Noncancerous Prostate Research Articles

Multifaceted Function of MicroRNA-299-3p Fosters an Antitumor Environment Through Modulation of Androgen Receptor and VEGFA Signaling Pathways in Prostate Cancer

Prostate cancer (PCa) is one of the most common cancers to affect men worldwide. Androgen receptor (AR) signaling is central to PCa and PCa therapy. MicroRNAs (miRNAs) play crucial roles in the regulation of prostate cancer through modulation of signaling pathways. In the present study, we illustrate the functional significance and therapeutic benefit of miR-299-3p, an AR targeting microRNA, in PCa progression. We noted loss of expression of miR-299-3p in prostate tumors compared to noncancerous prostate tissues. Replenishment of miR-299-3p in C4-2B, 22Rv-1 and PC-3 cells contributed to cell cycle arrest, reduced proliferation, migration and increased expression of apoptotic markers. Additionally, overexpression of miR-299-3p induced a reduction of AR, PSA and VEGFA expression. AGO-RNA pulldown experiment showed enrichment of AR, VEGFA and miR-299-3p in C4-2B cells overexpressing miR-299-3p. miR-299-3p overexpression also inhibited epithelial mesenchymal transition, expression of Slug, TGF-β3, phospho-AKT and phospho-PRAS40, but increased expression of E-cadherin. Furthermore, miR-299 overexpression resulted in reduced tumor growth in xenograft models and increased drug sensitivity. Overall, this study has identified novel mechanisms of antitumor and antimigration function of miR-299-3p through modulation of AR and VEGFA signaling pathways which lead to improved drug sensitivity of PCa.

Long non-coding RNA HANR as a biomarker for the diagnosis and prognosis of colorectal cancer.

Previous work suggests that the long noncoding RNA HCC associated long non-coding RNA (HANR) is associated with hepatocellular carcinoma (HCC) progression, but its significance in the context of colorectal cancer (CRC) remains to be determined. Therefore, in this study we assessed the prognostic and diagnostic value of HANR in patients suffering from CRC.The HANR expression in 165 pairs of CRC cancer and adjacent non-cancerous prostate tissues was measured by quantitative reverse transcription polymerase chain reaction (qRT-PCR) analysis. Student t test was conducted for intergroup comparison. Pearson correlation test was used for correlation analysis. Survival curves were carried out by the Kaplan-Meier method and evaluated using the log-rank test. Multivariable Cox proportional hazard risk regression model was performed to screen the independent factor affected the prognosis of CRC patients.In this study, levels of HANR were significantly higher in CRC tumor samples relative to adjacent normal tissue samples (P < .001). A ROC analysis suggested HANR expression could be reliably used to differentiate between normal and CRC tumor tissue. In addition, elevated HANR expression was positively correlated with more advanced and aggressive CRC features, such as a larger tumor size (P = .003), increased invasion depth (P = .012), and more advanced TNM stage (P = .011). Survival analyses revealed that elevated HANR expression was correlated with worse overall survival (P = .002) and disease-free survival (P = .003). A multivariate analysis further confirmed the relevance of HANR as an independent predictor of CRC patient outcomes.In summary, these results indicate that the lncRNA HANR is a promising prognostic indicator in CRC patients.

Acute prostatitis associated with noncancerous prostate at the Lubumbashi University Clinics: epidemioclinical and therapeutic features

