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PDF file, 22K, Analysis of miR-146a rs2910164 polymorphism association with non-muscle invasive bladder cancer patients' recurrence, stratified by selected variables.

PDF, 18K, Quantitative real-time PCR was used to measure the levels of mature miR-146a expression in transected T24 and EJ cells.

PDF file, 21K, Key information on the 14 selected miRNA polymorphisms.

PDF file, 21K, Primers and probes for genotype screening by TaqMan allelic discrimination.

PDF file, 22K, Stratified analysis of the association between miR-146a rs2910164 and risk of bladder cancer.

PDF file, 21K, Clinical characteristics of 64 bladder cancer tissue samples.

PDF file, 17K, Association between miR-146a rs2910164 and expression of mature miR-146a.

PDF file, 44K, The position of rs2910164 in the miRNA-146a. Sequences for mature miRNA are shown in red, and the position of the SNP in the miRNA is underlined.

PDF file, 73K, Stratification analyses of associations between miR-146a rs2910164 and bladder cancer risk.

Supplemental Methods and References, Supplemental Tables S1-S10, Supplemental Figures S1-S11

PDF file, 25K, The position of rs2910164 in the miRNA-146a.

PDF file, 355K, Primary information in miRNA SNPs.

PDF file, 27K.

Backgroud Ginsenoside compound K (GK) is a major metabolite of protopanaxadiol-type ginsenosides and has remarkable anticancer activities in vitro and in vivo. This work used an ionic cross-linking method to entrap GK within O-carboxymethyl chitosan (OCMC) nanoparticles (Nps) to form GK-loaded OCMC Nps (GK–OCMC Nps), which enhance the aqueous solubility and stability of GK. Methods The GK–OCMC Nps were characterized using several physicochemical techniques, including x-ray diffraction, transmission electron microscopy, zeta potential analysis, and particle size analysis via dynamic light scattering. GK was released from GK–OCMC Nps and was conducted using the dialysis bag diffusion method. The effects of GK and GK–OCMC Nps on PC3 cell viability were measured by using the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide assay. Fluorescent technology based on Cy5.5-labeled probes was used to explore the cellular uptake of GK–OCMC Nps. Results The GK–OCMC NPs had a suitable particle size and zeta potential; they were spherical with good dispersion. In vitro drug release from GK–OCMC NPs was pH dependent. Moreover, the in vitro cytotoxicity study and cellular uptake assays indicated that the GK–OCMC Nps significantly enhanced the cytotoxicity and cellular uptake of GK toward the PC3 cells. GK–OCMC Nps also significantly promoted the activities of both caspase-3 and caspase-9. Conclusion GK–OCMC Nps are potential nanocarriers for delivering hydrophobic drugs, thereby enhancing water solubility and permeability and improving the antiproliferative effects of GK.

Recently N6-Methyladenosine (m6A) has been identified to guide the interaction of RNA-binding protein hnRNP C and their target RNAs, which is termed as m6A-switches. We systematically investigated the association between genetic variants in m6A-switches and bladder cancer risk. A two-stage case–control study was performed to systematically calculate the association of single nucleotide polymorphisms (SNPs) in 2798 m6A-switches with bladder cancer risk in 3,997 subjects. A logistic regression model was used to assess the effects of SNPs on bladder cancer risk. A series of experiments were adopted to explore the role of genetic variants of m6A-switches. We identified that rs5746136 (G > A) of SOD2 in m6A-switches was significantly associated with the reduced risk of bladder cancer (additive model in discovery stage: OR = 0.80, 95% CI 0.69–0.93, P = 3.6 × 10−3; validation stage: adjusted OR = 0.88, 95% CI 0.79–0.99, P = 3.0 × 10−2; combined analysis: adjusted OR = 0.85, 95% CI 0.78–0.93, P = 4.0 × 10−4). The mRNA level of SOD2 was remarkably lower in bladder cancer tissues than the paired adjacent samples. SNP rs5746136 may affect m6A modification and regulate SOD2 expression by guiding the binding of hnRNP C to SOD2, which played a critical tumor suppressor role in bladder cancer cells by promoting cell apoptosis and inhibiting proliferation, migration and invasion. In conclusion, our findings suggest the important role of genetic variants in m6A modification. SOD2 polymorphisms may influence the expression of SOD2 via an m6A-hnRNP C-dependent mechanism and be promising predictors of bladder cancer risk.

Recurrent pregnancy loss (RPL) rates have continued to rise during the last few decades, yet the underlying mechanisms remain poorly understood. An emerging area of interest is the mediation of gene expression by DNA methylation during early pregnancy. Here, genome‐wide DNA methylation from placental villi was profiled in both RPL patients and controls. Subsequently, differentially expressed genes were analysed for changes in gene expression. Many significant differentially methylated regions (DMRs) were identified near genes dysregulated in RPL including PRDM1. Differentially expressed genes were enriched in immune response pathways indicating that abnormal immune regulation contributes to RPL. Integrated analysis of DNA methylome and transcriptome demonstrated that the expression level of PRDM1 is fine‐tuned by DNA methylation. Specifically, hypomethylation near the transcription start site of PRDM1 can recruit other transcription factors, like FOXA1 and GATA2, leading to up‐regulation of gene expression and resulting in changes to trophoblast cell apoptosis and migration. These phenotypic differences may be involved in RPL. Overall, our study provides new insights into PRDM1‐dependent regulatory effects during RPL and suggests both a mechanistic link between changes in PRDM1 expression, as well as a role for PRDM1 methylation as a potential biomarker for RPL diagnosis.

