potential role in oral carcinogenesis : a short report

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Author: Salem, Abdelhakim1,2; Almahmoudi, Rabeia2; Listyarifah, Dyah1,2,3;
Organizations: 1Department of Clinical Medicine, Clinicum, University of Helsinki, Helsinki, Finland
2Department of Oral and Maxillofacial Diseases, Clinicum, University of Helsinki, Haartmaninkatu 8, Biomedicum Helsinki 1, PO Box 63, FI-00029 HUS Helsinki, Finland
3Department of Dental Biomedical Sciences, Faculty of Dentistry, Universitas Gadjah Mada, Yogyakarta, Indonesia
4Department of Oral and Maxillofacial Diseases, Kuopio University Hospital, Kuopio, Finland
5Institute of Dentistry, Faculty of Health Sciences, University of Eastern Finland, Joensuu, Finland
6Wihuri Research Institute, Biomedicum Helsinki, Helsinki, Finland
7Cancer and Translational Medicine Research Unit, University of Oulu, Oulu, Finland
8Medical Research Center, Oulu University Hospital, Oulu, Finland
9Department of Rheumatology, Helsinki University and Helsinki University Hospital, Helsinki, Finland
Format: article
Version: accepted version
Access: open
Online Access: PDF Full Text (PDF, 0.1 MB)
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Language: English
Published: Springer Nature, 2017
Publish Date: 2018-06-26


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.

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Series: Cellular oncology
ISSN: 2211-3428
ISSN-E: 2211-3436
ISSN-L: 2211-3428
Volume: 40
Issue: 6
Pages: 621 - 630
DOI: 10.1007/s13402-017-0336-6
Type of Publication: A1 Journal article – refereed
Field of Science: 3122 Cancers
Funding: The authors acknowledge the funders of this study: the Finnish Doctoral Programme in Oral Sciences (FINDOS), the University of Helsinki, Finland; the Allergy Research Foundation (Allergiatutkimussäätiö); the Sigrid Juselius Foundation; the Finnish Cancer Society; the Oulu University Hospital MRC-grant and the Helsinki University Central Hospital research funds, Finland.
Copyright information: © International Society for Cellular Oncology 2017. This is a post-peer-review, pre-copyedit version of an article published in Cellular Oncology. The final authenticated version is available online at: