Development and Verification of a Prostate Cancer Prognostic Signature Based on an Immunogenomic Landscape Analysis

PurposeProstate cancer (PCa) has a high incidence among older men. Until now, there are no immunological markers available to predict PCa patients’ survival. Therefore, it is necessary to explore the immunological characteristics of PCa.MethodsFirst, we retrieved RNA-seq and clinical data of 499 PCa and 52 normal prostate tissue samples from the Cancer Genome Atlas (TCGA). We identified 193 differentially expressed immune-related genes (IRGs) between PCa and normal prostate tissues. Functional enrichment analyses showed that the immune system can participate in PCa initiation. Then, we constructed a correlation network between transcription factors (TFs) and IRGs. We performed univariate and multivariate Cox regression analyses and identified five key prognostic IRGs (S100A2, NOX1, IGHV7-81, AMH, and AGTR1). Finally, a predictive nomogram was established and verified by the C-index.ResultsWe successfully constructed and validated an immune-related PCa prediction model. The signature could independently predict PCa patients’ survival. Results showed that high-immune-risk patients were correlated with advanced stage. We also validated the S100A2 expression in vitro using PCa and normal prostate tissues. We found that higher S100A2 expressions were related to lower biochemical recurrences. Additionally, higher AMH expressions were related to higher Gleason score, lymph node metastasis and positive rate, and tumor stages, and higher ATGR1 expressions were related to lower PSA value.ConclusionOverall, we detected five IRGs (S100A2, NOX1, IGHV7-81, AMH, and AGTR1) that can be used as independent PCa prognostic factors.

Integrative Epigenome Map of the Normal Human Prostate Provides Insights Into Prostate Cancer Predisposition

Cells of all tissues in the human body share almost the exact same DNA sequence, but the epigenomic landscape can be drastically distinct. To improve our understanding of the epigenetic abnormalities in prostate-related diseases, it is important to use the epigenome of normal prostate as a reference. Although previous efforts have provided critical insights into the genetic and transcriptomic features of the normal prostate, a comprehensive epigenome map has been lacking. To address this need, we conducted a Roadmap Epigenomics legacy project integrating six histone marks (H3K4me1, H3K4me3, H3K9me3, H3K36me3, H3K27me3, and H3K27ac) with complete DNA methylome, transcriptome, and chromatin accessibility data to produce a comprehensive epigenome map of normal prostate tissue. Our epigenome map is composed of 18 chromatin states each with unique signatures of DNA methylation, chromatin accessibility, and gene expression. This map provides a high-resolution comprehensive annotation of regulatory regions of the prostate, including 105,593 enhancer and 70,481 promoter elements, which account for 5.3% of the genome. By comparing with other epigenomes, we identified 7,580 prostate-specific active enhancers associated with prostate development. Epigenomic annotation of GWAS SNPs associated with prostate cancers revealed that two out of nine SNPs within prostate enhancer regions destroyed putative androgen receptor (AR) binding motif. A notable SNP rs17694493, might decouple AR’s repressive effect on CDKN2B-AS1 and cell cycle regulation, thereby playing a causal role in predisposing cancer risk. The comprehensive epigenome map of the prostate is valuable for investigating prostate-related diseases.

miR-499a inhibits the proliferation and apoptosis of prostate cancer via targeting UBE2V2

Background Prostate cancer is one of the malignant tumors of the urinary system and ranks second among the fatal cancers in men. And with age, the incidence of prostate cancer will increase linearly. Methods In this study, we measured the expression of Ubiquitin Conjugating Enzyme E2 V2 (UBE2V2) in prostate cancer tissues and cell lines by WB and explored the effect of UBE2V2 on the proliferation characteristics of prostate cancer by MTT and colony formation test. Results In our research, we found that the UBE2V2 protein level in prostate cancer cell lines was significantly higher than the UBE2V2 protein level in normal prostate cells, and the mRNA expression level did not change significantly compared with normal prostate tissue cells. At the same time, we found that miR-499a combined with UBE2V2 inhibited the expression of UBE2V2 in prostate cancer cells. Conclusions In conclusion, our results indicate that miR-499a inhibits the proliferation of human prostate cancer cells by targeting UBE2V2, which will provide a potential target for the treatment of prostate cancer.

Magnetic resonance fingerprinting in prostate cancer before and after contrast enhancement

Objectives: To assess the apparent diffusion coefficient (ADC) values and the T1 and T2 values derived from nonenhanced (NE) and contrast-enhanced (CE) magnetic resonance fingerprinting (MRF) in the prostate gland and to evaluate differences in values among prostate cancer, the normal peripheral zone (PZ) and the normal transition zone (TZ). Methods: Fifty-seven patients (median age, 73 years; range, 48–86) with prostate cancer who underwent multiparametric MRI including NE and CE MRF were included in this study. T1 and T2 values were extracted from NE and CE MRF, respectively. Five quantitative values (the ADC, NE T1, NE T2, CE T1 and CE T2 values) were measured in three areas: prostate cancer, PZ and TZ. We compared the values among the three areas and evaluated the differences between NE MRF and CE MRF values. Results: ADC values and MRF-derived values were significantly higher in PZ than prostate cancer or TZ (p < 0.001). TZ had a significantly lower CE T1 but significantly higher values of the other variables than prostate cancer (p < 0.001). The T1 values in all three areas and the T2 values in prostate cancer and TZ were significantly lower on CE MRF than on NE MRF (p < 0.001). Conclusions: Quantitative analysis of NE and CE MRI can be conducted by using the MRF technique. The ADC value and the T1 and T2 values from CE MRF and NE MRF were found to be significantly different between prostate cancer and normal prostate tissue. Advances in knowledge The T1 and T2 values from contrast-enhanced MR fingerprinting are significantly different between prostate cancer and normal prostate tissue.

