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Prostate adenocarcinoma is the second most commonly diagnosed cancer in men worldwide, and the initiating factors are unknown. Oncogenic TMPRSS2:ERG (ERG+) gene fusions are facilitated by DNA breaks and occur in up to 50% of prostate cancers. Infection-driven inflammation is implicated in the formation of ERG+ fusions, and we hypothesized that these fusions initiate in early inflammation-associated prostate cancer precursor lesions, such as proliferative inflammatory atrophy (PIA), prior to cancer development. We investigated whether bacterial prostatitis is associated with ERG+ precancerous lesions in unique cases with active bacterial infections at the time of radical prostatectomy. We identified a high frequency of ERG+ non–neoplastic-appearing glands in these cases, including ERG+ PIA transitioning to early invasive cancer. These lesions were positive for ERG protein by immunohistochemistry and ERG messenger RNA by in situ hybridization. We additionally verified TMPRSS2:ERG genomic rearrangements in precursor lesions using tricolor fluorescence in situ hybridization. Identification of rearrangement patterns combined with whole-prostate mapping in three dimensions confirmed multiple (up to eight) distinct ERG+ precancerous lesions in infected cases. We further identified the pathogen-derived genotoxin colibactin as a potential source of DNA breaks in clinical cases as well as cultured prostate cells. Overall, we provide evidence that bacterial infections can initiate driver gene alterations in prostate cancer. In addition, our observations indicate that infection-induced ERG+ fusions are an early alteration in the carcinogenic process and that PIA may serve as a direct precursor to prostate cancer.

Background Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a common disorder associated with voiding symptoms and pain in the pelvic or perineal area. Macrophages, particularly the pro-inflammatory M1 subtype, are crucial initiating of CP/CPPS. Interferon regulatory factor 7 (Irf7) has been implicated in promoting M1 polarization, contributing to the onset and progression of autoimmunity. However, the role of Irf7 in the etiology and progression of CP/CPPS remains unclear. Method We established the experimental autoimmune prostatitis (EAP) mouse model by subcutaneous injection of prostate antigen combined with complete Freund’s adjuvant. Six weeks after the first immunization, we analyzed the prostates, spleen, and blood to assess the degree of prostate inflammation, Irf7 expression levels, glycolysis, and M1 polarization to evaluate whether Irf7 could exacerbate the development of EAP by enhancing Hif-1α transcription, thereby increasing glycolysis and M1 polarization. Further investigations included sh-Irf7 intervention, Dimethyloxalylglycine (a Hif-1α agonist), and in vitro M1 polarization experiments. We also employed ChIP assays, dual-luciferase reporter assays, and q-PCR to explore if Irf7 could directly interact with the Hif-1α promoter in macrophages. Results In the EAP mouse and cell models, elevated Irf7 expression was observed in inflamed tissues and cells. Reducing Irf7 expression decreased M1 cell glycolysis by inhibiting the nuclear translocation of Hif-1α, thus mitigating M1 cell polarization. Additionally, Irf7 was identified as a transcription factor that regulates Hif-1α transcription by interacting with its promoter in macrophages, confirmed through ChIP and dual-luciferase assays. Co-culturing macrophage cells with 3T3 fibroblasts with reduced Irf7 levels resulted in decreased fibrosis, and a significant reduction in prostate tissue fibrosis was noted in mice with Irf7 knockdown. Conclusion Our findings indicate that Irf7 can contribute to the development and progression of CP/CPPS by promoting glycolysis, which can enhance both M1 polarization as well as interstitial fibrosis in the prostate. This process was found to be mediated by the upregulation of Hif-1α transcription, presenting new potential therapeutic targets for managing CP/CPPS.