We compared the accuracy of magnetic resonance (MR) urethrography and X-ray urethrography with operative findings for urethral strictures and observed their effects on treatment. A total of 87 male patients (10–85 years of age) treated from January 2015 to December 2016 were included in the study. X-ray and MR urethrograms were performed for all patients to determine the location, length, and degree of urethral strictures and the organizational structure around the urethra, and the results were compared with the operative findings. One-way analysis of variance (ANOVA) was performed to compare the lengths of the urethral strictures determined by the two methods with the operative findings. A value of P

Recently N

Background: Bladder cancer (BC) is one of the most common malignant tumors in the urinary system. Long non-coding RNA (lncRNA) plays an important role in BC. Methods: LINC00662 expression was identified by quantitative real-time polymerase chain reaction (qPCR) and in situ hybridization (ISH). The effect of LINC00662 on cell proliferation, apoptosis, migration and invasion was measured by CCK8 assay, colony formation assay, transwell assay, and western blot. Dual-luciferase reporter gene assay, RNA pull-down and RIP assay confirm the interaction between LINC00662 and miR-195-5p/VEGFA. The in vivo effect of LINC00662 on BC was investigated using a mouse tumorigenicity model. Results: LINC00662 was overexpressed in BC tissues and cell lines, and negatively correlated with the survival of BC patients. Overexpression of LINC00662 promoted proliferation, migration and invasion and inhibited apoptosis of BC cells, and LINC00662 knockdown abrogated this effect. Silencing LINC00662 inhibited BC growth in a subcutaneous BC tumor mouse model. LINC00662 acted as an oncogene through regulating miR-195-5p/VEGFA axes. Decreased VEGFA expression caused by LINC00662 knockdown inhibited the phosphorylation of Raf-1, MEK1/2, and ERK1/2, while this regulation effect was abrogated by miR-195-5p inhibitor. Conclusion: LINC00662 regulated the proliferation, apoptosis, migration, and invasion of BC cells probably via miR-195-5p-mediated VEGFA/Ras/Raf/MEK/ERK signaling pathway.

Background: Bladder cancer (BCa) is a common and deadly disease. Over the past decade, a number of genetic alterations have been reported in BCa. Bladder urothelium expresses abundant urea transporter UT-B encoded by Slc14a1 gene at 18q12.3 locus, which plays an important role in preventing high concentrated urea-caused cell injury. Early genome-wide association studies (GWAS) showed that UT-B gene mutations are genetically linked to the urothelial bladder cancer. Methods: In this study, using a fluorescence in situ hybridization (FISH), we examined whether Slc14a1 gene has been changed in BCa with Slc14a1 break-apart DNA probes. We also performed immunohistochemistry evaluating bladder cancer markers. Results: We found Slc14a1 gene rearrangement in one case of BCa from 14 patients. The patient is a 59-year-old male with superficial BCa. Histology showed non-muscle invasive bladder transitional-cell carcinoma. Immunostaining was negative for Syn, CK7, CK20, Villin, and positive for HER2, BRCA1, GATA3. Conclusions: We for the first time report a patient diagnosed with urothelial carcinoma accompanied with split Slc14a1 gene abnormality, a crucial gene in bladder.

Background Particulate matter (PM) exposure is closely associated with male infertility. Even though an association between poor semen quality and PM exposure has been widely accepted, which and when the semen parameter could be affected are still controversial. The purpose of this study is to estimate the effects of PM exposure on semen quality in Huai'an, China. Objectives and methods The study included 1955 men with 2073 semen samples between 2015 and 2017 with moderate to high exposure to air pollution in Huai'an, China. Three multivariable linear regression models were used to conduct exposure-response analyses for PM exposure and semen quality and to estimate the influence during different exposure periods by every 15 days period before ejaculation in all participants group and normal semen quality participants group. Results The average age of the observations was 28.9 ± 5.4 old years and the average abstinence period was 4.2 ± 1.5 days. The results showed high correlations between both PM2.5 and PM10 exposures throughout entire spermatogenesis and the declines of sperm count (β: -0.93, p Conclusion The present study revealed that ambient PM exposure throughout spermatogenesis during a long period, especially at early and middle stage were adversely associated with semen quality, sperm count and sperm concentration in particular.