Introductionles prostatites aiguës sont une entité fréquente en urologie. L'objectif de cette étude était d'analyser les aspects épidémio-cliniques et thérapeutiques des prostatites aiguës sur des prostates non tumorales aux Cliniques Universitaires de Lubumbashi.Méthodesil s'est agi d'une étude descriptive transversale et rétrospective rapportant une série de 25 patients souffrant de prostatite aiguë documentée et pris en charge aux Cliniques Universitaires de Lubumbashi durant une période de quatre ans soit de 2015 à 2018. Tous les patients porteurs de tumeurs prostatiques ont été exclus de notre étude. Les données ont été recueillies sur base d´une fiche d´enquête reprenant différents paramètres d´étude répartis en 3 catégories à savoir les données épidémiologiques comprenant l´âge, la période d´étude, la résidence, les données cliniques reprenant les signes subjectifs, les signes objectifs, l´état général, les éléments du toucher rectal ainsi que les données paracliniques réparties en laboratoires et imagerie.Résultatsla prostatite aiguë sur prostate non tumorale a représenté 1,27% de l´ensemble de la pathologie chirurgicale et 7,66% en urologie. La tranche d´âge la plus touchée était celle de 19 à 37 ans avec 64% des cas, l´âge moyen est de 33,16±2,4 ans. Dix-sept patients (68%) étaient suivis en ambulatoires et 8 (32%) en hospitalisation. Sur le plan clinique, la fièvre au-delà de 38,5°celsius était retrouvée chez 15 patients (60%), la dysurie chez 11 patients (44%), rétention aiguë d´urine chez 3 patients (12%), les brulures mictionnelles chez 8 patients (32%), syndrome douloureux chez 21 patients (84%), la sensibilité prostatique au toucher rectal chez 18 patients (72%). Sur le plan de l´imagerie, l´échographie a été le seul examen réalisé et ce, chez 16 patients (64%). Sur le plan biologique, le bilan inflammatoire était quasi-systématique chez tous nos patients (100%) comprenant la NFS, la VS, la CRP; l´hémoculture réalisée chez 4 patients (16%) parmi lesquels 3 étaient positives. Tous nos patients avaient réalisé l´examen cytobactériologique des urines ou des sécrétions prostatiques recueillies par un massage prostatique. La culture d´urine était stérile chez 6 patients (24%) et positive chez 19 patients (76%) avec Escherichia coli comme germe le plus retrouvé, chez 16 patients sur les 19 (84,21%). Tous nos patients ont été mis sous anti-inflammatoire en intra-rectale et les fluoroquinolones ont été les antibiotiques les plus utilisés dans notre série chez 18 patients (64%) parmi lesquels 12 en monothérapie. Six cas sur les 25 (24%) étaient associés à une orchi-épidydimite. La durée de traitement allait de 2 semaines à 4 semaines avec comme critère d´arrêt de traitement soit la stérilisation des sécrétions ou des urines soit la disparition de la leucocyturie. Ainsi, sur les 19 patients avec culture positive à l´admission, 14 ont réalisé une deuxième culture (73,68%) à 2 semaines de traitement parmi lesquels 3 (12%) étaient encore positives et ont dû réaliser une troisième culture 4 semaines après le début de traitement. L´évolution était bonne chez 22 patients (88%) avec une rémission complète des signes cliniques et biologiques et 3 cas (12%) ont évolué vers une persistance des signes et un passage à la chronicité, aucun cas d´évolution vers un abcès prostatique.Conclusionla prostatite aiguë sur prostate non tumorale reste une entité nosologique urologique très préoccupante dont la prise en charge doit être rigoureuse d´autant plus que la population à risque est celle en période d´intense activité sexuelle. L´usage de l´échographie endorectale, la proscription du massage prostatique doivent s´intégrer dans la prise en charge aux cliniques universitaires de Lubumbashi.

Epstein-Barr and Bk Virus in Cancerous and Noncancerous Prostate Tissue

Aim: We conducted a case–control study to examine the presence of BK virus (BKV) and Epstein barr virus (EBV) genome in prostate specimens of benign prostatic hyperplasia (BPH) and prostate cancer (PCa) in Iran. Materials &amp; methods: 64 paraffin-embedded PCa specimens were included as case subjects and 57 paraffin-embedded BPH specimens as control. DNA extraction was carried out by phenol–chloroform technique and PCR for detection of BKV and EBV. Results: 90 (73%) out of 121 specimens were collected by prostatectomy and 31 (27%) by transurethral resection of the prostate. BKV was not detected in any of the samples and one positive EBV was reported. Conclusion: These findings provide further evidence against a causative role of BKV and EBV in the development of PCa.

