Tianyu Li

Formononetin Promotes Cell Cycle Arrest via Downregulation of Akt/Cyclin D1/CDK4 in Human Prostate Cancer Cells

Background: Formononetin is an O-methylated isoflavone isolated from the root of Astragalus membranaceus. It has already been reported that formononetin could inhibit cell proliferation and induce cell apoptosis in several cancers, including prostate cancer. This study aimed to further investigate whether cell cycle arrest is involved in formononetin-mediated antitumor effect in human prostate cancer cells, along with the underlying molecular mechanism. Methods: Human prostate cancer cells PC-3 and DU145 were respectively treated with various concentrations of formononetin. The inhibitory effect of formononetin on proliferation of prostate cancer cells was determined using MTT assays and flow cytometry. Next, formononetin-induced alterations in cyclin D1, CDK4 and Akt expression in PC-3 cells were detected by real-time PCR and western blot. Results: Formononetin dose-dependently inhibited prostate cancer cell proliferation via the induction of cell cycle arrest at G0/G1 phase in vitro, which was more evident in PC-3 cells. Meanwhile, concomitant with reduced phosphorylation of Akt in PC-3 cells, formononetin remarkably downregulated expression levels of cyclin D1 and CDK4 in a dose-dependent manner. More interestingly, in the in vivo studies, formononetin showed a noticeable inhibition of tumor growth in recipient mice. Conclusion: Formononetin could exhibit inhibitory activity against human prostate cancer cells in vivo and in vitro, which is associated with G1 cell cycle arrest by inactivation of Akt/cyclin D1/CDK4. Therefore, formononetin may be used as a candidate agent for clinical treatment of prostate cancer in the future.

The RTK/ERK pathway is associated with prostate cancer risk on the SNP level: a pooled analysis of 41 sets of data from case-control studies.

Prostate cancer (PCa) is a malignant disease influencing numerous men worldwide every year. However, the exact pathogenesis and the genes, environment, and other factors involved have not been explained clearly. Some studies have proposed that cell signaling pathways might play a key role in the development and progression of PCa. According to our previous study, the RTK/ERK pathway containing nearly 40 genes was associated with PCa risk. On the basis of these genes, we conducted a meta-analysis with our own Chinese Consortium for Prostate Cancer Genetics (ChinaPCa) study and available studies in the databases to describe the association between the pathway and PCa on the SNP level. The results suggested that rs4764695/IGF1 (recessive model: pooled OR=0.92, 95%CI=0.852-0.994, P=0.034; I(2)=0%, P=0.042; allele analysis: pooled OR=0.915, 95%CI=0.874-0.958, P=0; I(2)=0%, P=0.424; codominant model: OR=0.835, 95%CI=0.762-0.916, P=0; I(2)=0%, P=0.684) and rs1570360/VEGF (recessive model: OR=0.596, 95%CI=0.421-0.843, P=0.003; I(2)=23.9%, P=0.269; codominant model: OR=0.576, 95%CI=0.404-0.820, P=0.002; I(2)=49.1%, P=0.140) were significantly associated with PCa. In subgroup analysis, the relationship was also found in Caucasians for IGF1 (dominant model: OR=0.834, 95%CI=0.769-0.904, P=0; allele analysis: OR=0.908, 95%CI=0.863-0.955, P=0; AA vs CC: OR=0.829, 95%CI=0.750-0.916, P=0; AC vs CC: OR=0.837, 95%CI=0.768-0.912, P=0). In addition, in Asians (allele analysis: OR=0.21, 95%CI=0.168-0.262, P=0) and Caucasians (recessive model: OR=0.453, 95%CI: 0.240-0.855, P=0.015; codominant model: OR=0.464, 95%CI=0.240-0.898, P=0.023) for VEGF, the association was significant. The results indicated that rs4764695/IGF1 and rs1570360/VEGF might play a key role in the development and progression of PCa. On the SNP level, we suggest that the study gives us a new view of gene-pathway analysis and targeted therapy for PCa.

Serum Homocysteine Concentration Is Significantly Associated with Inflammatory/Immune Factors.