20(S)-ginsenoside Rh2 (Rh2), a well-known protopanaxadiol-type ginsenoside from Panax ginseng has especially gained attention for its anticancer activities on various types of human cancer cells. However, the molecular mechanism through which Rh2 promotes apoptosis in hepatocellular carcinoma (HePG2) cells is not known at the transcriptome level. Rh2 can specifically inhibit the proliferation of HePG2 in a dose- and time-dependent manner. Moreover, Rh2 can significantly increase the apoptosis which was related with an increase in protein expression levels of caspase-3, caspase-6, and poly (ADP-ribose) polymerase. Comparison of RNA-seq transcriptome profiles from control group and Rh2-treated group yielded a list of 2116 genes whose expression was significantly affected, which includes 971 up-regulated genes and 1145 down-regulated genes. The differentially expressed genes in p53 signaling pathway and DNA replication may have closely relationships to the cells apoptosis caused by Rh2 treatment. The results of qPCR validation showed that dynamic changes in mRNA, such as CDKN1A, CCND2, PMAIP1, GTSE1, and TP73.

Glycolysis, through anaerobic respiration, can supply energy for human sperm motility. MicroRNAs (miRNAs) could participate in the glycolytic pathway through regulating target genes. To investigate the potential role of glycolysis-related miRNAs in asthenozoospermia, TaqMan Low Density Array (TLDA) was used to screen potentially functional miRNAs, and seven glycolysis-related miRNAs were isolated to be related to asthenozoospermia. After qRT-PCR validation, only one seminal plasma miRNA, let-7b-5p, was found significantly decreased in severe asthenozoospermia cases compared with healthy controls. To further understand whether let-7b-5p is involved in asthenozoospermia by regulating the glycolytic pathway, we carried out gain-and-loss function study of let-7b-5p in GC-2 cells and detected the glycolytic activities. Our results showed that knocking down let-7b-5p could inhibit glycolytic activities. Besides, we also found overexpressed Aurkb (a target gene of let-7b-5p) could recapitulate the effects of knocking down let-7b-5p. Our findings indicated that low expression of let-7b-5p could repress glycolysis in asthenozoospermia by targeting AURKB.

In this study, we aim at investigating the expression and regulation role of long non-coding RNA (lncRNA) DLX6-AS1 in bladder cancer (BC). DLX6-AS1 was highly expressed in BC tissues and significant negative correlation with the 5-year survival in the BC patients. The results showed that the proliferation, migration and invasion activities of BC cells were promoted by DLX6-AS1 overexpression, while cell apoptosis was repressed. However, knockdown DLX6-AS1 presented an pposite regulatory effect, and DLX6-AS1 knockdown delayed tumor in vivo. The potential target of DLX6-AS1 in BC was predicted and verified by RIP, RNA pull-down, and dual-luciferase reporter assays as miR-195-5p. The results showed that miR-195-5p was down-regulated in BC tissues, the expression of which was significantly negative correlated with DLX6-AS1 expression. In addition, the results also showed that miR-195-5p targeted and down-regulated the VEGFA. Knockdown of DLX6-AS1 up-regulated miR-195-5p expression and down-regulated VEGFA expression. Moreover, down-regulation of VEGFA expression caused by DLX6-AS1 inhibited phosphorylation of Raf-1, MEK1/2, and ERK1/2, while miR-195-5p inhibitors abolished the effect of silencing DLX6-AS1 expression. Our study demonstrated that DLX6-AS1 played an oncogenic role in BC through miR-195-5p-mediated VEGFA/Ras/Raf/MEK/ERK pathway.

Bladder cancer (BCa) is a common urinary tract malignancy with frequent recurrences after initial resection. Submucosal injection of gemcitabine prior to transurethral resection of bladder tumor (TURBT) may prevent recurrence of urothelial cancer. However, the underlying mechanism remains unknown. In the present study, ultra-performance liquid chromatography Q-Exactive mass spectrometry was used to profile tissue metabolites from 12 BCa patients. The 48 samples included pre- and post-gemcitabine treatment BCa tissues, as well as adjacent normal tissues. Principal component analysis (PCA) revealed that the metabolic profiles of pre-gemcitabine BCa tissues differed significantly from those of pre-gemcitabine normal tissues. A total of 34 significantly altered metabolites were further analyzed. Pathway analysis using MetaboAnalyst identified three metabolic pathways closely associated with BCa, including glutathione, purine and thiamine metabolism, while gluta-thione metabolism was also identified by the enrichment analysis using MetaboAnalyst. In search of the possible targets of gemcitabine, metabolite profiles were compared between the pre-gemcitabine normal and post-gemcitabine BCa tissues. Among the 34 metabolites associated with BCa, the levels of bilirubin and retinal recovered in BCa tissues treated with gemcitabine. When comparing normal bladder tissues with and without gemcitabine treatment, among the 34 metabolites associated with BCa, it was observed that histamine change may be associated with the prevention of relapse, whereas thiamine change may be involved in possible side effects. Therefore, by employing a hypothesis-free tissue-based metabolomics study, the present study investigated the metabolic signatures of BCa and found that bilirubin and retinal may be involved in the mechanism underlying the biomolecular action of submucosal injection of gemcitabine in urothelial BCa.