Case Study: The Recurrent Fusion RNA DUS4L-BCAP29 in Noncancer Human Tissues and Cells.

Traditional gene fusions are involved in the development of various neoplasias. DUS4L-BCAP29, a chimeric fusion RNA, has been reported to be a cancer-related fusion in prostate and gastric cancers. This chimeric RNA is believed to play a tumorigenic role. Here, we showed that the DUS4L-BCAP29 fusion transcript exists in a variety of normal tissues. It is also present in noncancerous epithelial and fibroblast cell lines. Quantitatively, the fusion transcript has a similar expression level in noncancerous gastric and prostate cell lines and tissues to its expression in cancerous cell lines and tissues. Previously, a loss-of-function approach was used to report a probable functionality for this fusion. However, this approach is not sufficient to prove such functionality. Alternatively, a gain-of-function approach showed that overexpression of DUS4L-BCAP29 promotes cell growth and motility, even in noncancerous cell lines. Finally, we provide further evidence that the fusion transcript is a product of cis-splicing between adjacent genes. In summary, we believe that in contrast to traditional gene fusions, DUS4L-BCAP29 cannot be used as a cancer biomarker. Instead, it is a fusion transcript that exists in normal physiology and its progrowth effect is not unique to cancer situations.

Increased expression of miR-153 predicts poor prognosis for patients with prostate cancer.

Deregulation of miR-153 has recently been observed in several common human cancer, while miR-153 serves an oncogene or tumor suppressive role in different cancer types. Previously, miR-153 has been identified to be overexpressed in prostate cancer. miR-153 played an important role in promoting proliferation of human prostate cancer cells and presented a novel mechanism of microRNA-mediated direct suppression of phosphatase and tensin homolog (PTEN) expression in prostate cancer cells. Until now, little is known about the clinical significance of miR-153 expression in prostate cancer.The miR-153 expression in 143 pairs of prostate cancer and adjacent non-cancerous prostate tissues was measured by quantitative reverse transcription polymerase chain reaction (qRT-PCR) analysis. Student t test was conducted for intergroup comparison. Pearson correlation test was used for correlation analysis. Survival curves were carried out by the Kaplan–Meier method and evaluated using the log-rank test. Multivariable Cox proportional hazard risk regression model was performed to screen the independent factor affected the prognosis of prostate cancer patients.qRT-PCR analysis showed that the expression of miR-153 was significantly increased in the prostate cancer tissues in comparison with the adjacent noncancerous prostate tissues (P < .001). The high expression of miR-153 in prostate cancer tissues is closely correlated with aggressive clinical pathological parameters such as lymph node metastasis (P = .001); bone metastasis (P < .001); Gleason score (P < .001); and tumor-node-metastasis (TNM) stage (P < .001). Prostate cancer patients with a high expression of miR-153 had an evidently lower 5-year overall survival as compared with those with a low expression of miR-153 (P = .019). Notably, the multivariate Cox regression analysis indicated that miR-153 expression was an independent factor for predicting the 5-year overall survival of prostate cancer patients (hazard ratio [HR] = 2.481, 95% confidence interval [CI]: 1.582–10.727; P = .018).Our study demonstrated that high miR-153 expression was significantly associated with a poor overall survival independently of other factors in prostate cancer. Therefore, miR-153 may be an available biomarker for prostate cancer prognosis.

Extracellular Vesicles from Human Advanced-Stage Prostate Cancer Cells Modify the Inflammatory Response of Microenvironment-Residing Cells.