Recent studies suggest that serum homocysteine (HCY) level is correlated to inflammatory/immune factors that influence the development and progression of many diseases, such as cardiovascular disease. However, the association between serum HCY level and inflammatory/immune factors in healthy populations has not been systematically investigated. This study was conducted based on the Fangchenggang Area Male Health and Examination Survey (FAMHES) project. After comprehensive baseline analysis, we could not find any significant association between HCY level and inflammatory/immune factors. However, in the next linear regression analysis, serum C4 [age-adjusted: Beta = -0.053, 95%CI = (-3.798, -0.050), P = 0.044; multivariate adjusted: Beta = -0.064, 95%CI = (-4.271, -0.378), P = 0.019] and C-reactive protein (CRP) concentration [unadjusted: Beta = 0.056, 95%CI = (0.037, 0.740), P = 0.030] were positively related with HCY. In further binary regression analysis, a significant correlation was confirmed for C4 and HCY [age-adjusted: OR = 0.572, 95%CI = (0.359, 0.911); multivariate adjusted: OR = 0.558, 95%CI = (0.344, 0.905)]. In order to discover more potential associations, multivariate logistic regression analysis was applied and suggested that HCY and C4 were significantly correlated [age-adjusted: OR = 0.703, 95%CI = (0.519, 0.951); multivariate adjusted: OR = 0.696, 95%CI = (0.509, 0.951)]. In addition, immunoglobulin M (IgM) may influence the HCY level to some extent [unadjusted: OR = 1.427, 95%CI = (1.052, 1.936); age-adjusted: OR = 1.446, 95%CI = (1.061, 1.970); multivariate adjusted: OR = 1.447, 95%CI = (1.062, 1.973)]. Combining our results with recent studies, we propose that C4, CRP, and IgM in serum are significantly associated with HCY concentration. Further studies are needed on the mechanism of the interaction, especially among cardiovascular disease subjects.

RTK/ERK Pathway under Natural Selection Associated with Prostate Cancer

Prostate cancer (PCa) is a global disease causing large numbers of deaths every year. Recent studies have indicated the RTK/ERK pathway might be a key pathway in the development of PCa. However, the exact association and evolution-based mechanism remain unclear. This study was conducted by combining genotypic and phenotypic data from the Chinese Consortium for Prostate Cancer Genetics (ChinaPCa) with related databases such as the HapMap Project and Genevar. In this analysis, expression of quantitative trait loci (eQTLs) analysis, natural selection and gene-based pathway analysis were involved. The pathway analysis confirmed the positive relationship between PCa risk and several key genes. In addition, combined with the natural selection, it seems that 4 genes (EGFR, ERBB2, PTK2, and RAF1) with five SNPs (rs11238349, rs17172438, rs984654, rs11773818, and rs17172432) especially rs17172432, might be pivotal factors in the development of PCa. The results indicate that the RTK/ERK pathway under natural selection is a key link in PCa risk. The joint effect of the genes and loci with positive selection might be one reason for the development of PCa. Dealing with all the factors simultaneously might give insight into prevention and aid in predicting the success of potential therapies for PCa.

X-ray repair cross-complementing group 1 (XRCC1) Arg399Gln polymorphism significantly associated with prostate cancer.

