Tao Ning

Human papillomavirus 16 E6 oncoprotein interferences with insulin signaling pathway by binding to tuberin.

Tuberous sclerosis complex (TSC) is a genetic disorder caused by mutations in either TSC1 or TSC2 tumor suppressor gene. TSC1 and TSC2 products, Harmatin and Tuberin, form the functional complex to serve as the negative regulator for insulin-induced phosphorylation of S6 kinase and elF4E-binding protein 1. High-risk human papillomavirus (HPV) infection is the necessary cause for cervical cancer. E6 oncoprotein encoded by HPV plays a pivotal role in carcinogenesis by interference with the host intracellular protein functions. In this study, we show that HPV16 E6 interacts with tumor suppressor gene TSC2 product, Tuberin, and results in the phosphorylation of S6 kinase and S6 even in the absence of insulin. The overexpression of Tuberin overcomes the effect of E6 on S6 kinase phosphorylation. Binding with HPV16 E6 causes the proteasome-mediated degradation of Tuberin. A DILG motif and an ELVG motif located in the carboxyl-terminal of Tuberin are required for E6 binding. In addition, the Tuberin interaction region in E6 has been mapped in the amino-terminal portion of HPV16 E6, which is different from the binding domain with p53. These results provide a possible link between E6-induced oncogenesis and the insulin-stimulated cell proliferation signaling pathway.

Association of Cytotoxic T lymphocyte-associated antigen-4 gene haplotype with the susceptibility to gastric cancer.

Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) was widely accepted as a pivotal molecule in downregulating T-cell mediated immune responses. In this study we investigated the polymorphisms which would impact the CTLA-4 gene expression and function to assess the association with the risk of gastric cancer. 205 gastric cancer patients and 262 healthy controls were included in the case-control study. PCR and restriction fragment length polymorphism (RFLP) methods were performed to identify the +49A/G and promoter −1661A/G polymorphisms. The promoter −1772T/C polymorphism was detected by PCR amplification refractory mutation system (ARMS) technique. A significant difference was observed between case and control groups. The frequency of +49A/G polymorphism AG and −1661A/G polymorphism GG genotype were significantly higher in patients than in controls (ORxa0=xa02.15, ORxa0=xa01.88, respectively). No significant difference was found in the allelic frequency of −1772T/C polymorphism between cases and controls (Pxa0=xa00.478). By the haplotype analysis, logistic regression showed the frequency of haplotype A (GAT) and D (AGT) in the case group revealed significant difference compared with in control group(ORxa0=xa02.00, Pxa0<xa00.001; ORxa0=xa01.62, Pxa0=xa00.043, respectively). Our findings implied the genetic variations within CTLA-4 gene would be a critical risk factor to the susceptibility of gastric cancer.

Association of genetic polymorphisms in MDM2, PTEN and P53 with risk of esophageal squamous cell carcinoma

Genetic variations in MDM2, PTEN and P53 might be involved in cancer susceptibility. To assess the contribution of polymorphisms in these three genes to the risk of esophageal squamous cell carcinoma (ESCC) in a Chinese population, we genotyped MDM2 T309G, Del1518, PTEN rs701848, rs2735343 and P53 Arg72Pro polymorphisms using PCR-restriction fragment length polymorphism analysis in 226 ESCC cases and 226 cancer-free controls. Here we showed that the risk of ESCC was elevated in subjects with any of the variant genotypes of PTEN rs2735343 and P53 Arg72Pro polymorphisms, but not any genotype of MDM2 or PTEN rs701848. Moreover, multiplicative interactions were observed between PTEN rs2735343 and P53 Arg72Pro or smoking status on risk of ESCC. Our study firstly indicated that PTEN rs2735343 might be a susceptibility factor for ESCC and reaffirmed the role of P53 Arg72Pro in ESCC in this Chinese population, but did not replicate the positive association between MDM2 T309G and ESCC found previously.

