基因miR-205表达下调抑制前列腺肿瘤生长

本文旨在研究抑癌基凶has-miR-205在前列腺癌中的分子和功能机制。通过对早期和晚期前列腺癌组织进行miRNAs表达的基因芯片分析,从中选出异常表达的miR-205进行实时定量PCR分析,并对其在前列腺癌中的功能和靶基因c-SRC及其下游FAK／ERKI／2通路进行分析。结果发现miR-205在晚期前列腺癌中呈现低表达,其表达量与临床病理分期和总PSA及游离PSA呈负关联。体外功能试验分析显示高表达miR-205或是敲除C-SRC基因的表达可以抑制前列腺癌细胞的增殖与转移。裸鼠体内实验分析高表达miR-205可以抑制前列腺癌肿瘤形成。通过荧光素酶报告基因和Western blotting分析证实C—SRC是miR-205的靶基因,高表达的miR-205抑Nc-SRC及下游通路FAK,P—FAK,ERK1／2和P—ERK1／2的蛋白表达。抑癌基因miR-205在前列腺癌中低表达,并且通过靶基因C-SRC来抑制前列腺痛细胞的增殖和转移。     

MiR-30b-3p and miR-126-3p of urinary extracellular vesicles could be new biomarkers for prostate cancer

BackgroundExtracellular vesicles (EVs) including exosomes are present in blood, urine, and saliva and contain proteins, microRNAs, and messenger RNAs. We investigated microRNAs in urinary EVs to discover new biomarkers of prostate cancer (PCa).MethodsWe isolated EVs from urine obtained following digital rectal examination (DRE) of 14 men with elevated levels of serum prostate-specific antigen (PSA) [negative biopsy (n=4) and PCa with Gleason scores of 6 (n=3), 7 (n=3), and 8–9 (n=4)]. MicroRNAs extracted from EVs were analyzed by microRNA microarray.ResultsMicroRNAs miR-30b-3p and miR-126-3p were identified as being overexpressed in urinary EVs of the PCa patients versus the biopsy-negative men, but no microRNAs were associated with the Gleason score. In the independent cohort as well, these two microRNAs were overexpressed in urinary EVs from the PCa patients versus the negative-biopsy men. Logistic regression analysis adjusted by age and PSA showed that these two microRNAs were significantly associated with the prediction of PCa in biopsy specimens. Sensitivity and specificity of miR-30b-3p and miR-126-3p for the prediction of PCa were 46.4% and 88.0% and 60.7% and 80.0%, respectively, which were better than those of serum PSA (53.5% and 64.0%, respectively).ConclusionsMiR-30b-3p and miR-126-3p in urinary EVs could be potential biomarkers of PCa.     

Near-infrared fluorescence and nuclear imaging and targeting of prostate cancer

Despite advances in the treatment of castration-resistant and bone metastatic prostate cancer (PCa), there is still no clear demonstration that PCa growth and metastases can be unambiguously detected. We review recent advances including our own development of near-infrared fluorescence (NIRF) and near-infrared nuclear (NIRN) imaging approaches. We validated our results in experimental models of PCa bone and soft tissue metastases including PCa colonization at metastatic sites by injecting PCa cells either intratibially or intracardiacally. We describe our experience using noninvasive imaging and targeting modalities to probe PCa tumors grown at metastatic sites, molecular studies to understand the multiple molecular and cellular processes within tumor cells and their interactions with the tumor microenvironment, and targeting tumor growth at metastatic bone site. In this review, current knowledge and emerging technologies based on NIRF and NIRN disciplines will be summarized. Additionally the mechanisms of differential uptake of these agents by normal and cancerous cells will be described.     