Prostate cancer (Pca) is one of the noncutaneous cancers occurring worldwide. Its high morbidity and mortality make it a concern. X-ray repair cross-complementing group 1 (XRCC1) Arg399Gln polymorphism (rs25487) has been reported to be related to Pca. However, the conclusions are controversial. In this study, PubMed, HuGENet and Chinese National Knowledge Infrastructure (CNKI) databases were combined with a comprehensive literature search. Four models including dominant (AA + AG vs. GG), recessive (AA vs. AG+GG), codominant (AA vs. AG, AA vs. GG) and per-allele analysis (A vs. G) were applied. Finally, 15 studies with 18 sets of data were included. A positive association was discovered in pooled results for recessive (odds ratio [OR]=1.202, 95% confidence interval [95% CI], 1.060-1.363, I2=46.20%), codominant (AA vs. AG; OR=1.258, 95% CI, 1.099-1.439, I2=38.50%; AA vs. GG; OR=1.283, 95% CI, 1.027-1.602, I2=51.70%) and allele analysis (OR=1.116, 95% CI, 1.001-1.244, I2=58.00%). In ethnicity subgroup analysis, these 4 models were also significant in the Asian subgroup. However, for whites, only 2 models seemed to be significant (AA vs. AG+GG: OR=1.525, 95% CI, 1.111-2.093, I2=52.60%; AA vs. AG: OR=1.678, 95% CI, 1.185-2.375, I2=30.70%). In further analysis, we regrouped the data based on race, in which pooled results and Asian subgroup were again shown to be positive. In the next analysis, expression quantitative trait loci (eQTL), linkage disequilibrium (LD), TagSNP and functional analysis were used. The results showed that the SNP was a tag and functional SNP with LD block in both Asians and whites. In summary, we suggest that XRCC1 Arg399Gln might be significantly associated with development of Pca.

hOGG1 C1245G gene polymorphism associated with prostate cancer: a meta-analysis.

Background Prostate cancer (Pca) is one of the most frequently encountered multifactorial malignant diseases worldwide. The human oxoguanine glycosylase 1 (hOGG1) C1245G polymorphism (rs1052133) has been found to be associated with Pca. However, the conclusions have been controversial. Methods Based on the PubMed, Embase, HuGENet and Chinese National Knowledge Infrastructure (CNKI) databases, this meta-analysis was conducted with 4 models. Eleven qualified studies were included. Results Although no positive relation was discovered in the pooled analysis, significant associations between rs1052133 and Pca were found in the Asian population (recessive: odds ratio [OR] = 1.580, 95% confidence interval [95% CI], 1.189-2.098; GG vs. GC: OR = 1.504, 95% CI, 1.114-2.030; GG vs. CC: OR = 1.677, 95% CI, 1.201-2.342; allele analysis: OR = 1.249, 95% CI, 1.077-1.449), whites (dominant: OR = 2.138, 95% CI, 1.483-3.083; recessive: OR = 3.143, 95% CI, 1.171-8.437; GG vs. CC: OR = 3.992, 95% CI, 1.891-8.431; allele analysis: OR = 1.947, 95% CI, 1.467-2.586) and mixed populations (recessive: OR = 0.636, 95% CI, 0.484-0.834; GG vs. GC: OR = 0.654, 95% CI, 0.492-0.871; GG vs. CC: OR = 0.624, 95% CI, 0.473-0.823; allele analysis: OR = 0.857, 95% CI, 0.771-0.954). After excluding studies deviating from the Hardy-Weinberg equilibrium, a significant association was also found in the same ethnic groups. In addition, a new positive relation was identified in the “other country” subgroup (with China, South Korea and Australia included) (dominant: OR = 1.622, 95% CI, 1.163-2.261; recessive: OR = 1.773, 95% CI, 1.308-2.404; GG vs. GC: OR = 1.614, 95% CI, 1.169-2.230; GG vs. CC: OR = 2.108, 95% CI, 1.456-3.051; allele analysis: OR = 1.494, 95% CI, 1.235-1.808) and among the Chinese-Korean population. Conclusions In conclusion, we suggest that the hOGG1 C1245G polymorphism might be potentially associated with Pca risk in different ethnicities and countries, especially among Asians. Further studies are needed to confirm these relations.

The prevalence of and risk factors for prostatitis-like symptoms and its relation to erectile dysfunction in Chinese men.

