A functional variant at the miRNA binding site in HMGB1 gene is associated with risk of oral squamous cell carcinoma

Abstract

Oral squamous cell carcinoma (OSCC) is a common malignancy that has been causally associated with both hereditary and acquired factors. The high mobility group box 1 (HMGB1) gene plays an important role as a DNA chaperone to help maintain nuclear homeostasis. Altered expression of HMGB1 has been implicated in a wide range of pathological processes, including inflammation and cancer. The present study explores the impact of HMGB1 gene polymorphisms, combined with environmental risks regarding susceptibility to oral tumorigenesis. Four single-nucleotide polymorphisms (SNPs) of the HMGB1 gene, rs1412125, rs2249825, rs1045411, and rs1360485, were evaluated in 1,200 normal controls and 772 patients with OSCC. We found an association between the wild-type allele of rs1045411 and genotypes CT and CT/TT (AOR=0.754, 95% CI=0.582-0.978 and AOR=0.778, 95% CI=0.609-0.995, respectively). Additionally, bioinformatics analysis was used to characterize the functional relevance of these variants for the miRNA-505-5p binding site and transcriptional regulation by the HMGB1 3’-UTR and promoter regions. Moreover, in considering behavioral exposure to environmental carcinogens, the presence of the four HMGB1 SNPs, combined with/without betel quid chewing and smoking showed, profoundly synergistic effects on the risk of OSCC. In conclusion, we present a potential clinical relevance for HMGB1 variants in OSCC, as well as associations between HMGB1 polymorphisms, haplotypes and environmental risk factors. The finding may help in development of optimal therapeutic approaches for OSCC patients.

Single Nucleotide Polymorphisms in HMGB1 Correlate with Lung Cancer Risk in the Northeast Chinese Han Population

“…Although polymorphism rs1360485 could not change the sequence of HMGB1 protein, it might regulate transcription process of HMGB1 or other gene. A series of studies have reported the association between polymorphisms rs1412125 or rs1360485 and the risk of cancers such as oral squamous cell carcinoma [ 27 ], hepatocellular carcinoma [ 31 ], uterine cervical neoplasia [ 33 ], colorectal cancer [ 34 ] as well as the lung cancer chemotherapy response [ 37 ]. Lin et al conducted a study to verify the association between four SNPs (rs1412125, rs2249825, rs1045411, and rs1360485) in HMGB1 and the risk of oral squamous cell carcinoma (OSCC).…”

“…Lin et al conducted a study to verify the association between four SNPs (rs1412125, rs2249825, rs1045411, and rs1360485) in HMGB1 and the risk of oral squamous cell carcinoma (OSCC). They found that only the rs1045411 polymorphism could affect the risk of OSCC while other three SNPs might not be related to the susceptibility to OSCC [ 27 ]. Wu’s study showed an association of SNPs of HMGB1 with the risk of susceptibility to uterine cervical neoplasia for Taiwanese women.…”

“…It also involves in the cell survival and death by participating in the apoptosis, immune response as well as the autophagy in tumor progression [ 8 , 9 , 10 , 11 ]. In recent studies, HMGB1 has been proved to be related to the tumor development such as gastric carcinoma [ 12 ], colorectal carcinoma [ 13 , 14 ], pancreatic carcinoma [ 15 ], glioma [ 16 ], thymic epithelial tumors [ 17 ], non-Hodgkin lymphoma [ 18 ], breast cancer [ 19 ], cervical carcinoma [ 20 ], lung cancer [ 21 , 22 , 23 ], hepatocellular carcinoma [ 24 , 25 ] as well as oral cancer [ 26 , 27 ].…”

The Impact of HMGB1 Polymorphisms on Prostate Cancer Progression and Clinicopathological Characteristics

“…Moreover, HMGB1 was suggested as a novel target for potential therapeutics since highly expressed HMGB1 was found to be associated with the epithelial-to-mesenchymal transition (EMT) and the overexpression of MMP-1, MMP-3, and MMP-10 via the RAGE/NF-κB signaling pathways, facilitating prostate cancer metastasis [ 1 , 16 , 17 , 18 , 19 , 20 ]. Furthermore, polymorphisms of HMGB1 have been associated with many cancers, including oral squamous cell carcinoma (OSCC) [ 21 , 22 ], lung cancer [ 23 , 24 , 25 , 26 ], breast cancer [ 27 , 28 , 29 ], gastric cancer [ 30 ], hepatocellular carcinoma (HCC) [ 31 , 32 ], and colorectal cancer (CRC) [ 33 ], and it was suggested that the SNPs of HMGB1 may provide a potential biomarker for predicting cancer risk, tumor development, or chemotherapy responses [ 21 , 25 , 27 , 31 ]. However, the impact of HMGB1 polymorphisms on prostate cancer susceptibility and clinicopathologic characteristics has remained uninvestigated.…”

Polymorphisms in four microRNAs and risk of oral squamous cell cancer: a meta-analysis

“…Numerous studies have aimed to explore and uncover risk factors for developing OSCC. Genetic variation was highlighted in previous studies as a potential risk factor [ 4 , 5 ].…”