RAGE Gene Polymorphism and Environmental Factor in the Risk of Oral Cancer

Abstract

Oral squamous cell carcinoma is a common neoplasm that is known to be causally associated with genetic factors and environmental carcinogens. The receptor for advanced glycosylation endproducts (RAGE) is a transmembrane protein of the immunoglobulin superfamily with broad specificity for multiple ligands, and it has been shown to play vital roles in several pathophysiologic processes, including diabetes, Alzheimer disease, renal disease, cardiovascular disease, and cancer. The present study aimed to assess the influences of RAGE gene polymorphisms, combined with environmental carcinogens on the predisposition to oral tumorigenesis. Five polymorphisms of the RAGE gene—including −374T>A (rs1800624), −429T>C (rs1800625), 1704G>T (rs184003), Gly82Ser (rs2070600), and a 63-bp deletion allele (−407 to −345)—were examined from 592 controls and 618 patients with oral cancer. We found that individuals carrying the polymorphic allele of rs1800625 are more susceptible to oral cancer (odds ratio [OR], 1.899; 95% confidence interval [CI], 1.355 to 2.661; adjusted OR [AOR], 2.053; 95% CI, 1.269 to 3.345) after adjustment for age, sex, betel nut chewing, and tobacco consumption. Moreover, we observed a significant association of rs1800625 variants with late-stage tumors (stage III/IV, OR, 1.736; 95% CI, 1.126 to 2.677; AOR, 1.771; 95% CI, 1.101 to 2.851) and large-size tumors (>2 cm in the greatest dimension; OR, 1.644; 95% CI, 1.083 to 2.493; AOR, 1.728; 95% CI, 1.089 to 2.741). Based on behavioral exposure of environmental carcinogens, the presence of 4 RAGE single-nucleotide polymorphisms (SNPs), combined with betel quid chewing and/or tobacco use, greatly augmented the risk of oral cancer. In addition, carriers of particular haplotypes of the 4 RAGE SNPs examined are more prone to develop oral cancer. These results indicate an involvement of RAGE SNP rs1800625 in the development of oral squamous cell carcinoma and implicate the interaction between RAGE gene polymorphisms and environmental mutagens as a predisposing factor of oral carcinogenesis.

Update on Head and Neck Cancer: Current Knowledge on Epidemiology, Risk Factors, Molecular Features and Novel Therapies

“…Furthermore, a genome-wide association study performed on 8,605 upper aerodigestive cancer cases and 11,405 controls from the INHANCE consortium, identified five polymorphisms implicated in cancer susceptibility: three variants in the ADH gene cluster (rs1573496-ADH7, rs1229984-ADH1B, and rs698-ADH1C) and two variants (rs149496-4q21 and rs4767364-12q24) located near DNA repair genes and ALDH2 gene, respectively [27]. More recently, Su et al [28] have identified four SNPs in the receptor for advanced glycosylation end products (RAGE) gene which in association with betel quid chewing and/or tobacco use conferred increased risk for oral cancer in subjects with particular haplotypes of the 4 RAGE SNPs. These polymorphisms could represent inherited genetic factors which in combination with environmental mutagens may predispose subjects to head and neck cancer.…”

Scavenger Receptors

“…More than 30 gene polymorphisms in RAGE have been identified in multiple cancers, including renal caner, oral cancer, breast cancer, colorectal cancer, lung cancer, ovarian cancer, pancreatic cancer, nasopharyngeal carcinoma, and gastric cancer (Cheng et al, 2005; Chocholaty et al, 2014; Gu et al, 2008; Krechler et al, 2010; Pan et al, 2013; Qian, Sun, Zhang, Ke, & Zhu, 2014; Su, Chien, Lin, Chen, & Yang, 2015; Zhang et al, 2013; Zhou, Deng, Li, Yin, & Ye, 2014). A comprehensive meta-analysis suggested that the 82G/S polymorphism (3374 cancer cases vs. 3757 controls) in the RAGE promoter region is associated with a significantly increased risk of cancer, where −374T/A polymorphism (2936 cancer cases vs. 3,338 control) is associated with a reduced risk of cancer (Xia et al, 2015).…”

Inhibitory effects of Leucaena leucocephala on the metastasis and invasion of human oral cancer cells

“…Oral cancer is a subclass of head and neck cancer with substantial morbidity and mortality, and the worldwide incidence is estimated to be ∼275,000 cases annually . Epidemiological studies have indicated that smoking, betel nut chewing, and alcohol consumption are predominant risk factors triggering oral cancer . Oral cancer possesses high local invasiveness and great metastatic ability in cervical lymph nodes with poor patient prognoses.…”