The aim of this study was to describe the prevalence of and risk factors for prostatitis‐like symptoms and its relation to erectile dysfunction (ED) among southern Chinese men. Data were collected from 2790 men attending the Fangchenggang Area Male Healthy and Examination Survey from September 2009 to December 2009. The prostatitis‐like symptoms were assessed by the NIH Chronic Prostatitis Symptom Index and ED was assessed using the 5‐item International Index of Erectile Function. Lifestyle and demographic characteristics were obtained through a questionnaire. Prevalence of prostatitis‐like symptoms was 12.4% among 2790 Chinese men aged 20–84 years. In smokers who smoked ≥20 cigarettes per day (age‐adjusted OR = 1.29; 95% CI = 1.00–1.66; p = 0.04), physical inactivity (age‐adjusted OR = 1.31; 95% CI = 1.03–1.66; p = 0.02) was a significant risk factor for prostatitis‐like symptoms. Alcohol consumption (daily drinking) also was a risk factor for prostatitis‐like symptoms, although the differences were not statistically significant (age‐adjusted OR = 1.36; 95% CI = 0.96–1.92; p = 0.07). Those with diabetes may also be at higher risk for prostatitis‐like symptoms (age‐adjusted OR = 1.37; 95% CI = 0.85–2.21; p = 0.19). In addition, men with ED were more likely to have had prostatitis‐like symptoms (age‐adjusted OR = 1.86; 95% CI = 0.47–2.36; p < 0.0001), and the ORs increased with increasing severity of ED status (mild ED, mild to moderate ED, and moderate to severe ED were 1.57, 2.62, and 3.24, respectively. Test for trend, p = 0.0001). Our results show that prostatitis‐like symptoms are prevalent in Southern China affecting men of all ages. Smoking, drinking, lack of physical activity, and elevated plasma glucose level were associated with an increased risk of prostatitis‐like symptoms. In addition, our results reveal that ED accounted for a large proportion (61.5%) among men with prostatitis‐like symptoms; we also confirm the magnitude of ED associated with prostatitis‐like symptoms. Thus, interventions to evaluate and improve ED might help ameliorate prostatitis‐like symptoms and vice versa.

Comparative analyses of fecal microbiota in Chinese isolated Yao population, minority Zhuang and rural Han by 16sRNA sequencing

The gut microbiome in humans is associated with geography, diet, lifestyles and so on, but its relationship with some isolated populations is not clear. We used the 16sRNA technique to sequence the fecal microbiome in the Chinese isolated Yao population and compared it with the major minority Zhuang and the major ethnic Han populations living in the same rural area. Information about diet frequency and health status and routine serum measurements were collected. The unweighted UniFrac principal coordinates analysis showed significant structural differences in fecal microbiota among the three ethnic groups. Statistically significant differences were observed in the community richness estimator (chaos) and the diversity estimator (Shannon) among the three groups. At the genus level, the fecal samples of the isolated Yao population presented the lowest relative abundance of the Megamonas genus, which was potentially related to the high frequency of bean consumption in the diet. Two enterotypes were identified in the overall fecal microbiota in the three populations. In the isolated Yao population, a higher Bacteroides abundance was observed, but the Prevotella abundance decreased with increased alcohol consumption.

Promoter DNA methylation analysis reveals a combined diagnosis of CpG-based biomarker for prostate cancer

