Ruixia Wang

Genetic Variations in Key MicroRNA Processing Genes and Risk of Head and Neck Cancer: A Case-Control Study in Chinese Population

MicroRNAs (miRNAs) have been reported to play a key role in oncogenesis. Genetic variations in miRNA processing genes and miRNA binding sites may affect the biogenesis of miRNA and the miRNA-mRNA interactions, hence promoting tumorigenesis. In the present study, we hypothesized that potentially functional polymorphisms in miRNA processing genes may contribute to head and neck cancer (HNC) susceptibility. To test this hypothesis, we genotyped three SNPs at miRNA binding sites of miRNA processing genes (rs1057035 in 3′UTR of DICER, rs3803012 in 3′UTR of RAN and rs10773771 in 3′UTR of HIWI) with a case-control study including 397 HNC cases and 900 controls matched by age and sex in Chinese. Although none of three SNPs was significantly associated with overall risk of HNC, rs1057035 in 3′UTR of DICER was associated with a significantly decreased risk of oral cancer (TC/CC vs. TT: adjusted OR  = 0.65, 95% CI  = 0.46–0.92). Furthermore, luciferase activity assay showed that rs1057035 variant C allele led to significantly lower expression levels as compared to the T allele, which may be due to the relatively high inhibition of hsa-miR-574-3p on DICER mRNA. These findings indicated that rs1057035 located at 3′UTR of DICER may contribute to the risk of oral cancer by affecting the binding of miRNAs to DICER. Large-scale and well-designed studies are warranted to validate our findings.

Association of TLR2 and TLR4 polymorphisms with risk of cancer: a meta-analysis.

Backgrounds The activation of Toll-like receptors (TLRs) may be an important event in the immune evasion of tumor cell. Recently, numerous studies have investigated the associations between TLR2 −196 to −174 del and two SNPs of TLR4 (rs4986790 and rs4986791) and the susceptibility to different types of cancer; however, the results remain conflicting. The aim of this study was to assess the association between TLR2 and TLR4 polymorphisms and cancer risk in a meta-analysis with eligible published studies. Methodology/Principle Findings A dataset composed of 14627 cases and 17438 controls from 34 publications were included in a meta-analysis to evaluate the association between overall cancer risk or cancer-specific risk and three SNPs of TLRs (TLR2 −196 to −174 del, TLR4 rs4986790 and rs4986791). The results showed that all of these three polymorphisms were significantly associated with the increased cancer risk (dominant model: OR = 1.64, 95% CI: 1.04–2.60 for TLR2 −196 to −174 del; OR = 1.19, 95% CI: 1.01–1.41 for TLR4 rs4986790; and OR = 1.47, 95% CI: 1.120–1.80 for TLR4 rs4986791; respectively). In stratified analysis, we found the effect of TLR2 −196 to −174 del on cancer risk remained significant in the subgroup of Caucasians and South Asians, but not in East Asians. However, the association between rs4986791 and cancer risk was significant in both South Asians and East Asians, but not in Caucasians. Furthermore, the association between rs4986790 and cancer risk was statistically significant in digestive cancers (dominant model: OR = 1.76, 95% CI: 1.13–2.73) and female-specific cancers (dominant model: OR = 1.50, 95% CI: 1.16–1.94). However, no significant association with risk of digestive system cancers was observed for TLR2 −196 to −174 del and TLR4 rs4986791. Conclusions/Significance This meta-analysis presented additional evidence for the association between TLR2 and TLR4 polymorphisms and cancer risk. Further well-designed investigations with large sample sizes are required to confirm this conclusion.

Different levels in alcohol and tobacco consumption in head and neck cancer patients from 1957 to 2013.

Objective To provide a precise quantification of the association between alcohol and tobacco consumption trends in head and neck cancer patients over the past 45 years. Methods We combined findings from all studies published until March 2014 and evaluated the association between different levels in alcohol and tobacco consumption and head and neck cancers through a meta-analytic approach. Results We included 28 studies involving 13830 patients with head and neck cancer. In patients with alcohol consumption, the pooled odds ratio (OR) and 95% confidence interval (CI) were 1.29(1.06-1.57), 2.67(2.05-3.48) and 6.63(5.02-8.74) for light drinkers, moderate drinkers and heavy drinkers, respectively. In patients with tobacco consumption, the pooled OR and 95% CI were 2.33(1.84-2.95), 4.97(3.67-6.71) and 6.77(4.81-9.53) for light smokers, moderate smokers and heavy smokers, respectively. Conclusion The increased alcohol and tobacco consumption trends increased the risk of head and neck cancer over the past 45 years. Tobacco consumption was found to be a stronger risk factor for head and neck cancer than alcohol consumption. Thus, the control should be considered to limit the intake of alcohol and tobacco.