HLA polymorphisms are associated with Helicobacter pylori infected gastric cancer in a high risk population, China

Helicobacter pylori is one of the most common bacterial infections associated with an increased risk of gastric cancer, but its association with host factors, particularly polymorphisms of the immune response genes, such as human leukocyte antigen (HLA) genes, is still unclear. To investigate the role of HLA polymorphisms in the risk of gastric cancer among subjects with H. pylori infection, a case-control study involving 52 gastric cancer patients and 139 non-cancer controls was conducted in Linqu County, China, an area with a high incidence of gastric cancer. Polymorphisms of HLA class I and class II alleles were determined by PCR with sequence-specific primers (PCR-SSP). The information about H. pylori infection was obtained from previous records. Among 48 class I and 19 class II HLA alleles detected in this study, two alleles, CW*03 and DRB1*01, were found to be distributed significantly differently between patients and controls [odds ratio(OR)=1.95, 95% confidence interval (CI)=1.13–3.35, P=0.017 and OR=4.39, 95% CI=1.39–13.84, P=0.012, respectively). The OR of gastric cancer risk in individuals carrying CW*03/CW*03 or CW*03/CW*N was 2.06, 95% CI=1.05–4.02, P=0.035, while the OR was 3.49, 95% CI=1.0–12.4, P=0.04 for DRB1*01/DRB1*01 or DRB1*01/DRB1*N carriers. The analysis of the interaction between H. pylori infection and HLA risk genotypes of CW*03 or DRB1*01 revealed that the effect of CW*03 and DRB1*01 genotypes on gastric cancer risk was manifested stronger in H. pylori-positive individuals (OR=5.30, 95% CI=1.73–16.29, P=0.004 and OR=13.38, 95% CI=2.52–70.98, P=0.002, respectively) than in H. pylori-negative ones (OR=1.25, 95% CI=0.25–6.12, P=0.785 and OR=2.26, 95% CI=0.18–28.88, P=0.531, respectively). The combined effect of the two risk HLA genotypes on gastric cancer risk was also analysed. The result showed that the individuals carrying both the CW*03 and DRB1*01 alleles could only be found in cancer patients (5/52), and not in controls (0/139), further suggesting that CW*03 and DRB1*01 are risk alleles advancing the progression of tumorigenesis. These observations demonstrate that host HLA genotypes may play an important role in the risk of gastric cancer, especially among persons with H. pylori infection.

Genetic polymorphisms of NAMPT related with susceptibility to esophageal Squamous cell carcinoma

BackgroundNicotinamide phosphoribosyl transferase (Nampt) plays a crucial role in tumorigenesis. The present study examines whether genetic polymorphisms of NAMPT are related to the risk of developing esophageal squamous cell carcinoma (ESCC).MethodsA total of 810 subjects were enrolled in this study, including 405 ESCC patients and 405 healthy controls. Using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), genotypes at rs61330082, rs2505568 and rs9034 of NAMPT were identified. Haplotypes were constructed using PHASE software. Multivariate logistic regression models were used to evaluate the potentiating effects of the genotypes, alleles and haplotypes on the development of ESCC.ResultsThe presence of genotypes CT and TT and allele T at rs61330082 was less frequent in ESCC cases than in controls (48.89% vs. 53.33%, Pu2009<u20090.01, 95% CI: 0.33-0.68; 18.52% vs. 30.37%, Pu2009<u20090.01, 95% CI: 0.22-0.50; 42.96% vs. 57.04%, Pu2009<u20090.01, 95% CI: 0.38-0.61; respectively). No statistically significant differences existed in the distributions of genotypes or alleles at rs2505568 or rs9034 between ESCC cases and controls. Of five haplotypes constructed, haplotypes CTC, CTT and CAC were higher in ESCC cases (Pu2009<u20090.01, ORu2009=u20091.57, 95% CI: 1.16-2.12; Pu2009=u20090.04, ORu2009=u20091.72, 95% CI: 1.03-2.85; Pu2009<u20090.01, ORu2009=u20093.39, 95% CI: 1.99-5.75; respectively) than in controls.ConclusionGenetic polymorphisms of NAMPT, specifically genotype CC and allele C at rs61330082 as well as haplotypes CTC, CTT and CAC, were significantly correlated with ESCC susceptibility.