Combined impacts of histamine receptor H1 gene polymorphisms and an environmental carcinogen on the susceptibility to and progression of oral squamous cell carcinoma

Abstract

Oral squamous cell carcinoma (OSCC) is the most frequently encountered type of oral cancer. Histamine receptor H1 (HRH1) was reported to play a crucial role in OSCC carcinogenesis, but impacts of genetic variants of HRH1 on OSCC remain unclear. Herein, we investigated the association between functional single-nucleotide polymorphisms (SNPs) of HRH1 and OSCC susceptibility or clinicopathologic variables by logistic regression models. HRH1 genotypes at four loci (rs346074, rs346076, rs901865, and rs2606731) were analyzed by a TaqMan allelic discrimination assay, and we found that patients harboring HRH1 rs901865 T and rs346074 T alleles had a significantly lower risk of developing larger tumor sizes (>T2) under a dominant model. Based on the environmental carcinogen exposure status, we observed that HRH1 rs901865 polymorphic variants were also associated with a lower risk of developing more-advanced clinical stages (III or IV) in patients with a betel-quid-chewing habit. Moreover, genotype screening of rs901865 and rs346074 in OSCC cell lines showed that cells respectively carrying the CT and TT genotypes expressed lower HRH1 levels compared to cells carrying the CC genotype of rs901865 and rs346074. Furthermore, analyses of TCGA and GEO databases revealed that HRH1 expression levels were upregulated in head and neck squamous cell carcinoma (HNSCC) and OSCC tissues compared to normal tissues and were correlated with larger tumor sizes and poorer prognoses. These results indicated the involvement of HRH1 SNPs rs901865 and rs346074 in OSCC development and support the interaction between HRH1 gene polymorphisms and an environmental carcinogen as a predisposing factor for OSCC progression.

Keywords: histamine H1 receptor; oral squamous cell carcinoma; progression; single-nucleotide polymorphisms; susceptibility.

Figure 1

Clinical relevance of histamine receptor H1 (HRH1) levels in head and neck squamous cell carcinoma (HNSCC) or oral squamous cell carcinoma (OSCC) patients obtained from TCGA and GEO databases. (A, B) HRH1 expression was higher in HNSCC tissues (A) and OSCC tissues (B) than in normal tissues (database sources: TCGA and GSE78060). (C) HRH1 expression levels in OSCC from GSE78060 were compared according to the tumor size (T stages). (D) Kaplan-Meier curves for overall and disease-specific survival (left panel) and recurrence-free survival (right panel) of patients with HNSCC and OSCC, as categorized according to high or low expression of HRH1. The p value indicates a comparison between patients with HRH1^high and HRH1^low. (database sources: TCGA and GSE31056).

Figure 2

Correlations of histamine receptor H1 (HRH1) rs346074 and rs901865 genotypes with HRH1 protein levels in five oral squamous cell carcinoma (OSCC) cell lines. Upper panel, HRH1 rs346074 or rs901865 genotypes in OSCC cells (SAS, HSC-3M, HSC-3, SCC9, and OECM1) were detected by a TaqMan SNP Genotyping Assay. Lower panel, protein levels of HRH1 were detected by a Western blot analysis using two HRH1-specific antibodies.