Background C-X-C receptor 4(CXCR4) is widely considered to be a highly conserved G protein-coupled receptor, widely involved in the pathophysiological processes in the human body, including fibrosis. However, its role in regulating macrophage-related inflammation in the fibrotic process of prostatitis has not been confirmed. Here, we aim to describe the role of CXCR4 in modulating macrophage M1 polarization through glycolysis in the development of prostatitis fibrosis. Methods Use inducible experimental chronic prostatitis as a model of prostatic fibrosis. Reduce CXCR4 expression in immortalized bone marrow-derived macrophages using lentivirus. In the fibrotic mouse model, use adenovirus carrying CXCR4 agonists to detect the silencing of CXCR4 and assess the in vivo effects. Results In this study, we demonstrated that reducing CXCR4 expression during LPS treatment of macrophages can alleviate M1 polarization. Silencing CXCR4 can inhibit glycolytic metabolism, enhance mitochondrial function, and promote macrophage transition from M1 to M2. Additionally, in vivo functional experiments using AAV carrying CXCR4 showed that blocking CXCR4 in experimental autoimmune prostatitis (EAP) can alleviate inflammation and experimental prostate fibrosis development. Mechanistically, CXCR4, a chemokine receptor, when silenced, weakens the PI3K/AKT/mTOR pathway as its downstream signal, reducing c-MYC expression. PFKFB3, a key enzyme involved in glucose metabolism, is a target gene of c-MYC, thus impacting macrophage polarization and glycolytic metabolism processes.

Chronic prostatitis/chronic pelvic pain syndrome is common, and it impacts men’s health and quality of life. The genetic basis of this condition remains largely unknown. Here, we conduct a GWAS using data from the Million Veteran Program of over 590,000 men of European, African, and Hispanic ancestry, including 14,575 chronic prostatitis/chronic pelvic pain syndrome cases. The multi-ancestry analysis identifies eight novel loci associated with chronic prostatitis/chronic pelvic pain syndrome risk, an increase from three significant genome-wide loci found in the European participants alone. We also estimate the genetic correlations between chronic prostatitis/chronic pelvic pain syndrome and 12 phenotypes. Notably, the genetic correlation between chronic prostatitis/chronic pelvic pain syndrome and prostate cancer is not significant. Further, Mendelian randomization shows a significant, potentially bidirectional causal relationship between chronic prostatitis/chronic pelvic pain syndrome and benign prostatic hyperplasia, but not between chronic prostatitis/chronic pelvic pain syndrome and prostate cancer, suggesting a complex interplay between chronic prostatitis/chronic pelvic pain syndrome and benign prostatic hyperplasia. Results of bivariate causal mixture modeling indicate that some of the same genetic variants likely contribute to the development of chronic prostatitis/chronic pelvic pain syndrome, benign prostatic hyperplasia, and prostate cancer. The genetic basis of chronic prostatitis/chronic pelvic pain syndrome remains poorly understood. Here, the authors present a multi-ancestry GWAS of this syndrome, identifying eight loci linked with higher risk.

Background Although it is thought that prostatitis or benign prostatic hyperplasia (BPH) is related to prostate cancer (PCa), the underlying causal effects of these diseases are unclear. Methods We assessed the causal relationship between prostatitis or BPH and PCa using a two-sample Mendelian randomization (MR) approach. The data utilized in this study were sourced from genome-wide association study. The association of genetic variants from cohorts of prostatitis or BPH and PCa patients was determined using inverse-variance weighted and MR Egger regression techniques. The direction of chance was determined using independent genetic variants with genome-wide significance ( P  < 5 × 10 –6 ). The accuracy of the results was confirmed using sensitivity analyses. Results MR analysis showed that BPH had a significant causal effect on PCa (Odds Ratio = 1.209, 95% Confidence Interval: 0.098–0.281, P  = 5.079 × 10 − 5 ) while prostatitis had no significant causal effect on PCa ( P  > 0.05). Additionally, the pleiotropic test and leave-one-out analysis showed the two-sample MR analyses were valid and reliable. Conclusions This MR study supports that BPH has a positive causal effect on PCa, while genetically predicted prostatitis has no causal effect on PCa. Nonetheless, further studies should explore the underlying biochemical mechanism and potential therapeutic targets for the prevention of these diseases.

