The expression of miR-375 in prostate cancer: A study based on GEO,TCGA data and bioinformatics analysis

BackgroundMiR-375, as a member of miRNA family, plays essential roles in prostate cancer (PC). We purpose to explore the expression and possible molecular mechanism of the miR-375 in PC using database analysis.MethodsFirst, Student’s t-test, overall and subgroup meta-analyses with 20 eligible datasets in the Gene Expression Omnibus (GEO) database were performed to explore the expression of miR-375 in PC. Then the results of meta-analyses were verified in The Cancer Genome Atlas (TCGA) database by Student’s t-test and Paired t-test. The candidate genes of miR-375 were predicted by four platforms. Protein-protein interaction (PPI) networks, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed to investigate the potential molecular mechanism of miR-375 in PC.ResultsThe overall meta-analysis showed the expression of miR-375 was significantly up-regulated in PC groups compared with non-cancerous group (SMD; 0.71; 95% CI: 0.38–1.04). In addition, the meta-analyses by subgroup showed the expression of miR-375 in PC tissues was higher than that in healthy prostate tissues and adjacent non-cancerous tissues. The results of TCGA database verified the expression of miR-375 in PC tissues was obviously higher than that in adjacent non-cancerous tissues. Moreover, GO and KEGG analysis revealed that the latent target genes were mainly involved in protein binding function and ubiquitin mediated proteolysis. PPI analysis identified JAK2, EHMT1 and QKI as the hub genes (highly connected genes with high degree in PPI).ConclusionsMiR-375 was up-regulated in PC tissues. Meanwhile, miR-375 may play an important role in aggressive PC by targeting its potential target genes.     

微小RNA活性分析法筛选前列腺癌去势抵抗转化相关微小RNA的实验研究

目的 探讨微小RNA(miRNA)活性分析法筛选前列腺癌去势抵抗转化相关miRNA的效率。方法 应用miRNA活性分析法筛选出在前列腺癌去势抵抗过程中潜在的发挥活性作用的miRNAs。培养人激素敏感型前列腺癌LNCAP细胞(对照组)及人去势抵抗型前列腺癌C4-2细胞(C4-2组)、PC-3细胞(PC-3组)、DU-145细胞(DU-145组),提取各组细胞总RNA,采用实时荧光定量PCR(qPCR)检测miRNAs,比较各组细胞miRNAs的表达情况。结果 应用miRNA活性分析法,依据筛选流程,共选出9个差异表达的miRNAs,分别为miR-1、miR-122、miR-218、miR-145、miR-155、miR-210、miR-197、 miR-346、let-7b。采用qPCR检测这9个miRNAs,结果显示,7个miRNAs在两种不同状态下的前列腺癌细胞中存在差异表达;在不同去势抵抗型前列腺癌细胞中,miR-210、miR-197、miR-346、miR-218均明显高表达,而miR-122、miR-145、let-7b均明显低表达。结论 采用miRNA活性分析法筛选前列腺癌去势抵抗转化相关miRNA,有着较高的准确性与可信度;其具体转化过程还需进一步证实。     

Prostate hyperplasia in St Mary's Hospital Lacor: utility of prostate specific antigen in screening for prostate malignancy

IntroductionProstate cancer is the second commonest cancer in men worldwide. At present, every patient with lower urinary tract symptoms (LUTS) in St. Mary''s Hospital Lacor is undergoing prostate biopsy regardless of the prostate specific antigen (PSA) level. We sought to determine the association between PSA and malignant prostate histology.MethodsThis was a retrospective study. Data on age, PSA, prostate volume and prostate histology reported between Jan 2012 and Dec 2019 were retrieved from St. Mary''s Hospital Lacor archive and analyzed using STATA SE/13.0.ResultsRecords of 97 patients with LUTS was analyzed. The median (range) age of the patients was 71 (43–100) years. Median (range) of prostate volume was 91.8 (8.0–360.0) cc. Overall, PSA ranged from 0.21 to 399.2 ng/ml. Prostate histology showed 3.1% acinar adenocarcinoma, 24.7% adenocarcinoma and 72.2% benign prostatic hyperplasia. The median PSA amongst patients with malignant and non-malignant prostates were 15.8 ng/ml and 6.07 ng/ml respectively. Serum PSA level was significantly higher in patients with malignant prostate histology (Difference of mean= 9.7; p=0.001).ConclusionPatients with LUTS and PSA levels of 15ng/ml or more were more likely to have malignant prostate histology.     