Identification of novel biomarkers of prostate cancer through integrated analysis

BackgroundThe current methods adopted to screen for prostate cancer (PCa) can sometimes be misleading and inaccurate. Moreover, for advanced stages of PCa, the current effect of treatment is not satisfactory for some patients. Accordingly, we aimed to identify new biomarkers for the diagnosis and prognosis of PCa.MethodsA series of bioinformatic tools were utilized to search for potential new biomarkers of PCa and analyze their functions, expression, clinical relevance, prognostic value, and underlying mechanisms.ResultsAlthough ASPN was overexpressed in PCa, EDN3, PENK, MEIS2, IGF1, and CXCL12 were downregulated. The univariate Cox regression analysis showed that abnormally high expression of ASPN and low expression of other genes predicted worse prognosis. Moreover, the multivariate Cox regression analysis showed that ASPN, PENK, and MEIS2 were independently associated with the overall survival (OS) of patients, whereas other markers were not. The outcomes of gene ontology and gene set enrichment analysis showed that the expression levels of these genes might be associated with cell proliferation and infiltration of immune cells in PCa.ConclusionsWe demonstrated that ASPN, EDN3, PENK, MEIS2, IGF1, and CXCL12 are possibly novel diagnostic indicators for PCa, whereas ASPN, PENK, and MEIS2 show appealing potential to predict the prognosis of this disease.     

Urinary biomarkers for prostate cancer: a review

Although the routine use of serum prostate-specific antigen (PSA) testing has undoubtedly increased prostate cancer (PCa) detection, one of its main drawbacks is its lack of specificity. As a consequence, many men undergo unnecessary biopsies or treatments for indolent tumours. PCa-specific markers are needed for the early detection of the disease and the prediction of aggressiveness of a prostate tumour. Since PCa is a heterogeneous disease, a panel of tumour markers is fundamental for a more precise diagnosis. Several biomarkers are promising due to their specificity for the disease in tissue. However, tissue is unsuitable as a possible screening tool. Since urine can be easily obtained in a non-invasive manner, it is a promising substrate for biomarker testing. This article reviews the biomarkers for the non-invasive testing of PCa in urine.     

Perioperative complications of radical retropubic prostatectomy in patients with locally advanced prostate cancer: a comparison with clinically localized prostate cancer

Radical prostatectomy (RP) continues to be an effective surgical therapy for prostate carcinoma, particularly for organ-confined prostate cancer (PCa). Recently, RP has also been used in the treatment of locally advanced prostate cancer. However, little research has been performed to elucidate the perioperative complications associated with RP in patients with clinically localized or locally advanced PCa. We sought to analyse the incidence of complications in these two groups after radical retropubic prostatectomy (RRP). From June 2002 to July 2010, we reviewed 379 PCa patients who underwent RRP in our hospital. Among these cases, 196 had clinically localized PCa (T_1a–T_2c: group 1), and 183 had locally advanced PCa (≥T_3a: group 2). The overall complication incidence was 21.9%, which was lower than other studies have reported. Perioperative complications in patients with locally advanced PCa mirror those in patients with clinically localized PCa (26.2% vs. 17.8%, P=0.91). Our results showed that perioperative complications could not be regarded as a factor to consider in regarding RP in patients with cT₃ or greater.     

Effect of obesity on the prognosis and recurrence of prostate cancer after radical prostatectomy: a meta-analysis

BackgroundObesity has been found to be closely related to the increased risk of fatal prostate cancer (PCa), however there remains no evidence that further clarifies the relationship between obesity and the postoperative recurrence and poor prognosis of PCa. In this study, a systematic review and meta-analysis were performed to systematically evaluate the effect of obesity on the prognosis and recurrence of PCa after radical prostatectomy (RP).MethodsA literature search of the PubMed, Web of Science, and Embase databases was performed covering articles published between January 2013 and January 2020. Articles regarding the correlation between body mass index (BMI) and the prognosis and recurrence of PCa following RP were included in the meta-analysis. Two investigators independently screened the literature and extracted relevant data including publication information, key results, number of cancer cases, and multivariable-adjusted odds ratios (ORs) with 95% confidence intervals (CIs). Meta-analysis was performed using RevMan 5.3 and Stata 16.0 software, and forest plots, funnel plots, and sensitivity analysis were also conducted.ResultsA total of 14 articles were included, all of which were analyzed for clinicopathological characteristics. Eight articles reported the biochemical recurrence (BCR) with prostate-specific antigen (PSA) as the predictor, and six articles reported the positive surgical margins (PSM). The meta-analysis showed that obese PCa patients had more postoperative recurrence and poor prognosis compared with the normal weight PCa patients, and the difference was statistically significant (OR =1.25, 95% CI: 1.10, 1.43). BCR exhibited no significant difference between obese and non-obese PCa patients after surgery (OR =1.2, 95% CI: 0.96, 1.46), and there were also no notable differences in PSM between the groups (OR =1.16, 95% CI: 0.99, 1.36). Subgroup analysis showed that obese PCa patients in the Americas (95% CI: 1.11, 1.37) and Europe (95% CI: 1.11, 1.78) were more likely to have surgical recurrence and poor prognosis (OR =1.40). Obese patients in the Americas were also more likely to have BCR after surgery (95% CI: 1.07, 1.36).ConclusionsObesity easily leads to poor prognosis and recurrence of PCa after RP.     