BACKGROUND Prostate cancer (PCa) is the most common tumor in elderly men. However, the specificity and sensitivity of serum prostate-specific antigen levels in PCa diagnosis are controversial. This study aims to reveal a novel diagnosis biomarker in PCa. MATERIALS AND METHODS The differential methylated CpG sites between 423 primary PCa and 39 adjacent samples from The Cancer Genome Atlas (TCGA) on Illumina HumanMethylation 450 platform were analyzed. The diagnostic methylation markers were mined using the Prediction Analysis of Microarrays package in Bioconductor. Then, the Gene Expression Omnibus data was used for verification. Pyrosequencing was applied to improve methylation levels of five CpGs (cg06363129, cg08843517, cg05385513, cg07220448 and cg11417025). RESULTS The area under curve of receiver operating characteristic of eight diagnostic methylation CpGs (cg06363129, cg08843517, cg03576469, cg05385513, cg07220448, cg11417025, cg20883831, and cg23824801) in TCGA data ranged from 0.910 to 0.939. Except for cg20883831 and cg23824801, the correlations between methylation levels of six other sites and their expressions in patients were significant (r > 0.5 and P < 0.001). The methylation level of cg06363129 was significantly different between the groups of Gleason Score (GS) = 7 and GS ≥ 8 (P < 0.05). Pyrosequencing in our samples confirmed that four diagnostic methylation sites (cg06363129, cg08843517, cg05385513, and cg11417025) had high diagnostic efficacy. CONCLUSIONS The combined diagnosis of four methylation CpGs sites (cg06363129, cg08843517, cg05385513, and cg11417025) in the gene promoter has high tissue specificity and diagnostic efficacy for PCa. Results revealed a novel potential biomarker for prostate cancer diagnosis.Background Prostate cancer (PCa) is the most common tumor in elderly men. However, the specificity and sensitivity of serum prostate-specific antigen levels in PCa diagnosis are controversial. This study aims to reveal a novel diagnosis biomarker in PCa. Materials and Methods The differential methylated CpG sites between 423 primary PCa and 39 adjacent samples from The Cancer Genome Atlas (TCGA) on Illumina HumanMethylation 450 platform were analyzed. The diagnostic methylation markers were mined using the Prediction Analysis of Microarrays package in Bioconductor. Then, the Gene Expression Omnibus data was used for verification. Pyrosequencing was applied to improve methylation levels of five CpGs (cg06363129, cg08843517, cg05385513, cg07220448 and cg11417025). Results The area under curve of receiver operating characteristic of eight diagnostic methylation CpGs (cg06363129, cg08843517, cg03576469, cg05385513, cg07220448, cg11417025, cg20883831, and cg23824801) in TCGA data ranged from 0.910 to 0.939. Except for cg20883831 and cg23824801, the correlations between methylation levels of six other sites and their expressions in patients were significant (r > 0.5 and P < 0.001). The methylation level of cg06363129 was significantly different between the groups of Gleason Score (GS) = 7 and GS ≥ 8 (P < 0.05). Pyrosequencing in our samples confirmed that four diagnostic methylation sites (cg06363129, cg08843517, cg05385513, and cg11417025) had high diagnostic efficacy. Conclusions The combined diagnosis of four methylation CpGs sites (cg06363129, cg08843517, cg05385513, and cg11417025) in the gene promoter has high tissue specificity and diagnostic efficacy for PCa. Results revealed a novel potential biomarker for prostate cancer diagnosis.

Significant association of catechol-O-methyltransferase Val158Met polymorphism with bladder cancer instead of prostate and kidney cancer.

Background Urological cancers occur worldwide. Many factors, among which the catechol-O-methyltransferase (COMT) Val158Met polymorphism, are said to be associated with the cancer risk. We conducted a meta-analysis to investigate the association between urological cancer susceptibility and COMT Val158Met in different genetic models. Methods This study was based on material obtained from the PubMed, HuGENet and Embase databases. Four models including dominant (AA + AG vs. GG), recessive (AA vs. AG + GG), codominant (AA vs. AG, AA vs. GG) and per-allele analysis (A vs. G) were applied. Odds ratios (OR) and the corresponding 95% confidence intervals (CI) were used to evaluate the power of the associations. Results Fourteen eligible studies comprising 3,285 cases and 3,594 controls were included. Although we could not detect a positive function of the COMT Val158Met polymorphism in urological cancers, the polymorphism might be significantly associated with bladder cancer risk (dominant model [AA + AG vs. GG]: OR = 0.736, 95% CI = 0.586-0.925, I2 = 0.00%; recessive model [AA vs. AG + GG]: OR = 0.822, 95%CI = 0.653-1.035, I2 = 6.30%; codominant model [AA vs. AG]: OR = 0.908, 95% CI = 0.710-1.161, I2 = 0.00%; codominant model [AA vs. GG]: OR = 0.693, 95% CI = 0.524-0.917, I2 = 30.20%; allele analysis [A vs. G]: OR = 0.826, 95%CI = 0.717-0.951, I2 = 30.20%). The same significant associations were not found for kidney cancer and prostate cancer risk in different ethnicities. There also seemed to be no distinct effect of the polymorphism on benign prostatic hyperplasia. Conclusions We suggest that bladder cancer but not prostate cancer and kidney cancer could be significantly associated with the Val158Met polymorphism. Interaction of COMT genetic and related environmental factors for urological cancers should not be ignored in future.