Improving patient prostate cancer risk assessment: Moving from static,globally-applied to dynamic,practice-specific risk calculators

Clinical risk calculators are now widely available but have generally been implemented in a static and one-size-fits-all fashion. The objective of this study was to challenge these notions and show via a case study concerning risk-based screening for prostate cancer how calculators can be dynamically and locally tailored to improve on-site patient accuracy. Yearly data from five international prostate biopsy cohorts (3 in the US, 1 in Austria, 1 in England) were used to compare 6 methods for annual risk prediction: static use of the online US-developed Prostate Cancer Prevention Trial Risk Calculator (PCPTRC); recalibration of the PCPTRC; revision of the PCPTRC; building a new model each year using logistic regression, Bayesian prior-to-posterior updating, or random forests. All methods performed similarly with respect to discrimination, except for random forests, which were worse. All methods except for random forests greatly improved calibration over the static PCPTRC in all cohorts except for Austria, where the PCPTRC had the best calibration followed closely by recalibration. The case study shows that a simple annual recalibration of a general online risk tool for prostate cancer can improve its accuracy with respect to the local patient practice at hand.     

Interobserver and intraobserver reproducibility in digital and routine microscopic assessment of prostate needle biopsies

Advances in whole slide digital imaging in the past decade necessitate validation of these tools in each organ system in advance of clinical adoption. We assessed reproducibility in reporting prostate needle biopsy parameters among urologic pathologists using routine and digital microscopy in a consultation/second opinion-like setting. Four urologic pathologists evaluated a single core level from 50 diagnostically challenging needle biopsy specimens by routine microscopy and whole slide digital imaging. Interobserver and intraobserver agreement were calculated for primary and secondary Gleason grades, Gleason score, tumor quantitation (percentage and size in millimeters), and perineural invasion. Interobserver agreement for routine microscopy was excellent for primary Gleason grade (κ = 0.72) and good for all other parameters (κ ranging from 0.36 to 0.55). Whole slide digital imaging assessment yielded similar agreement for all parameters. Intraobserver agreement for primary Gleason grade and Gleason score was very good to excellent for all pathologists (all κ ≥ 0.65 and ≥ 0.73, respectively). Size of tumor in millimeters consistently displayed higher levels of agreement than percentage of tumor across media and pathologists. Digital assessment of routinely reported cancer parameters on prostatic needle biopsy for a given scanned core level is comparable to that of routine microscopy. These findings imply that histologic interpretation using dynamic whole slide images may accurately simulate routine microscopic evaluation in the consultation setting. Implementation of whole slide digital imaging in these scenarios may significantly reduce the workload of large referral centers in the near future and impact the manner in which pathologists seek second opinion consultation on challenging cases.     

The value of endothelin receptor type B promoter methylation as a biomarker for the risk assessment and diagnosis of prostate cancer: A meta-analysis

Previous researches have demonstrated that the methylation status of the EDNRB promoter was associated with the prostate cancer (PCa), but these conclusions remained controversial. Thus, the aim of this meta-analysis was to evaluate the association between EDNRB promoter methylation and the PCa. According to the PRISMA statement, the Web of Science, PubMed, EMBASE, and Cochrane Library databases were retrieved. The ORs and 95 % CIs were analyzed to evaluate the associations between EDNRB promoter methylation and the risk and clinical features of PCa. Heterogeneity among the included studies was estimated by I² statistic and Q test. Publication bias and sensitivity analysis were utilized to test the robustness of our outcomes. In addition, the pooled sensitivity and specificity were calculated to assess the diagnostic value of EDNRB methylation for PCa. Ultimately, 11 eligible studies were included. Under the random-effects model, the pooled OR shown that the frequency of EDNRB methylation was substantially higher in cases compared with controls (OR = 5.42, 95 % CI = 1.98–14.88, P = 0.001). The similar results were also found by the data from TCGA database. Subgroup analysis according to the methylation detection method showed that the heterogeneity in quantitative methylation-specific polymerase chain reaction (qMSP) group was insignificant (I² = 0.0 %, P = 0.669). Moreover, the pooled sensitivity for all-inclusive studies was 0.55 (95 % CI: 0.26-0.81), and the pooled specificity was 0.93 (95 % CI: 0.55-0.99). The methylation of EDNRB promoter might increase the risk of PCa. Meanwhile, EDNRB promoter methylation test combined with PSA testing and/or other biomarkers could be promising diagnostic biomarkers for more accurate detection of PCa.     

