4.6 Article

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

Journal

AGING-US
Volume 14, Issue 10, Pages 4500-4512

Publisher

IMPACT JOURNALS LLC

Keywords

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

Funding

  1. TMU Research Center of Cancer Translational Medicine from The Featured Areas Research Center Program by the Ministry of Education (MOE) in Taiwan
  2. Taipei Medical UniversityWan Fang Hospital [110-phd-03]

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This study investigated the association between genetic variants of HRH1 and OSCC susceptibility and clinicopathologic variables. The results showed that certain genotypes of HRH1 were associated with a lower risk of developing larger tumor sizes, especially in patients with a betelquid-chewing habit. Furthermore, HRH1 expression levels were upregulated in OSCC tissues and correlated with tumor sizes and prognoses.
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 betelquid-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.

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