Genetic variants in let-7/Lin28 modulate the risk of oral cavity cancer in a Chinese Han Population

Let-7 and Lin28 establish a double-negative feedback loop to affect several biological processes, such as differentiation of stem cell, invasion and metastasis, and tumorigenesis. In this study, we systematically investigated the associations between 6 potentially functional SNPs of let7 and Lin28 genes and the risk of oral cavity cancer with a case-control study including 384 oral cavity cancer cases and 731 controls. We found that the variant allele (T) of rs221636 of Lin28B was significantly associated with a reduced risk of oral cavity cancer [odds ratio (OR) = 0.73, 95% confidence interval (CI) = 0.58–0.92, P = 7.55 × 10−3 in additive model]. Bioinformatics prediction indicated that rs221636 was located at the binding site of hsa-miR-548p in the 3′ UTR of Lin28B. Luciferase activity assay also showed a lower expression level for rs221636 T allele compared with A allele. These findings indicated that rs221236 located at Lin28B may contribute to the risk of oral cavity cancer through the interruption of miRNA binding.

Genetic variants at 4q23 and 12q24 are associated with head and neck cancer risk in China.

A recent genome‐wide association study (GWAS) reported significant associations of several novel genetic variants with risk of upper aerodigestive tract (UADT) cancers including head and neck cancer (HNC) in Europeans. However, these findings have not been confirmed in other populations including Chinese. According to the findings from the GWAS and other publications, we genotyped six genetic variants (rs1494961, rs1229984, rs1789924, rs971074, rs4767364, and rs671) in a case–control study with 397 HNC cases and 900 controls in China, by using the TaqMan allelic discrimination assay. We found that rs1229984 at 4q23 significantly increased the risk of HNC [dominant model: adjusted odds ratio (OR) = 1.34, 95% confidence interval (CI) = 1.05–1.71; additive model: adjusted OR = 1.24, 95% CI = 1.04–1.50], while rs671 at 12q24 significantly decreased the risk of HNC (recessive model: adjusted OR = 0.46, 95% CI = 0.25–0.85). Furthermore, when these two loci were evaluated together by the number (0–4) of putative risk alleles (rs1229984 G and rs671 G), a significant locus–dosage effect was found between the groups and risk of HNC (Ptrend = 0.016). Compared with the “0–1” group, groups with “2” risk alleles and “3–4” risk alleles significantly increased the risk of HNC with adjusted ORs of 1.17 (95% CI = 0.84–1.64) and 1.51 (95% CI = 1.06–2.15), respectively. However, no significant association was detected between other four variants (rs1494961, rs1789924, rs971074, and rs4767364) and HNC risk. These findings suggest that rs1229984 at 4q23 and rs671 at 12q24 may serve as candidate markers for susceptibility to HNC in Chinese population.

Lentivirus-mediated RNA interference of E2F-1 suppresses Tca8113 cell proliferation.

In most types of human cancer, inactivation of pRb/E2F complexes occurs, and released E2Fs initiate transcription of genes required for cell cycle progression. Evidence reveals that phosphorylated pRb deregulates E2F-1, and the levels of E2F-1 expression can accurately predict prognosis of oral squamous cell carcinoma (OSCC). Paradoxically, numerous reports indicate that E2F-1 is also capable of inducing apoptosis under certain cellular circumstances. In the present study, lentivirus-mediated shRNA was used to downregulate endogenous E2F-1 expression in order to study the function of E2F-1 in the pRb/E2F-1 pathway in the OSCC cell line Tca8113, and to investigate the alteration of Tca8113 cells in proliferation and apoptosis. The data from real-time quantitative RT-PCR and Western blot analysis showed that E2F-1-shRNA led to the inhibition of endogenous E2F-1 mRNA and protein expression, and E2F-1 may be associated with proliferation and apoptosis pathways. Growth kinetics data showed that Tca8113-E2F-1-shRNA cells presented more active proliferation properties than Tca8113-NC cells, and flow cytometry data demonstrated that the percentages of cells in the G1 phase, G2 phase and undergoing apoptosis differed between groups. In conclusion, silencing of E2F-1 inhibits proliferation and induces apoptosis. E2F-1 may also be involved in multi-level regulation networks; therefore, its role in OSCC requires further clarification.