Lycopene for the prevention and treatment of benign prostatic hyperplasia and prostate cancer: a systematic review

Background

Prostate cancer is a leading cancer affecting men worldwide. Benign prostatic hyperplasia (BPH) is a common disease of the prostate affecting men as they age, and a risk factor for developing prostate cancer. Lycopene is a member of the carotenoid family, whose strong anti-oxidant properties have been hypothesised to assist in the prevention and treatment of BPH and prostate cancer. The aim of this systematic review was to examine the effectiveness of lycopene for the prevention and treatment of BPH and prostate cancer.

Methods

A search of the MEDLINE, EMBASE, AMED (Allied and Complementary Medicine) and the Cochrane Library databases was performed for published randomised controlled trials (RCTs) comparing lycopene to placebo (or other interventions) for the treatment of BPH and prostate cancer. All included studies were assessed for methodological quality using the Cochrane Collaboration's risk of bias tool.

Results

Eight RCTs met the inclusion criteria for this systematic review. All included studies were heterogeneous with respect to their design and implementation of lycopene. Methodological quality of three studies was assessed as posing a ‘high’ risk of bias, two a ‘low’ risk of bias and the remaining three an ‘unclear’ risk of bias. Meta-analysis of four studies identified no significant decrease in the incidence of BPH (RR (relative risk) = 0.95, 95%CI 0.63, 1.44) or prostate cancer diagnosis (RR = 0.92, 95%CI 0.66, 1.29) between men randomised to receive lycopene and the comparison group. Meta-analysis of two studies indicated a decrease in PSA levels in men diagnosed with prostate cancer, who received lycopene (MD (mean difference) = −1.58, 95%CI −2.61, −0.55).

Conclusions

Given the limited number of RCTs published, and the varying quality of existing studies, it is not possible to support, or refute, the use of lycopene for the prevention or treatment of BPH or prostate cancer.     

Quantitative RT-PCR assay of HER2 mRNA expression in formalin-fixed and paraffin-embedded breast cancer tissues

Detection of human epidermal growth factor receptor 2 gene (HER2, also known as erbB2) expression is a preparatory process to decide a treatment strategy for breast cancer patients. 20-30% of breast cancer patients have HER2 overexpression, and they usually show poor recovery rate. For detection of HER2 expression, immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) methods are conventionally used. Although these methods are accurate and reliable, their time-consuming process and high cost need a concise method with high sensitivity and accuracy. As a complementary method to the current IHC/FISH standard techniques, PCR-based methods have been developed. Here we employed a quantitative PCR method to detect HER2 expression in one hundred ninety nine formalin-fixed and paraffin-embedded (FFPE) breast cancer tissue samples from the patients treated over two years at the Yonsei University Severance Hospital, Republic of Korea. Relative expression of HER2 mRNA in the FFPE samples was analyzed using a quantitative RT-PCR (RT-qPCR) method and the obtained HER2 expression levels were compared with those from IHC/FISH methods. Our results show that the RT-qPCR method was highly concordant with IHC/FISH methods for detecting HER2 expression. Overall sensitivity and specificity of the BrightGen HER2 RT-qDx assay kit (Syantra, Calgary, Canada), which is a kit we used for RT-qPCR analyses, were 93.0% and 89.8% (P < 0.0001), respectively. The diagnostic cut-off value of HER2 RT-qDx for the clinical samples was determined by likelihood ratio, among which the highest likelihood ratio of relative HER2 mRNA levels was over 105.5 (AUC = 0.9466) with the highest sensitivity and specificity. Our study indicates that quantification of HER2 mRNA expression with the RT-qPCR could be an alternative method of conventional IHC/FISH methods.     