Prostate cancer (PCa) progression is strictly associated with microenvironmental conditions, which can be modified by cancer-released extracellular vesicles (EVs), important mediators of cell-cell communication. However, the role of EVs in the inflammatory cross-talk between cancer cells and microenvironment-residing cells remains largely unknown. To evaluate the role of EVs in the tumour microenvironment, we treated the non-cancerous prostate cell line PNT2 with EVs isolated from advanced-stage prostate cancer PC3 (PC3-EVs). Caspase-1-mediated IL-1β maturation was evaluated after 24 h incubation with EVs. Moreover, the effect of PC3-EVs on differentiated macrophagic THP-1 cells was assessed by analyzing cytokine expression and PC3 cells migration and proliferation profiles. We illustrated that PC3 cells contain active NLRP3-inflammasome cascade and secrete IL-1β. PC3-EVs affect the PNT2 inflammatory response, inducing caspase-1-mediated IL-1β maturation via ERK1/2-mediated lysosomal destabilization and cathepsin B activation. We also verified that PC3-EVs induce a functional TAM-like polarization in differentiated THP-1 cells. Our results demonstrated that cancer-derived EVs induce an inflammatory response in non-cancerous prostate cells, while inducing an immunomodulatory phenotype in immune cells. These apparently contradictory effects are both committed to strengthening the tumour-promoting microenvironment

Prostate cancer cells enhance interleukin-15-mediated expansion of NK cells.

To identify cytokines that can activate and expand NK cells in the presence of prostate cancer cells in order to determine whether these agents may be useful in future intra-tumoural administration in pre-clinical and clinical prostate cancer trials. Lymphocytes isolated from normal donor blood were set up in co-cultures with either cancer or non-cancerous prostate cell lines, together with each of the cytokines interleukin (IL)-2, IL-12, IL-15, interferon (IFN)-γ or IL-21 for a period of 7days. Then, expansion of NK cells, NKT cells and CD8 T cells was measured by flow cytometry and compared with the expansion of the same cells in the absence of prostate cells. The cytotoxic activity of NK cells, as measured by perforin and tumour cell killing, was also assessed. NK cell receptors and their corresponding ligands on prostate tumour cells were analysed to determine whether any of these were modulated by co-culture. The role of the tumour-secreted heat shock proteins HSP90 and HSP70 in the expansion of NK cells in the co-cultures was also investigated because of their effects on NK and CD8 T-cell activation. We showed that, among a panel of cytokines known to cause NK cell activation and expansion, only IL-15 could actively induce expansion of NK, NKT and CD8 T cells in the presence of prostate cancer cell lines. Furthermore, the expansion of NK cells was far greater (up to 50% greater) in the presence of the cancer cells (LNCaP, PC3) than when lymphocytes were incubated alone. In contrast, non-cancerous cell lines (PNT2 and WPMY-1) did not exert any expansion of NK cells. The cytolytic activity of the NK cells, as measured by perforin, CD107a and killing of tumour cells, was also greatest in co-cultures with IL-15. Examination of NK cell receptors shows that NKG2D is upregulated to a greater degree in the presence of prostate cancer cells, compared with the upregulation with IL-15 in lymphocytes alone. However, blocking of NKG2D does not inhibit the enhanced expansion of NK cells in the presence of tumour cells. Among a panel of NK cell-activating cytokines, IL-15 was the only cytokine that could stimulate expansion of NK cells in the presence of prostate cancer cells; therefore IL-15 may be a good candidate for novel future intra-tumoural therapy of the disease.