Genome-wide association studies (GWAS) of bladder cancer have identified a number of susceptibility loci in European populations but have yet to uncover the genetic determinants underlying bladder cancer incidence among other ethnicities. Therefore, we performed the first GWAS in a Chinese cohort comprising 3,406 cases of bladder cancer and 4,645 controls. We identified a new susceptibility locus for bladder cancer at 5q12.3, located in the intron of CWC27 (rs2042329), that was significantly associated with disease risk (OR = 1.40; P = 4.61 × 10−11). However, rs2042329 was not associated with bladder cancer risk in patients of European descent. The rs2042329 risk allele was also related to significantly increased expression levels of CWC27 mRNA and protein in bladder cancer tissues from Chinese patients. Additional functional analyses suggested that CWC27 played an oncogenic role in bladder cancer by inducing cell proliferation and suppressing apoptosis. In conclusion, the identification of a risk-associated locus at 5q12.3 provides new insights into the inherited susceptibility to bladder cancer in Chinese populations and may help to identify high-risk individuals. Cancer Res; 76(11); 3277–84. ©2016 AACR.

The first genome-wide association study (GWAS) for bladder cancer has identified a susceptibility locus at 3q28 in the European ancestry. However, the causal variant at 3q28 remains unknown. We conducted a three-stage fine mapping study to identify potential causal variants in the region. A total of 41 single nucleotide polymorphisms (SNPs) across 120 kb at 3q28 were tested for association with bladder cancer risk among 3,094 bladder cancer cases and 3,738 controls. Resequencing and functional assays were further evaluated. The SNP rs35592567 in the 3'-UTR of TP63 was consistently associated with bladder cancer risk in all three stages. In the combined analysis, the T allele of rs35592567 was significantly associated with a decreased risk for bladder cancer (OR = 0.82, 95% CI = 0.75-0.90, P = 9.797 × 10(-6) in the additive model). Biochemical assays revealed that the T allele reduced the post-transcriptional levels of TP63 mediated by interfering binding efficiency of miR-140-5p. In addition, overexpression of miR-140-5p inhibited bladder cancer cell proliferation and attenuated cell migration, invasion and G1 cell-cycle arrest. Together, these results suggest that rs35592567 in TP63 may be a novel causal variant contributing to the susceptibility to bladder cancer, which provides additional insight into the pathogenesis of bladder carcinogenesis.

Phytoestrogens (PEs) are naturally occurring chemical constituents of certain plants. The internal PE exposures, mainly from diet, vary among different populations and in different regions due to various eating habits. To investigate the potential relationship between urinary PE levels and idiopathic male infertility and semen quality in Chinese adult males, 608 idiopathic infertile men and 469 fertile controls were recruited by eligibility screening procedures. Individual exposure to PEs was measured using UPLC–MS/MS as spot urinary concentrations of 6 PEs (daidzein, DAI; equol, EQU; genistein, GEN; naringenin, NAR; coumestrol, COU; and secoisolariciresinol, SEC), which were adjusted with urinary creatinine (CR). Semen quality was assessed by sperm concentration, number per ejaculum and motility. We found that exposures to DAI, GEN and SEC were significantly associated with idiopathic male infertility (P-value for trend = 0.036; 0.002; and 0.0001, respectively), while these exposures had stronger association with infertile subjects with at least one abnormal semen parameter than those with all normal semen parameters. Exposures to DAI, GEN and SEC were also related to idiopathic male infertility with abnormal sperm concentration, number per ejaculum and motility (P-value for trend

Much evidence show that over-expression of epidermal growth factor receptor (EGFR) plays an important role in regulating carcinogenesis. Genetic variations in 3' untranslated region (3'UTR) of gene have been reported to affect gene expression by interfering with microRNAs (miRNAs), which are thought to function as either tumour suppressors or oncogenes by binding to their target mRNA. In this study, we investigated the association between the EGFR 3'UTR 774T>C polymorphism and bladder cancer risk. We used the TaqMan technology to genotype this genetic variant in a hospital-based case-control study of 908 bladder cancer patients and 1239 controls in a Chinese population. We found that the 774CC genotype was associated with a statistically significantly increased risk of bladder cancer [adjusted odds ratio = 1.29, 95% confidence interval = 1.05-1.58], compared with the 774TT/TC genotype, and this increased risk was more pronounced among subgroups of age > 65 years, non-smokers and patients' tumour invasive stage. Furthermore, luciferase assays in T24 cell showed that EGFR 3'UTR 774 T to C substitution could increase the expression of EGFR, which was consistent with the association study finding. Additionally, we also provide evidence that 774T>C polymorphism increasing EGFR expression was not regulated by hsa-miR-214 binding. These findings suggested that EGFR 3'UTR 774T>C polymorphism may contribute to susceptibility to bladder cancer.