Dietary supplements and prostate cancer: a systematic review of double-blind,placebo-controlled randomised clinical trials

Dietary supplements are popular among patients with prostate cancer (PC). The objective of this systematic review was to critically examine double-blind, placebo-controlled randomised clinical trials (RCTs) of non-herbal dietary supplements and vitamins (NHDS) for evidence that prostate specific antigen (PSA) levels were reduced in PC patients. Five databases were searched from their inception through December 2012 to identify studies that met our inclusion criteria. Methodological quality was independently assessed by two reviewers using the Cochrane tool. Eight RCTs met the eligibility criteria and were of high methodological quality. The following supplements were tested: isoflavones (genistein, daidzein, and glycitein), minerals (Se) or vitamins (vitamin D) or a combination of antioxidants, bioflavonoids, carotenoids, lycopenes, minerals (Se, Zn, Cu, and Mg), phytoestrogens, phytosterols, vitamins (B2, B6, B9, B12, C, and E), and other substances (CoQ10 and n-acetyl-l cysteine). Five RCTs reported no significant effects compared with placebo. Two RCTs reported that a combination of antioxidants, isoflavones, lycopenes, minerals, plant oestrogens and vitamins significantly decreased PSA levels compared with placebo. One RCT did not report differences in PSA levels between the groups. In conclusion, the hypothesis that dietary supplements are effective treatments for PC patients is not supported by sound clinical evidence. There are promising data for only two specific remedies, which contained a mixture of ingredients, but even for these supplements, additional high quality evidence is necessary before firm recommendations would be justified.     

CPAS: A trans-omics pathway analysis tool for jointly analyzing DNA copy number variations and mRNA expression profiles data

Pathway-based analysis approaches provide additional insights into the pathogenesis of complex diseases. Copy number variations (CNVs) play an important role in gene expression regulation. Joint pathway analysis of CNVs and gene expression data should provide more useful information for revealing the molecular mechanism of complex diseases. To implement trans-omics pathway analysis of genome-wide CNVs and mRNA expression profiles data, we extended the gene set enrichment analysis algorithm and developed a flexible trans-omics pathway analysis tool CPAS. CPAS was developed by C to interface with R for efficient data analysis. CNV-gene and pathway-gene annotation files derived from public database were included in CPAS. We hope that CPAS could help to identify disease-relevant biological pathways that were undetectable using traditional single-omic analysis approaches.     

Neural network analysis of employment history as a risk factor for prostate cancer

Background

Prostate cancer is the most common non-cutaneous malignancy in men. Its etiology likely involves environmental exposures and demographic factors.

Objective

Investigate the potential relationship between occupation history and prostate cancer risk in a population-based, case-control study (n=1365).

Methods

The variables: race, age group, smoking status, income, marital status, education and the first 15 years of employment history were examined by sequential odds ratio analysis then compared to a neural network consensus model.

Results

Both the sequential odds ratio method and the neural network consensus model identified a similar hypothetical case of greatest risk: a Black, married man, older than 60 years, with at best a high school diploma who made between $25,000-$65,000. The work history determined by odds ratio analysis consisted of 10 years in the chemical industry with 3 yrs in the processing plant. Neural network analysis showed a similar work history with 8 years in the chemical industry and 2 years in the processing plant.

Discussion

Neural network outcomes are similar to sequential odds ratio calculations. This work supported previous studies by finding well known demographic risk factors for prostate cancer including certain processing jobs and chemical related jobs.     

CASP8 promoter polymorphism,mRNA expression and risk of prostate cancer among Chinese men

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.     

