Bingtao Hao

Identification of genetic variants in base excision repair pathway and their associations with risk of esophageal squamous cell carcinoma.

The etiology of esophageal squamous cell carcinoma (ESCC) has been shown to be associated with genetic and certain environmental factors that produce DNA damage. Base excision repair (BER) genes are responsible for repair of DNA damage caused by reactive oxygen species and other electrophiles and therefore are good candidate susceptibility genes for ESCC. We first screened eight BER genes for new and potential functional polymorphisms by resequencing 27 DNA samples. We then identified and genotyped for important tagging single nucleotide polymorphisms (SNPs) in a case-control study of 419 patients with newly diagnosed esophageal cancer and 480 healthy controls by frequency matching on age and sex. The association between genotypes and ESCC risk was estimated by unconditional multivariate logistic regression analysis, and stepwise regression procedure was used for constructing the final logistic regression model. We identified 129 SNPs in the eight BER genes, including 18 SNPs that cause amino acid changes. In the final model, 4 SNPs, including 2 in the coding regions (ADPRT Val762Ala and MBD4 Glu346Lys) and others in noncoding regions (LIG3 A3704G and XRCC1 T-77C), remained as significant predictors for the risk of ESCC. The adjusted odd ratios were 1.25 [95% confidence interval (CI) 1.02–1.53] for the ADPRT 762Ala allele, 1.25 (95% CI 1.02–1.53) for the MBD4 346 Lys allele, 0.78 (95% CI 0.63–0.97) for the LIG3 3704G allele, and 1.38 (95% CI 1.01–1.89) for the XRCC1–77C allele. In addition, we observed a significant gene-gene interaction between XRCC1 Gln399Arg and ADPRT Val762Ala. The results suggest that the polymorphisms in five BER genes may be associated with the susceptibility to ESCC in a Chinese population.

A novel T-77C polymorphism in DNA repair gene XRCC1 contributes to diminished promoter activity and increased risk of non-small cell lung cancer.

X-ray repair cross-complementing 1 (XRCC1) plays a key role in DNA base excision repair and cells lacking its activity are hypersensitive to DNA damage. Recently, we reported a SNP (rs3213245, −77T>C) in the XRCC1 gene 5′ untranslated region (UTR) was significantly associated with the risk of developing esophageal squamous-cell carcinoma. Computer analysis predicted that this SNP was in the core of Sp1-binding motif, which suggested its functional significance. Gel shift and super shift assays confirmed that −77T>C polymorphic site in the XRCC1 promoter was within the Sp1-binding motif and the T>C substitution greatly enhanced the binding affinity of Sp1 to this region. Luciferase assays indicated that the Sp1-high-affinity C-allelic XRCC1 promoter was associated with a reduced transcriptional activity. The association between −77T>C and three other amino-acid substitution-causing polymorphisms in XRCC1 and risk of lung cancer was examined in 1024 patients and 1118 controls and the results showed that only the −77T>C polymorphism was significantly associated with an increased risk of developing lung cancer. Multivariate logistic regression analysis found that an increased risk of lung cancer was associated with the variant XRCC1 −77 genotypes (TC and CC) compared with the TT genotype (OR=1.46, 95% CI=1.18–1.82; P=0.001) and the increased risk was more pronounced in smokers (OR=1.63, 95% CI=1.20–2.21) than in non-smokers (OR=1.28, 95% CI=0.94–1.76). Taken together, these results showed that the functional SNP −77T>C in XRCC1 5′UTR was associated with cancer development owing to the decreased transcriptional activity of C-allele-containing promoter with higher affinity to Sp1 binding.

The G–113A polymorphism in CYP1A2 affects the caffeine metabolic ratio in a Chinese population

This study was designed to better understand genetic variation in the cytochrome P450 (CYP) gene CYP1A2 and its impact on CYP1A2 activity in Chinese subjects.

C-type lectin LSECtin interacts with DC-SIGNR and is involved in hepatitis C virus binding

Hepatitis C virus (HCV) is a major cause of liver disease. However, the detailed mechanism underlying hepatocyte infection with HCV is not yet completely understood. We previously identified a novel C-type lectin—LSECtin predominantly expressed on liver sinusoidal endothelial cells. Here we demonstrate that LSECtin can interact with two HCV receptors, DC-SIGNR and CD81, through its central ectodomain. Furthermore, cells expressing LSECtin specifically can be attached by the naturally occurring HCV in the sera of infected individuals. This binding was found to be mediated by the HCV E2 glycoprotein and could be efficiently inhibited by EGTA but not by mannan treatment. The present study suggests that LSECtin interaction with DC-SIGNR might contribute to HCV binding to liver sinusoidal endothelial cells.

Association of the variable number of tandem repeats polymorphism in the promoter region of the SMYD3 gene with risk of esophageal squamous cell carcinoma in relation to tobacco smoking

The etiology of esophageal squamous cell carcinoma (ESCC) has been shown to be multifactorial, including genetic, epigenetic, and environmental factors, such as tobacco smoking. A variable number of tandem repeats (VNTR) polymorphism in the promoter region of SMYD3, a recently characterized histone lysine methyltransferase gene that is implicated in cell proliferation and carcinogenesis, has been shown to be functional, but its association with cancer risk has not been well established because of apparently discrepant results in different populations. In this case‐control study, we genotyped 567 patients with newly diagnosed ESCC and 567 healthy controls and found an increased ESCC risk (odds ratio [OR] = 1.42, 95% confidence interval [CI] = 1.05–1.91) associated with the common SMYD3 VNTR genotype. Stratification analysis revealed that the increased risk was limited to smokers (OR = 1.99; 95% CI = 1.27–3.12). Furthermore, compared with the reference group of non‐smokers carrying the homozygous or heterozygous genotype, ORs (95% CI) of the wild genotype for non‐smokers, smokers who smoked <25, and ≥25 pack‐years were 1.03 (0.70–1.53), 2.80 (1.66–4.70), and 4.76 (2.67–8.46), respectively (P < 0.001 for trend test), suggesting an interaction between this genetic polymorphism and smoking status. These findings provide additional evidence that the common VNTR polymorphism in the promoter region of SMYD3 gene may be a susceptibility factor for human cancers such as ESCC by interacting with tobacco carcinogens. (Cancer Sci 2008; 99: 787–791)

Ceap/BLOS2 interacts with BRD7 and selectively inhibits its transcription-suppressing effect on cellular proliferation-associated genes

The centrosome associated protein Ceap-16 (also termed BLOS2) can accelerate the proliferation of mouse fibroblast NIH3T3 cells, which mechanism remains unclear. Here we identified tumor suppressor candidate BRD7 (bromodomain containing protein 7), which could negatively regulate cell proliferation and growth, as a novel Ceap-16-interacting protein. Ceap-16 and BRD7 interacted with each other both in vitro and in vivo. The C-terminus of BRD7 and the central region of Ceap-16 mediated the interaction. Through this binding, Ceap-16 could translocate from cytoplasm to the nucleus where it selectively inhibited the transcriptional suppression activity of BRD7 towards certain target genes including E2F3 and cyclin A. Moreover, Ceap-16, BRD7 and histone H3/H4 could form a complex and Ceap-16 did not compete with BRD7 binding to histones. These findings suggest a novel function for Ceap-16 in the transcriptional regulation through associating with BRD7.