HOXC6 in the prognosis of prostate cancer

Aims Our study aimed to investigate the expression and prognostic role of homeobox C6 (HOXC6) in prostate cancer (PCa). Methods Relative expression of HOXC6 at mRNA and protein levels in tissues and cell lines of PCa were measured using quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot analysis, respectively. Association between HOXC6 expression and clinical factors was analyzed by Chi-square test. HOXC6 effects on the proliferation, invasion and metastasis of PCa cells were severally examined through CCK-8 and transwell assays. Results Relative expressions of HOXC6 at mRNA and protein levels were obviously higher in both PCa tissues and cells than in adjacent non-cancerous tissues and normal human prostate epithelial cells (p < .05). Chi-square test demonstrated that high expression of HOXC6 was significantly associated with PSA concentration, Gleason score and TNM stage (p < .05). The down-regulation of HOCX6 remarkably inhibited the proliferation, migration and invasion of PCa cells. Kaplan-Meier analysis showed that patients with high HOXC6 expression had shorter overall survival than those with low HOXC6 expression (log rank test, p < .001). Conclusion Up-regulated HOXC6, in PCa patients, could not only participate in the progression of PCa but also function as an independent prognostic marker for the cancer.

Differentiating Cancerous and Non-cancerous Prostate Tissue Using Multi-scale Texture Analysis on MRI.

Prostate cancer (PCa) diagnosis is established by pathological examination via biopsies, which are associated with significant complications and false negatives. Using MRIs to identify locations with high probability of containing cancer could instead be used to guide the biopsy procedure. The present investigation aims to identify target regions within different prostatic zones on MRI with high probability of being cancerous for assisting in the decision of where and how to perform biopsy. Our approach involved extracting multi-scale texture features for capturing local patterns to distinguish cancer and healthy tissue in different T2W-MRI prostate zones. Three different classification models were fed by the proposed strategy, namely support vector machine (SVM), Adaboost, and Random Forest. SVM with a linear kernel showed the best classification performance, with AUC scores of 0.91 in the anterior fibromuscular stroma area, 0.85 in the peripheral zone, and 0.87 when classification is performed independently of the prostate zone. The proposed method demonstrated that discriminant multi-scale texture features can accurately identify regions of prostate cancer in a zone-specific fashion, via MRI.

Histone variant MacroH2A1 is downregulated in prostate cancer and influences malignant cell phenotype

BackgroundProstate cancer (PCa), a major cause of cancer-related morbidity and mortality worldwide and mostly asymptomatic at earliest stages, is characterized by disruption of genetic and epigenetic balance. A better understanding of how those mechanisms orchestrate disease might improve diagnostic and prognostic tools, allowing for improvements in treatment efficacy. Replacement of canonical histones, an epigenetic mechanism, is highly conserved among species and altered expression of histones variants (e.g., MacroH2A1) has been associated with tumorigenesis. H2AFY gene encodes two isoforms of H2A histone variant MacroH2A1: MacroH2A1.1 and MacroH2A1.2. Specifically, MacroH2A1.1 isoform inhibits cell proliferation and promotes cellular differentiation. Because the contribution of this histone variant to carcinogenesis has been reported in several cancer types, but not for PCa, we aimed to investigate the contribution of MacroH2A1 for prostate carcinogenesis.MethodsMacroH2A1, MacroH2A1.1 and MacroH2A1.2 isoforms and the corresponding splicing regulators transcript levels were evaluated by RT-qPCR, in a tissue cohort composed by PCa, prostatic intraepithelial neoplasia (PIN) and normal prostate cases. Knockdown for MacroH2A1 and MacroH2A1.1 was performed through lentiviral transduction in DU145 cells, and MacroH2A1.1 overexpression was achieved in LNCaP cells by plasmid transfection, followed by functional assays. Biological and/or experimental replicates were performed when necessary, and specific statistical tests were applied to perform data analysis.ResultsMacroH2A1.1 transcript levels were downregulated in PIN and primary PCa compared to normal prostate tissues. The same was found for QKI, a MacroH2A1.1’s splicing regulator. Moreover, lower MacroH2A1.1 and QKI expression levels associated with less differentiated tumors (Gleason score ≥ 7). Interestingly, MacroH2A1.1, but more impressively DDX17 (AUC = 0.93; p < 0.0001) and QKI (AUC = 0.94; p < 0.0001), accurately discriminated cancerous from noncancerous prostate tissues. Furthermore, in PCa cell lines, total MacroH2A1 knockdown augmented malignant features, whereas MacroH2A1.1 overexpression impressively attenuated the malignant phenotype.ConclusionsOverall, our data, derived from primary PCa tissues and cell lines, anticipate a tumor suppressive role for MacroH2A1, particularly for the MacroH2A1.1 isoform, in prostate carcinogenesis.