Breast and prostate cancer risk: The interplay of polygenic risk,rare pathogenic germline variants,and family history

PurposeWe aimed to investigate to what extent polygenic risk scores (PRS), rare pathogenic germline variants (PVs), and family history jointly influence breast cancer and prostate cancer risk.MethodsA total of 200,643 individuals from the UK Biobank were categorized as follows: (1) heterozygotes or nonheterozygotes for PVs in moderate to high-risk cancer genes, (2) PRS strata, and (3) with or without a family history of cancer. Multivariable logistic regression and Cox proportional hazards models were used to compute the odds ratio across groups and the cumulative incidence through life.ResultsCumulative incidence by age 70 years among the nonheterozygotes across PRS strata ranged from 9% to 32% and from 9% to 35% for breast cancer and prostate cancer, respectively. Among the PV heterozygotes it ranged from 20% to 48% in moderate-risk genes and from 51% to 74% in high-risk genes for breast cancer, and it ranged from 30% to 59% in prostate cancer risk genes. Family history was always associated with an increased cancer odds ratio.ConclusionPRS alone provides a meaningful risk gradient leading to a cancer risk stratification comparable to PVs in moderate risk genes, whereas acts as a risk modifier when considering high-risk genes. Including family history along with PV and PRS further improves cancer risk stratification.     

Immunohistochemical expression of prostate tumor overexpressed 1 in cystoprostatectomies with incidental and insignificant prostate cancer. Further evidence for field effect in prostatic carcinogenesis

Prostate tumor overexpressed 1 was recently identified as a novel gene and protein during a differential display screening for genes overexpressed in prostate cancer. It has been suggested that overexpression of prostate tumor overexpressed 1 can contribute to the proliferative status of prostate tumor cells and, thus, to their biologic behavior. Prostate tumor overexpressed 1 and Ki-67 were immunohistochemically evaluated in prostate cancer, high-grade prostatic intraepithelial neoplasia, and normal-looking epithelium in 20 cystoprostatectomies and 20 radical prostatectomies with pT2a Gleason score 6 prostate cancer. The aim was to see whether there were differences in marker expression between cystoprostatectomies and radical prostatectomies. The proportions of prostate tumor overexpressed 1– and Ki-67–positive cells in the cystoprostatectomies and radical prostatectomies increased from normal-looking epithelium through high-grade prostatic intraepithelial neoplasia, away from and adjacent to prostate cancer, to prostate cancer. Prostate tumor overexpressed 1 expression in prostate cancer in cystoprostatectomies was lower than in radical prostatectomies, the differences being significant; there were significant differences in Ki-67 indices. In conclusion, our findings related to prostate tumor overexpressed 1 expression in high-grade prostatic intraepithelial neoplasia, evaluated adjacent and away from prostate cancer, and in incidental and clinical cancers give further support to the concept of field effect in prostatic carcinogenesis as well as to differences in the process of prostatic carcinogenesis between cystoprostatectomies and radical prostatectomies.     

Base excision repair pathway genes polymorphism in prostate and bladder cancer risk in North Indian population

Purpose

Carcinogens causes DNA damage, including oxidative lesions that are removed efficiently by the base excision repair (BER) pathway. Variations in BER genes may reduce DNA repair capacity, leading to development of urological cancers.

Methods

This study included 195 prostate cancer (PCa) and 212 bladder cancer (BC) patients and 250 controls who had been frequency matched by age, sex, and ethnicity. We genotyped XRCC1 Exon 6 (C > T), 9 (G > A), 10 (G > A), OGG1 Exon 7 (C > G) and APE1 Exon 5 (T > G) genes polymorphism using PCR-RFLP and ARMS.

Results

GA of XRCC1 Exon 9 demonstrated increased risk with PCa as well as in BC (p = 0.001; p = 0.006). Similarly variant containing genotype revealed association with PCa (p = 0.031). Haplotype of XRCC1 also associated with significant risk for PCa and BC. The APE1 GG genotype showed a decreased risk of BC (OR = 0.25; p = 0.017). Variant genotype GG of OGG1 demonstrated significant risk with BC (p = 0.028).

Conclusions

Our observations suggested increased risk for PCa and BC in case of GA genotype for XRCC1, and variant GG in case of OGG1. However APE1 GG genotype conferred a protective association with BC susceptibility. Larger studies and the more SNPs in the same pathway are needed to verify these findings.