miR-152对前列腺癌细胞株迁移和侵袭能力的影响

目的研究miR-152在前列腺癌、前列腺正常组织中的表达情况及其在前列腺癌细胞系中的作用。方法采用TaqMan荧光定量RT—PCR方法检测8例前列腺癌和8例前列腺正常组织的样本中miR-152的表达水平。运用Transwell细胞迁移实验及侵袭实验评估miR一152对前列腺细胞系PC-3和DU145细胞功能的影响。结果与正常前列腺组织相比,miR-152在前列腺癌组织中的表达水平显著下调（P〈0．05）。体外实验中上调miR152的表达可以显著降低前列腺癌细胞的迁移和侵袭能力（P〈O．05）。结论miR-152在前列腺癌中可作为一种肿瘤抑制因子,影响前列腺癌细胞的迁移和侵袭能力。     

Urinary exosome-based androgen receptor-variant 7 detection in metastatic castration-resistant prostate cancer patients

BackgroundAndrogen receptor variant 7 (AR-V7) detection provides important information for the clinical management of abiraterone in metastatic castration-resistant prostate cancer (mCRPC). We performed a non-invasive urine-derived exosomal AR-V7 analysis of mCRPC patients.MethodsA total of 34 mCRPC patients were recruited including 16 patients treated with abiraterone (ABI) with stable prostate-specific antigen (PSA)/radiograph response (the ABI-Sta group) and 18 were resistant to abiraterone (the ABI-Res group). Urine was collected from patients and healthy control patients for the analysis. Exosomal ribonucleic acid was isolated from urine. Urinary exosome-based androgen receptor-variant 7 was detected by quantitative real-time polymerase chain reaction assay. Characteristics of patients and survival data were collected. The correlation between AR-V7 expression and the therapeutic effect/survival outcomes of abiraterone was analyzed.ResultsUrine is the ideal biological sample for exosome separation and AR full-length analysis. Positive urine-derived exosomal AR-V7 was detected in 32.4% (11 of 34) of the mCRPC patients’ urine samples. Positive AR-V7 was more common in the ABI-Res patients than the ABI-Sta patients (50.0% vs. 12.5%, respectively; P=0.009), and was associated with a higher PSA progression rate and poorer overall survival (OS) (P=0.0031, and P=0.0012, respectively).ConclusionsThe present study showed that the detection of urine-derived exosomal AR-V7 provides a sensitive and feasible clinical workflow. The predicting role of urine-derived exosomal AR-V7 in mCRPC patients should be further verified using studies with greater sample sizes.     

Association of 5-alpha-reductase inhibitor and prostate cancer incidence and mortality: a meta-analysis