The nucleotide-excision repair (NER) system is crucial for the removal of bulky DNA adducts during spermatogenesis. Dysfunction of its repair capacity is likely related to the increased susceptibility to DNA damage. In this study, four polymorphisms in NER pathway (XPA(–4) G/A, ERCC1 C8092A, XPD Lys751Gln and XPF Ser835Ser) were selected to evaluate their potential impact on sperm DNA damage and male infertility. Genotypes were determined by PCR-restriction fragment length polymorphism. Sperm DNA damage was evaluated by TdT-mediated dUDP nick-end labelling assay. A case-only study of 620 infertile men found a significant association between XPA(–4) G/A polymorphism and sperm DNA damage. Individuals with the XPA(–4) A allele showed more sperm DNA damage and lower sperm concentration than G allele carriers. Further analysis, including 620 patients and 385 controls, revealed a 1.52-fold risk (95% CI 1.08–2.02) of developing male infertility in the XPA(–4) AA carriers compared with noncarriers. Luciferase assay verified that the promoter with the XPA(–4) A allele had a lower transcriptional activity than that with the G allele. These data provide the first evidence that –4 G/A polymorphism in XPA promoter alters its transcriptional activity and, thus, might contribute to sperm DNA damage and male infertility. Sperm DNA integrity is essential for the accurate transmission of genetic information. To our knowledge, few studies have elucidated the effect of DNA repair gene single-nucleotide polymorphisms on sperm DNA integrity, although the DNA repair system is indispensable in maintaining genetic stability and normal spermatogenesis. In this original study, we evaluated the potential impact of the polymorphisms in the nucleotide-excision repair pathway on the risk of sperm DNA damage based on 620 infertile patients and 385 controls, and provided the first evidence that –4 G/A polymorphism in the promoter for the xeroderma pigmentosum group A gene altered its transcriptional activity, which might contribute to sperm DNA damage and male infertility.

A limited number of studies have suggested that exposure to PAHs may affect reproductive hormones. Subjects (n=642) in this study were from the affiliated hospitals of Nanjing Medical University. Individual exposures to PAHs were measured as spot urinary concentrations of four PAH metabolites, including 1-naphthol (1-N), 2-naphthol (2-N), 2-hydroxyfluorene (2-OF) and 1-hydroxypyrene (1-OP), which were adjusted by urinary creatinine (CR). Blood samples were collected to measure serum levels of reproductive hormones, including follicle-stimulating hormone (FSH), luteotrophic hormone (LH), estradiol (E2), testosterone (T) and prolactin (PRL). All of the subjects had detectable levels of the four metabolites of PAHs in their urine samples. The median concentrations of 1-N, 2-N, 2-OF and 1-OP were 2.440, 4.176, 2.843 and 1.148 microg/g of CR. There were significant P-values between increased CR-adjusted 1-N tertiles and E2 concentration, 2-OF tertiles and LH, FSH level, 1-OP and E2 level. The multivariate linear regression results also showed significant correlation between the levels of serum LH and 1-OP (the adjusting P-value was 0.048), but no correlations were found between other hormones and the level of PAH metabolites. These observed correlations between levels of hydroxy-PAH and some altered hormones indicated slight endocrine effects on adult men with PAH exposure.

Background The FAS/FASLG system has been proposed to play a key role in germ cell apoptosis. To elucidate the role of the genetic variants of cell death pathway genes in male infertility, we genotyped the polymorphisms of FAS, FASLG and caspase-8 (CASP8) genes and evaluated their effects on sperm apoptosis and semen quality in infertile men. Methods The genotypes of FAS, FASLG and CASP8 were determined in 620 infertile men. Sperm apoptosis rates were measured by terminal deoxynucleotidyl transferase (Tdt)-mediated dUTP nick end labelling (TUNEL) assay, and the semen quality analysis was performed using computer assisted sperm analysis. Results We found that polymorphisms of FAS-670A/G (rs1800682: A>G) and CASP8-652 6N ins/del (rs3834129: -/CTTACT) were associated with sperm apoptosis and semen quality. Individuals with FAS-670GG showed low apoptosis rate and decreased sperm concentration, compared with the FAS-670AA genotype. Similarly, in comparison with the CASP8-652 6N ins/ins genotype, the CASP8-652 6N (ins/del+del/del) genotypes also showed significantly decreased sperm apoptosis rate and poor sperm motility. Other polymorphisms investigated did not appear to affect sperm apoptosis and semen quality. Conclusions This study showed for the first time that functional variants of FAS and CASP8 might contribute to the dysfunctional apoptotic mechanism in germ cells, which could result in poor semen quality of ejaculated sperm.

Death receptor 4 (DR4) is an important mediator of apoptosis, and its dysfunction may be related to carcinogenesis and cancer development. We hypothesized that common variants in the DR4 gene are associated with risk of bladder cancer and test this hypothesis in a case-control study of 368 bladder cancer patients and 368 cancer-free controls. We genotyped six tagging single nucleotide polymorphisms (tagSNPs) in these subjects and found a significantly increased risk of bladder cancer associated with the SNP1-397GT/TT genotype (adjusted OR=1.55; 95% CI=1.15-2.09) compared with the GG genotype. This increased risk was more pronounced for superficial bladder cancer. A luciferase assay, performed in vitro, revealed that the -397T allele had a lower transcriptional activity than the -397G allele. Multifactor dimensionality reduction (MDR) analysis indicated that the two-factor model including -397G>T and pack-years of smoking was best for predicting bladder cancer risk. Moreover, a significant additive (but not multiplicative) interaction, was found between the -397G>T polymorphism and smoking on bladder cancer risk. In conclusion, genetic variants of the DR4 gene may be involved in the etiology of bladder cancer, and our findings need further validation by larger studies.