TACR2 is associated with the immune microenvironment and inhibits migration and proliferation via the Wnt/β-catenin signaling pathway in prostate cancer

Background The tachykinin receptor 2 (TACR2) is encoded by the tachykinin receptor correlation gene. Recent microarray analysis for prostate cancer suggests that TACR2 expression is associated with clinical phenotype and disease-free survival among patients with prostate cancer. Results TACR2 protein levels were lower in prostate cancer tissues than in adjacent normal prostate tissue. TACR2 expression significantly correlated with clinical stage, Gleason scores, and survival outcomes. TACR2 expression positively correlated with mast cells and negatively correlated with M2 macrophages. Overexpression of TACR2 promoted the migration and proliferation of prostate cancer cells by regulating the Wnt signaling pathway. Conclusions The TACR2-Wnt/β-catenin signaling pathway is critical in prostate cancer. TACR2 may affect tumor cells’ occurrence and development by changing the content of immune cells in the tumor microenvironment. These findings suggest that TACR2 may be a candidate molecular biomarker for prostate cancer therapy.

Pyruvate kinase M1 suppresses development and progression of prostate adenocarcinoma

Most cancers, including prostate cancers, express the M2 splice isoform of pyruvate kinase (Pkm2). This isoform can promote anabolic metabolism to support cell proliferation; however, Pkm2 expression is dispensable for many cancers in vivo. Pyruvate kinase M1 (Pkm1) isoform expression is restricted to relatively few tissues and has been reported to promote growth of select tumors, but the role of PKM1 in cancer has been less studied. Pkm1 is expressed in normal prostate tissue; thus, to test how differential pyruvate kinase isoform expression affects cancer initiation and progression we generated mice harboring a conditional allele of Pkm1 and crossed this allele, as well as a Pkm2 conditional allele, to a Pten loss-driven prostate cancer model. We found that Pkm1 loss leads to Pkm2 expression and accelerates prostate cancer, while deletion of Pkm2 leads to increased Pkm1 expression and suppresses cancer. Consistent with these data, a small molecule pyruvate kinase activator that mimics a PKM1-like state suppresses progression of established prostate tumors. PKM2 expression is retained in most human prostate cancers, arguing that pharmacological PKM2 activation may be beneficial for some prostate cancer patients.

MYC DNA Methylation in Prostate Tumor Tissue is Associated with Gleason Score

Increasing evidence suggests a role of epigenetic mechanisms at chromosome 8q24, an important cancer genetic susceptibility region, in prostate cancer. We investigated whether MYC DNA methylation at 8q24 (six CpG sites from exon 3 to the 3′ UTR) in prostate tumor was associated with tumor aggressiveness (based on Gleason score, GS), and we incorporated RNA expression data to investigate the function. We accessed radical prostatectomy tissue for 50 Caucasian and 50 African American prostate cancer patients at the University of Maryland Medical Center, selecting an equal number of GS 6 and GS 7 cases per group. MYC DNA methylation was lower in tumor than paired normal prostate tissue for all six CpG sites (median difference: −14.74 to −0.20 percentage points), and we observed similar results for two nearby sites in The Cancer Genome Atlas (p < 0.0001). We observed significantly lower methylation for more aggressive (GS 7) than less aggressive (GS 6) tumors for three exon 3 sites (for CpG 212 (chr8:128753145), GS 6 median = 89.7%; GS 7 median = 85.8%; p-value = 9.4 × 10−4). MYC DNA methylation was not associated with MYC expression, but was inversely associated with PRNCR1 expression after multiple comparison adjustment (q-value = 0.04). Findings suggest that prostate tumor MYC exon 3 hypomethylation is associated with increased aggressiveness.

Expression of miR-132 and miR-212 in prostate cancer and metastatic lymph node: Case report and revision of the literature

MicroRNAs (miRNAs) are a class of small, non-coding RNAs that act as key regulators in various physiological and pathological processes as prostate cancer (PCa). In this study we describe molecular evaluation of 132 and 212 miRNAs expression, by Real-time reverse-transcription PCR (qRT-PCR), in a Caucasian man 64-year-old with locally advanced PCa (PSA 160 ng/ml, Gleason score 4+3/ISUP Grade Group 3, clinical stage T3NXM0) who underwent radical retropubic prostatectomy plus extended pelvic lymphadenectomy (LAD) as first step of a multimodal therapeutic treatment. A normal prostate of a 67-year-old man removed by post mortem autopsy was used as a control in the study. The mRNA for this study was conducted on paraffined prostatic sections of: a) index case of PCa; b) metastatic lymph node of index case; c) normal prostate. MiRNA-132, miRNA- 212 and Glyceraldehyde 3-phosphate dehydrogenase (as reference gene) assays were obtained. Definitive specimen showed a pT3bN1R1 stage: acinar cells adenocarcinoma with involvement of the seminal vesicles, multifocal positive surgical margins, Gleason score 8 (4+4/ISUP Grade Group 4), metastases in 5/25 iliac lymph nodes. An increased expression of miRNA-132 and miRNA-212 in index case of prostatic adenocarcinoma compared to normal prostate tissue was found; moreover, a lower expression of miR-132 and miR-212 in metastatic lymph node compared to primitive PCa and normal prostate tissue was demonstrated. Although a greater number of patients should be evaluated, these data suggest that the biology of the primary PCa, in our clinical case, was different from metastatic lymph node.