Background5-Alpha-reductase inhibitors (5-ARIs) have been suggested as potential chemopreventive agents for prostate cancer (PCa). This study was conducted to evaluate the effect of 5-ARIs on the incidence and mortality of PCa.MethodsThe PubMed, Embase and Cochrane Library databases were searched comprehensively from database inception to October 2019. The clinical outcomes included the incidence of overall PCa, high-grade (Gleason8-10) PCa, metastatic PCa, overall survival (OS), and cancer-specific survival (CSS).ResultsOverall, 23 studies were included in the present study, representing 11 cohort studies, 5 case-control studies, and 8 randomized controlled trials. The use of 5-ARIs was associated with a decreased risk of overall PCa [relative risk (RR) =0.77; 95% CI: 0.67–0.88; P<0.001] and increased risk of Gleason 8–10 PCa (RR=1.19; 95% CI: 1.01–1.40; P=0.036). In terms of metastatic PCa, there were no significant between-group differences (RR=1.23; 95% CI: 0.69–2.18; P=0.487). Furthermore, we found that prediagnostic 5-ARI usage was not associated with an increased risk of overall or prostate cancer mortality, with HRs of 1.00 (95% CI: 0.92–1.08; P=0.938) and 0.98 (95% CI: 0.80–1.21; P=0.881), respectively.ConclusionsIn conclusion, while male 5-ARI users were associated with a decreased risk of overall prostate cancer and increased risk of high-grade prostate cancer (Gleason 8–10), they were not associated with an increased risk of overall or prostate cancer mortality. 5-ARIs should be recommended carefully for use as chemopreventive agents.     

Enzalutamide-resistant related lncRNA NONHSAT210528 promotes the proliferation and invasion of prostate cancer

BackgroundAs a new-generation androgen-receptor antagonist, enzalutamide is a first-choice drug for advanced prostate cancer (PCa) patients. However, secondary resistance to enzalutamide poses a new challenge in the treatment of cancer. Long non-coding RNA (lncRNA) regulates cell function through many levels and mechanisms, and also plays an important role in the biological behaviors of tumors.MethodsLncRNA microarrays were used to detect enzalutamide-resistant related lncRNA in Enzalutamide-resistant C4-2 (C4-2 ENZ-R) cells and corresponding parent cells. Cell Counting Kit 8, flow cytometry, and transwell assays were used to test the effect of lncRNA NONHSAT210528 on the function of PCa cells. RNA pulls down and the luciferase report gene was used to detect the competitive endogenous RNA (ceRNA) mechanism. The culture supernatant of C4-2 and C4-2b cells was transferred to the lower chamber for transwell assay of human umbilical endothelial cells (HUVECs).ResultsThe lncRNA microarray analysis showed that there were significant differences in the expression of many lncRNAs between the C4-2 ENZ-R and C4-2 cells. The real-time polymerase chain reaction (PCR) detection showed that the expression of lncRNA NONHSAT210528 was significantly higher in the C4-2 ENZ-R cells than the C4-2 cells. The Transwell assays showed that lncRNA NONHSAT210528 overexpression increased the invasion of the C4-2 and C4-2b cells. The cell-wound scratch and the transwell assays showed that the culture supernatant of C4-2 and C4-2b cells with overexpressed lncRNA NONHSAT210528 promoted the migration and invasion of HUVECs. Furthermore, lncRNA NONHSAT210528 regulated the expression of YOD1 dependent on miR-21.ConclusionsEnzalutamide-resistant related lncRNA NONHSAT210528 appears to promote the proliferation and invasion of PCa cells by functioning as a ceRNA and regulating the miR-21-5p/YOD1 signal pathway.     

CircRNA pappalysin 1 facilitates prostate cancer development through miR-515-5p/FKBP1A axis

The role of circular RNA (circRNA) pappalysin 1 (circ-PAPPA; hsa_circ_0088233) in prostate cancer (PCa) cells was explored in the current study. Circ-PAPPA abundance was markedly enhanced in PCa. Circ-PAPPA interference restrained cell viability, proliferation, motility and glycolysis while elevated the apoptosis rate of PCa cells. Circ-PAPPA negatively regulated microRNA-515-5p (miR-515-5p) abundance. MiR-515-5p silencing largely diminished circ-PAPPA knockdown-mediated effects in PCa cells. MiR-515-5p directly bound to FKBP prolyl isomerase 1A (FKBP1A). MiR-515-5p overexpression-mediated impacts were partly counteracted by FKBP1A overexpression. Circ-PAPPA silencing reduced FKBP1A protein level partly by elevating miR-515-5p expression. Circ-PAPPA knockdown significantly restrained the tumour growth in vivo. Circ-PAPPA elevated the malignant phenotypes of PCa cells by sequestering miR-515-5p to induce the expression of FKBP1A.