Objective p53 is a tumor suppressor gene and is involved in the etiology of ovarian cancer. Studies investigating the associations between the p53 codon 72 polymorphism and ovarian cancer risk showed conflicting results. We performed this meta-analysis from eligible studies to evaluate this purported relationship. Methods This meta-analysis was performed from 9 case-control studies, including 825 ovarian cases and 1073 controls. T he fixed and random effect models were used to estimate the odds ratios(ORs) for various contrasts of this polymorphism. Results The combined results based on all studies showed that a significantly decreased risk was associated with the variant Pro/Pro genotype, compared with Arg/Pro+Arg/Arg genotypes(OR, 0.70; 95%CI, 0.51∼0.95). When stratifying the studies by ethnicity, we found that individuals with the variant genotype Pro/Pro had a significantly decreased risk of ovarian cancer compared with Arg/Arg genotype(OR, 0.43; 95%CI, 0.20∼0.89) and Arg/Pro+Arg/Arg genotypes(OR, 0.61; 95%CI, 0.37∼0.99) among Africans. Conclusion This meta-analysis suggests that the p53 codon 72 polymorphism may contribute to genetic susceptibility to ovarian cancer. More studies based on larger sample size should be performed to confirm the findings.

The first genome-wide association study (GWAS) for bladder cancer has identified a susceptibility locus at 3q28 in the European ancestry. However, the causal variant at 3q28 remains unknown. We conducted a three-stage fine mapping study to identify potential causal variants in the region. A total of 41 single nucleotide polymorphisms (SNPs) across 120 kb at 3q28 were tested for association with bladder cancer risk among 3,094 bladder cancer cases and 3,738 controls. Resequencing and functional assays were further evaluated. The SNP rs35592567 in the 3'-UTR of TP63 was consistently associated with bladder cancer risk in all three stages. In the combined analysis, the T allele of rs35592567 was significantly associated with a decreased risk for bladder cancer (OR = 0.82, 95% CI = 0.75-0.90, P = 9.797 × 10(-6) in the additive model). Biochemical assays revealed that the T allele reduced the post-transcriptional levels of TP63 mediated by interfering binding efficiency of miR-140-5p. In addition, overexpression of miR-140-5p inhibited bladder cancer cell proliferation and attenuated cell migration, invasion and G1 cell-cycle arrest. Together, these results suggest that rs35592567 in TP63 may be a novel causal variant contributing to the susceptibility to bladder cancer, which provides additional insight into the pathogenesis of bladder carcinogenesis.

Recent genome-wide association studies have identified 14 genetic variants associated with bladder cancer in Caucasians. The effects of these risk variants and their cumulative effects in Asian populations are unknown. We genotyped these newly identified variants in a case-control study of 1,050 patients diagnosed with bladder cancer and 1,404 controls in the Chinese population. Odds rations (ORs) and 95% confidence intervals (CIs) were computed by logistic regression, and cumulative effect of risk alleles were evaluated. Overall, seven of the 14 variants were significantly associated with bladder cancer risk (p = 9.763 × 10(-3) for rs9642880 at 8q24.21, p = 3.004 × 10(-3) for rs2294008 at 8q24.3, p = 0.012 for rs798766 at 4p16.3, p = 0.034 for rs1495741 at 8p22, p = 2.306 × 10(-4) for GSTM1, p = 8.507 × 10(-8) for rs17674580 at 18q12.3, p = 7.179 × 10(-4) for rs10936599 at 3q26.2) and the odds ratios (ORs) ranged from 1.13 to 1.65. Moreover, there were a significant increased risk for bladder cancer positively correlated numbers of risk alleles and smoking status (Ptrend = 7.060 × 10(-16) ). However, no allelic interaction effects on bladder cancer risk were observed between cumulative effects of variants and clinical characteristics. These findings suggest that seven bladder cancer risk-associated variants (rs9642880, rs2294008, rs798766, rs1495741, GSTM1 null, rs17674580 and rs10936599) may be used, collectively, to effectively measure inherited risk for bladder cancer.