In recent observational studies, a potential link between prostatitis and prostate cancer (PCa) has been hinted at, yet the causality remains ambiguous. In our endeavor to scrutinize the conceivable causal nexus between prostatitis and PCa, we embarked upon a Mendelian randomization (MR) study. MR circumvents arbitrary groupings by employing genetic variations that have a strong association with the exposure as instrumental variables to infer causal relationships between exposures and outcomes. The etiology of PCa remains elusive. Given that prostatitis and prostate cancer occupy the same anatomical region, MR can more effectively delineate their relationship by mitigating confounding variables. This method can indirectly elucidate disease correlations, thereby contributing to cancer prevention strategies. FinnGen Consortium data were used for the prostatitis genome-wide association study (GWAS), including 74,658 participants. UK biobank baseline data (ncase = 3436, ncontrol = 459574), European Bioinformatics Institute Database (ncase = 79148, ncontrol = 61106), and IEU openGWAS database (ncase = 79148, ncontrol = 61106) were used for PCa outcomes, mostly for European population samples. Data from the GWSAs for prostatitis were compared with data from the three GWASs for PCa, respectively, in an analysis of an MR. Utilizing the inverse variance weighting (IVW) methodology as our primary analytical framework, we delved into a meticulous exploration of the conceivable causal association between prostatitis and PCa. Furthermore, we deployed supplementary methodologies, including Maximum Likelihood, MR-Egger, weighted median, and MR-PRESSO, to thoroughly assess and scrutinize the causality aspect comprehensively. Cochran’s Q statistic is employed as a metric to quantify the heterogeneity inherent in instrumental variables. The inverse variance weighted analysis revealed no discernible effect of prostatitis on PCa in the three PCa GWAS databases (odds ratio [OR]: 1.001, 95% Confidence Interval [CI]: 0.999–1.002, p =  0.28), (OR: 1.015, 95% CI: 0.981–1.050, p =  0.40), (OR: 1.015, 95% CI: 0.981–1.050, p =  0.40). Similarly, employing MR-Egger did not yield substantial evidence (OR: 0.999, 95% CI: 0.999–1.002, p =  0.89), (OR: 1.103, 95% CI: 1.006–1.209, p =  0.07), (OR: 1.103, 95% CI: 1.006–1.209, p =  0.07). The weighted median analysis also failed to provide convincing support for the impact of prostatitis on the incidence of PCa (OR: 1.001, 95% CI: 1.000-1.002, p =  0.064), (OR: 0.989, 95% CI: 0.946–1.034, p =  0.64), (OR: 0.989, 95% CI: 0.945–1.036, p =  0.65). The results of the MR showed no causality from prostatitis to PCa.

Previous research has suggested that circulating inflammatory proteins are associated with benign prostatic disease (BPD). This Mendelian randomization (MR) study was conducted to further investigate the causal relationship between 91 inflammatory proteins and BPD. Genome-wide association study (GWAS) summarized data of benign prostatic hyperplasia (BPH) and prostatitis were obtained from the FinnGen Biobank. The latest study offered the GWAS data on 91 proteins related to inflammation. We performed a bidirectional MR to investigate the causal association between inflammatory proteins and BPD. The outcomes of the IVW method indicated that decreased levels of circulating interleukin-17 C (IL-17 C) (OR = 0.92, 95%CI = 0.85–0.99, p-value = 0.0344) were suggestively associated with a higher risk of BPH and elevated levels of interleukin-10 receptor subunit alpha (IL-10RA) (OR = 1.24, 95%CI = 1.05–1.47, p-value = 0.0132) and urokinase-type plasminogen activator (uPA) (OR = 1.13, 95%CI = 1.00–1.28, p-value = 0.0421) were suggestively related to a higher risk of prostatitis. Furthermore, reverse MR revealed that BPH may promote the expression of circulating factors, including natural killer cell receptor 2B4 (CD244) (OR = 1.07, 95%CI = 1.01–1.13, p-value = 0.0192), T-cell surface glycoprotein CD6 isoform (CD6) (OR = 1.07, 95%CI = 1.01–1.13, p-value = 0.0192), and leukemia inhibitory factor receptor (LIF-R) (OR = 1.07, 95%CI = 1.01–1.15, p-value = 0.0163). Moreover, the results of sensitivity analyses indicate that heterogeneity and horizontal pleiotropy are unlikely to distort the findings. The results of this study indicate a potential association between circulating inflammatory proteins and BPD, which may become new diagnostic indicators or drug targets for clinical application in the prevention and treatment of BPD. However, further investigation is required.