Association between BRCA1 P871L polymorphism and cancer risk: evidence from a meta-analysis

Breast cancer 1 (BRCA1) gene makes great contributions to the repair of DNA. The association between BRCA1 P871L polymorphism and cancer risk has been investigated in a growing number of studies, but the conclusions are not conclusive. To obtain a comprehensive conclusion, we performed a meta-analysis of 24 studies with 13762 cases and 22388 controls. The pooled results indicated that BRCA1 gene P871L variant decreased risk of overall cancer (homozygous model: odds ratio (OR) = 0.89, 95%confidence interval (CI) = 0.79-1.00; recessive model: OR = 0.89, 95% CI = 0.80-0.99). The stratified analysis observed decreased risk associated with BRCA1 P871L in subgroups among Asians and high score studies, but not Caucasians or low score studies. In conclusion, despite several limitations, this meta-analysis suggested that BRCA1 P871L genetic variation may be associated with decreased susceptibility to cancer.

Meta-analysis of phospholipase C epsilon 1 polymorphism and cancer risk.

BACKGROUND Phospholipase C epsilon 1 (PLCE1) plays crucial roles in carcinogenesis and progression of several cancers. A single nucleotide polymorphism (SNP, rs2274223) in PLCE1 has been identified as a novel susceptibility locus. METHODS To evaluate the role of the Phospholipase C epsilon 1 (PLCE1) polymorphism in cancer susceptibility. We performed a meta-analysis of all available studies, including 8,689 cases and 10,794 controls to derive a more precise relationship. An odds ratio (OR) with a 95% confidence interval (CI) was applied to assess the association between PLCE1 rs2274223 polymorphism and cancer risk. RESULTS A total of 14 case-control studies were included in the present meta-analysis. Overall significant associations were observed (AG vs. AA: OR=1.17, 95%CI=1.04-1.31; GG vs. AA: OR=1.32, 95%CI=1.06-1.66; AG/GG vs. AA: OR=1.19, 95%CI=1.05-1.34; G vs. A: OR=1.16, 95%CI=1.04-1.29) in all cancer types. In the subgroup analysis, PLCE1 rs2274223 polymorphism was significantly increased risk of cancer in Chinese population by ethnicity and upper aerodigestive tract cancer by cancer types. CONCLUSIONS Our meta-analysis suggested the PLCE1 rs2274223 might act as a cancer risk factor among all subjects, especially in the Chinese population and upper aerodigestive tract cancer.

Genetic variants in lncRNA H19 are associated with the risk of oral squamous cell carcinoma in a Chinese population

To evaluate whether the genetic variants in H19 influence the risk of oral squamous cell carcinoma (OSCC) in a Chinese population, a case-control study was conducted to analyze four functional single nucleotide polymorphisms (SNPs) in H19. The cohort comprised of 444 OSCC cases and 984 healthy controls, and the study further evaluated the biological effect by bioinformatics prediction and functional experiments. Two SNPs, rs217727 and rs2839701, were found to be associated with the risk of OSCC [rs217727: odds ratio (OR) = 1.32, 95% confidence interval (CI) = 1.11–1.58, P = 0.002; rs2839701: OR = 1.23, 95% CI = 1.04–1.46, P = 0.019].Bioinformatics predicted that rs2839701 C>G might alter the secondary structure of H19. In addition, rs2839701 C>G inhibited the transcription activity and was correlated with the decreased expression of downstream gene MRPL23-AS1 that was downregulated in OSCC. The current results suggested that the SNPs in H19 may play a major role in genetic susceptibility to OSCC.

Genetic variants at 6p21.1 are associated with head and neck cancer in Chinese Han population.

BACKGROUND A recent study synthesized several published genome-wide association studies (GWAS) on three types of cancers and identified variants at 6p21.1 and 7p15.3 as candidate susceptibility loci for multiple types of human cancers. However, the role of these loci in the development of head and neck cancer (HNC) is still unclear. METHODS To evaluate the relationships between genetic variants in these regions and HNC risk, we genotyped two common SNPs rs2494938 at 6p21.1 and rs2285947 at 7p15.3 in a case-control study with a total of 503 HNC cases and 900 controls in Han Chinese. RESULTS We found that rs2494938 at 6p21.1 was associated with a significantly increased risk of HNC in our population [AA vs. GG: adjusted odds ratio (OR)=1.84, 95% confidence interval (CI)=1.13-3.00, P=0.014; AAvs. GA/GG adjusted OR=1.78, 95% CI=1.10-2.87, P=0.018]. However, no significant association was observed between rs2285947 at 7p15.3 and HNC risk. CONCLUSION Our results suggest that genetic variants at 6p21.1 may play an important role in HNC development in Han Chinese, and rs2494938 may be a candidate marker for HNC susceptibility.