AICAR Induces Apoptosis and Inhibits Migration and Invasion in Prostate Cancer Cells Through an AMPK/mTOR-Dependent Pathway.

Current clinical challenges of prostate cancer management are to restrict tumor growth and prohibit metastasis. AICAR (5-aminoimidazole-4-carbox-amide-1-β-d-ribofuranoside), an AMP-activated protein kinase (AMPK) agonist, has demonstrated antitumor activities for several types of cancers. However, the activity of AICAR on the cell growth and metastasis of prostate cancer has not been extensively studied. Herein we examine the effects of AICAR on the cell growth and metastasis of prostate cancer cells. Cell growth was performed by MTT assay and soft agar assay; cell apoptosis was examined by Annexin V/propidium iodide (PI) staining and poly ADP ribose polymerase (PARP) cleavage western blot, while cell migration and invasion were evaluated by wound-healing assay and transwell assay respectively. Epithelial–mesenchymal transition (EMT)-related protein expression and AMPK/mTOR-dependent signaling axis were analyzed by western blot. In addition, we also tested the effect of AICAR on the chemosensitivity to docetaxel using MTT assay. Our results indicated that AICAR inhibits cell growth in prostate cancer cells, but not in non-cancerous prostate cells. In addition, our results demonstrated that AICAR induces apoptosis, attenuates transforming growth factor (TGF)-β-induced cell migration, invasion and EMT-related protein expression, and enhances the chemosensitivity to docetaxel in prostate cancer cells through regulating the AMPK/mTOR-dependent pathway. These findings support AICAR as a potential therapeutic agent for the treatment of prostate cancer.

RRBP1 is highly expressed in prostate cancer and correlates with prognosis.

Objective: Recently, ribosome binding protein 1 (RRBP1) is reported to be involved in tumorigenesis. However, the expression and clinical significance of RRBP1 in prostate cancer (PCa) remains unknown. This study is aimed to investigate the expression and clinical significance of RRBP1 in PCa. Materials and methods: RRBP1 expression was firstly detected in 6 cases of PCa and matched adjacent non-cancerous prostate tissues by reverse transcription-quantitative PCR (RT-qPCR) and Western blot. Then, RRBP1 expression was further detected in 127 cases of PCa and 40 cases of non-cancerous prostate tissues by immunohistochemistry (IHC). The relationship of RRBP1 with clinical-pathological characters and patients’ prognosis was analyzed in PCa.Results: RT-qPCR and Western blot analysis showed that RRBP1 expression levels in PCa tissues were significantly higher compared with those in matched adjacent non-cancerous prostate tissues. IHC results shown that the high-expression rate of RRBP1 in PCa was 69.3%, which was significantly greater than those in non-cancerous prostate tissues (15.0%, P<0.001). RRBP1 expression was significantly associated with T stage, lymph node metastasis, PSA and Gleason score in PCa. Survival analysis indicated that patients with RRBP1 low-expression presented longer survival time compared with those with RRBP1 high-expression. Moreover, RRBP1 as well as T stage, lymph node metastasis and Gleason score could serve as independent prognostic factors in PCa.Conclusion: RRBP1 is highly expressed in PCa and correlates with prognosis, which may serve as a potential biomarker in PCa.

Cellular Refractive Index Comparison of Various Prostate Cancer and Noncancerous Cell Lines via Photonic-Crystal Biosensor.