PURPOSE: miRNAs can regulate the biological processes, including differentiation, proliferation and apoptosis. DICER and DROSHA are two members of RNase III family, playing pivotal roles in the pathway of miRNAs biogenesis. In this study, we hypothesized that genetic variations of the DICER and DROSHA genes were associated with the bladder cancer risk. EXPERIMENTAL DESIGN: We performed a case-control study of 685 bladder cancer cases and 730 controls to investigate the association between the seven functional SNPs of DICER and DROSHA genes and bladder cancer risk. We then evaluated the functionality of the important SNPs. RESULTS: We found that rs10719T>C polymorphism located in 3' untranslated region (UTR) of DROSHA gene was associated with the increased risk of bladder cancer. Stratified analysis suggested that rs10719TC/CC genotype can increase risk of bladder cancer among male patients (Adjusted OR = 1.34, 95% CI = 1.05-1.70, P = 0.018), and ever smokers (1.56, 1.14-2.14, 0.006), compared with TT genotype. Furthermore, DROSHA rs10719T>C polymorphism was predicted to regulate the binding activity of hsa-miR-27a/b. Luciferase reported gene assay confirmed that rs10719 T to G substitution disrupted the binding site for hsa-miR-27b, resulting the increased levels of DROSHA protein. CONCLUSIONS: Taken together, these findings suggested that DROSHA rs10719T>C polymorphism may be associated with bladder cancer risk in a Chinese population, and hsa-miR-27b can influence the expression of DROSHA protein by binding with 3'UTR.

Widespread human exposure to phenols has been documented recently, and some phenols which are potential endocrine disruptors have demonstrated adverse effects on male reproduction in animal and in vitro studies. However, implications about exposure to phenols and male infertility are scarce in humans. Case-control study of 877 idiopathic infertile men and 713 fertile controls was conducted. Urinary levels of bisphenol A, benzophenone-3, pentachlorophenol, triclosan, 4-tert-octylphenol (4-t-OP), 4-n-octylphenol (4-n-OP) and 4-n-nonylphenol (4-n-NP) and semen parameters were measured. After multivariate adjustment, we found 4-t-OP, 4-n-OP and 4-n-NP exposure was associated with idiopathic male infertility (p-value for trend

miRNAs play important roles in numerous cellular processes, including development, proliferation, apoptosis, and carcinogenesis. Because altered expression and function of miRNAs has been observed in bladder cancer, we investigated whether genetic variations in miRNAs are associated with bladder cancer risk and prognosis. Using bioinformatics tools, we selected five single-nucleotide polymorphisms located in miRNAs and used these to evaluate miRNA–disease associations in a two-stage model, consisting of 1,019 bladder cancer cases and 1,182 controls (683 cases and 728 controls in the training set and 336 cases and 454 controls in the test set). We found that miR-146a rs2910164 C allele was associated with significantly decreased risk of bladder cancer in both the training and test sets, as well as the combined set [OR = 0.80, 95% confidence interval (CI) = 0.71–0.90, P = 2.92 × 10−4]. Furthermore, the rs2910164 GC/CC genotypes conferred a significantly reduced risk of recurrence, compared with the GG genotype (P = 0.016). Functional analysis revealed that miR-146a rs2910164 C allele inhibited cell proliferation and significantly downregulated expression of IRAK1 and TRAF6 in bladder cancer cells. Additional examination of 64 bladder cancer tissues showed that individuals carrying the C allele had increased expression levels of miR-146a compared with those carrying the G allele (P = 0.010). Taken together, our findings show that miR-146a rs2910164 plays an important role in the risk and recurrence of bladder cancer, suggesting it may represent a biomarker for risk prevention and therapeutic intervention. Further larger and prospective cohorts are needed to validate our findings. Cancer Res; 72(23); 6173–82. ©2012 AACR.

Caspase-8 (CASP8) plays a key role in apoptosis. We examined by genotyping whether the −652 six-nucleotide insertion-deletion (6N ins/del) polymorphism in the CASP8 promoter region was associated with prostate cancer risk in a hospital-based case-control study of 406 Chinese prostate cancer patients and 408 age-matched cancerfree controls. Additionally, 23 prostate cancer tissues were analyzed for CASP8 mRNA expression. We found a significantly decreased prostate cancer risk for the 6N ins/del genotype [adjusted odds ratio ( OR )=0.68; 95% confidence interval ( CI )=0.51-0.92] and del/del genotype ( OR =0.34; 95% CI =0.19-0.63) compared with the ins/ins genotype. The 6N del allele was associated dose-dependently with decreased prostate cancer risk ( P trend = 0.001). RT-PCR showed that individuals with the 6N del allele had lower CASP8 mRNA levels than those with the ins/ins genotype ( P = 0.024). These findings suggested that the CASP8 -652 6N ins/del polymorphism may affect the susceptibility to prostate cancer and reduce prostate cancer risk among Chinese men.