Prostatitis is a common condition in andrology and urology that significantly impacts the quality of life of affected individuals. Current treatments often fail to provide lasting benefits. To identify novel therapeutic targets, we conducted a drug-targeted Mendelian randomization (MR) study. Using cis-expression quantitative trait loci (cis-eQTL) data from the eQTLGen Consortium combined with Genome-Wide Association Studies (GWAS) data on prostatitis from FinnGen, we performed a two-sample MR analysis. This analysis identified nine potential causal genes: ANXA1, CRY2, DSTYK, FKBP1A, LAMA5, NENF, PTGIR, STK39, and TGFA. Following heterogeneity testing, horizontal pleiotropy assessment, and bidirectional MR, CRY2 and PTGIR were validated in the Genotype-Tissue Expression (GTEx) portal replication phase. Bayesian colocalization analysis and genetic correlation analysis investigations provided strong evidence of shared causal variants with prostatitis and negative genetic correlations for these genes. PheWAS indicated negligible horizontal pleiotropy, and drug prediction analysis identified potential targeting agents for CRY2 and PTGIR. This study highlights CRY2 and PTGIR as promising therapeutic targets for prostatitis, providing new insights into its genetic underpinnings and offering potential pathways for developing effective treatments.

The etiology of benign prostatic hyperplasia (BPH) is multifactorial, and chronic inflammation plays a pivotal role in its pathogenesis. Growth hormone-releasing hormone (GHRH) is a hypothalamic neuropeptide that has been shown to act as paracrine/autocrine factor in various malignancies including prostate cancer. GHRH and its receptors are expressed in experimental models of BPH, in which antagonists of GHRH suppressed the levels of proinflammatory cytokines and altered the expression of genes related to epithelial-to-mesenchymal transition (EMT). We investigated the effects of GHRH antagonist on prostatic enlargement induced by inflammation. Autoimmune prostatitis in Balb/C mice was induced by a homogenate of reproductive tissues of male rats. During the 8-wk induction of chronic prostatitis, we detected a progressive increase in prostatic volume reaching 92% at week 8 compared with control (P < 0.001). Daily treatment for 1 mo with GHRH antagonist MIA-690 caused a 30% reduction in prostate volume (P < 0.05). Conditioned medium derived from macrophages increased the average volume of spheres by 82.7% (P < 0.001) and elevated the expression of mRNA for N-cadherin, Snail, and GHRH. GHRH antagonist reduced the average volume of spheres stimulated by inflammation by 75.5% (P < 0.05), and TGF-β2 by 91.8% (P < 0.01). The proliferation of primary epithelial cells stimulated by IL-17A or TGF-β2 was also inhibited by 124.1% and 69.9%, respectively. GHRH stimulated the growth of BPH-1 and primary prostate spheres. This study provides evidence that GHRH plays important roles in prostatic inflammation and EMT and suggests the merit of further investigation to elucidate the effects of GHRH antagonists in prostatitis and BPH.

Chronic pelvic pain syndrome (CPPS) is the most common form of prostatitis, accounting for 90-95% of all diagnoses. It is a complex multi-symptom syndrome with unknown etiology and limited effective treatments. Previous investigations highlight roles for inflammatory mediators in disease progression by correlating levels of cytokines and chemokines with patient reported symptom scores. It is hypothesized that alteration of adaptive immune mechanisms results in autoimmunity and subsequent development of pain. Mouse models of CPPS have been developed to delineate these immune mechanisms driving pain in humans. Using the experimental autoimmune prostatitis (EAP) in C57BL/6 mice model of CPPS we examined the role of CD4+T-cell subsets in the development and maintenance of prostate pain, by tactile allodynia behavioral testing and flow cytometry. In tandem with increased CD4+IL17A+ T-cells upon EAP induction, prophylactic treatment with an anti-IL17 antibody one-day prior to EAP induction prevented the onset of pelvic pain. Therapeutic blockade of IL17 did not reverse pain symptoms indicating that IL17 is essential for development but not maintenance of chronic pain in EAP. Furthermore we identified a cytokine, IL7, to be associated with increased symptom severity in CPPS patients and is increased in patient prostatic secretions and the prostates of EAP mice. IL7 is fundamental to development of IL17 producing cells and plays a role in maturation of auto-reactive T-cells, it is also associated with autoimmune disorders including multiple sclerosis and type-1 diabetes. More recently a growing body of research has pointed to IL17's role in development of neuropathic and chronic pain. This report presents novel data on the role of CD4+IL17+ T-cells in development and maintenance of pain in EAP and CPPS.