DNA damaged by exposure to exogenous and endogenous carcinogens could be removed effectively by the base excision repair pathway, in which the XRCC1, APE1, and ADPRT genes play a key role. Genetic variations in these important genes may alter repair function and contribute to cancer risk. We hypothesized that XRCC1, APE1, and ADPRT polymorphisms are associated with risk of bladder cancer. In a hospital-based case-control study of 234 patients with bladder cancer and 253 cancer-free controls, we genotyped the XRCC1-77TC, Arg194Trp, Arg280His, Arg399Gln, APE1-656TG, Asp148Glu, ADPRT-442GA, and Val762Ala polymorphisms using polymerase chain reaction-restriction fragment length polymorphism method. We found an increased risk of bladder cancer associated with the XRCC1 194Trp/Trp and 280Arg/His genotypes (adjusted odds ratio = 3.90, 95% confidence interval = 1.69-8.98 for 194Trp/Trp and 2.53, 1.67-3.83 for 280Arg/His) compared with the 194Arg/Arg and 280Arg/Arg genotypes, respectively. In contrast, the APE1-656GG genotype was associated with a decreased risk of bladder cancer (0.57, 0.33-0.98) compared with the TT genotype. When we evaluated these eight polymorphisms together, we found that the combined genotypes with 9-13 variant (risk) alleles were associated with an increased risk of bladder cancer (2.25, 1.48-3.40) compared with those with 3-8 variants. These findings suggest that the XRCC1 and APE1 polymorphisms may contribute to susceptibility to bladder cancer. Larger studies are warranted to verify these findings.

Objective To evaluate the effects of polycyclic aromatic hydrocarbon (PAH) exposure and four functional genetic polymorphisms in the nucleotide excision repair pathway, alone or combined, on sperm DNA integrity and male fertility. Design Retrospective case-only and case-control study. Setting One university and three centers of clinical reproductive medicine in the Jiangsu Province of China. Patient(s) Six hundred twenty infertile men and 273 controls were recruited for the study. Intervention(s) None. Main Outcome Measure(s) Exposure to PAHs was detected as urinary 1-hydroxypyrene level. Genotypes were determined by polymerase chain reaction–restriction fragment length polymorphism, and sperm DNA damage was detected by terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate nick end labeling assay with use of flow cytometry. Result(s) Increased sperm DNA damage was found to be associated significantly with increased urinary concentrations of 1-hydroxypyrene. We also observed that the xeroderma pigmentosum group A (XPA)-4 G/A polymorphism was associated with sperm DNA damage. Subjects homozygous for XPA-4 AA had significantly more sperm DNA damage compared with subjects for XPA-4 GG. Moreover, on the basis of a case-control study, a significant interaction was found between XPA-4 G/A polymorphism and PAH exposures on the sperm DNA damage risk (odds ratio=2.86, 95% confidence interval=1.77–4.61). Conclusion(s) We provide the first evidence for potential gene-environment interactions between nucleotide excision repair polymorphisms and PAH exposure on the sperm DNA damage and male factor infertility in men with no occupational exposure to PAHs.

A recent genome-wide association study identified two common variants that confer susceptibility to bladder cancer. We hypothesized that these variants are associated with risk of bladder cancer in Chinese populations. We genotyped rs9642880 G>T on 8q24 and rs710521 A>G on 3q28 in a two-stage case-control study of bladder cancer to evaluate the association and further examined the expression of MYC. We found that the rs9642880 G>T, but not the rs710521 A>G polymorphism, was associated with an increased risk of bladder cancer. Compared with the rs9642880 GG genotype, the GT/TT genotypes were associated with an odds ratio of 1.65 (95% confidence interval = 1.25-2.17), and this risk was more pronounced in young men and for low-risk tumors. Additional experiments revealed that the rs9642880 GT/TT genotypes were associated with enhanced levels of both MYC mRNA and protein in bladder tissues. Our findings suggested that the rs9642880 G>T polymorphism on 8q24 was independently associated with the risk of bladder cancer in Chinese populations.

BACKGROUND: Limited studies have suggested that male reproductive function might be associated with exposure to polycyclic aromatic hydrocarbons (PAHs). METHODS: Five hundred and thirteen idiopathic infertile male subjects and 273 fertile males as controls were recruited in this study, through eligibility screening procedures. Individual exposures to PAHs were measured as spot urinary concentrations of four PAH metabolites, including I-hydroxynaphthalene (I-N), 2-hydroxynaphthalene (2-N), I-hydroxypyrene (I-OHP) and 2-hydroxyfluorene (2-OHF), which were adjusted by urinary creatinine (CR). Subjects with idiopathic infertility were further divided into 'normal' and 'abnormal' semen quality groups based on their semen volume, sperm concentration, sperm number per ejaculum and sperm motility. RESULTS: The median CR-adjusted urinary concentrations of I-N, 2-N, I-OHP, 2-OHF and Sum PAH metabolites (sum of all four metabolites) of control group were lower than those found in case groups. Subjects with higher urinary concentrations of I -OHP, 2-OHF and Sum PAH metabolites (assessed as tertiles) were more likely to have idiopathic male infertility (P-value for trend = 0.034, 0.022 and 0.022, respectively). Comparing the two groups of idiopathic infertile subjects with different semen quality, a higher idiopathic infertility risk was found in the group with abnormal semen quality. CONCLUSIONS: Increased urinary concentrations of I-OHP, 2-OHF and Sum PAH metabolites were associated with increased male idiopathic infertility risks, while the idiopathic infertile subjects with abnormal semen might be at higher risk.