The current clinical standard for mass screening of prostate cancer are prostate-specific antigen (PSA) biomarker assays. Unfortunately, the low specificity of PSA's bioassays to prostate cancer leads to high false-positive rates, as such there is an urgent need for the development of a more specific detection system independent of PSA levels. In our previous research, we have successfully demonstrated, with the use of our Photonic-Crystal based biosensor in a Total-Internal-Reflection (PC-TIR) configuration, detection of prostate cancer (PC-3) cells against benign prostate hyperplasia (BPH-1) cells. The PC-TIR biosensor achieved detection of individual prostate cancer cells utilizing cellular refractive index (RI) as the only contrast parameter. To further study this methodology in vitro, we report a comprehensive study of the cellular RI's of various prostate cancer and noncancerous cell lines (i.e. RWPE-1, BPH-1, PC-3, DU-145, and LNCaP) via reflectance spectroscopy and single-cell RI imaging utilizing the PC-TIR biosensor. Our study shows promising clinical potential in utilizing the PC-TIR biosensor system for the detection of prostate cancer against noncancerous prostate epithelial cells.

Modified MR dispersion imaging in prostate dynamic contrast‐enhanced MRI

An estimation of an intravascular dispersion parameter was previously proposed to improve the overall accuracy and precision of the model parameters, but the high computation complexity can limit its practical usability in prostate dynamic contrast-enhanced MRI (DCE-MRI). To compare and evaluate the model fitting uncertainty and error in the model parameter estimation using different DCE-MRI analysis models and to evaluate the ability of the intravascular dispersion parameter to delineate between noncancerous and cancerous prostate tissue in the transition and peripheral zones. Retrospective. Fifty-three patients who underwent radical prostatectomy. 3 T/3D RF-spoiled gradient echo sequence. The coefficient of variation was used to assess the model fitting uncertainty by adding random noise to the time-concentration curves, and the Akaike information criterion was used to assess the model fitting error. The parametric maps derived from four DCE-MRI analysis models were evaluated by evaluating the delineation between noncancerous tissue and prostate cancer or clinically significant prostate cancer. The receiver operating curve analysis was performed to compare the ability to delineate between noncancerous and prostate cancer tissue in the transition and peripheral zones. Both MR dispersion imaging (MRDI) and Weinmann analysis models had the maximum coefficient of variation in different tissue types, while the model fitting uncertainty of modified (m)MRDI was similar to the standard Toft model. In mMRDI, the model fitting error was minimum, and the delineation between noncancerous and clinically significant prostate cancer tissue was improved in both transition (area under the curve [AUC] = 0.92) and peripheral zones (AUC = 0.92), in comparison with MRDI (AUC = 0.89 and AUC = 0.85, respectively). The mMRDI showed promising results in detecting prostate cancer while maintaining a similar model fitting uncertainty. 3 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2019;50:1307-1317.

Downregulation of DACT-2 by Promoter Methylation and its Clinicopathological Significance in Prostate Cancer.

Backgrounds: Dapper homolog (DACT) 2, a member of DACT gene family, is frequently down-regulated in various malignancies and linked to tumor progression. However, the regulatory mechanism of DACT-2 expression and its biological role in human prostate cancer (PCa) remains elusive. Here, we investigated the expression and an epigenetic change of DACT-2 in prostate cancer, and determined if these findings were correlated with clinicopathologic characteristics of PCa.Methods: The expression profile of DACT-2 of was detected by qRT-PCR, Western blotting, and immunohistochemistry in four prostate cell lines (RWPE-1, LNCaP, PC-3 and DU145), 56 cases of frozen prostate tissues (forty-seven primary prostate carcinomas, nine paired noncancerous and cancerous prostate tissues) and a tissue microarray sets including 100 paraffin-embedded prostate samples (3 normal tissues, 2 cases of adjacent tissues and 95 cases of cancer). Subsequently, the regulatory mechanism of DACT-2 down-regulation was investigated through methylation-specific PCR (MSP) and bisulfite sequencing (BSP). The role of DACT-2 in prostate cancer cell migration and invasion was respectively examined by wound healing and transwell assay. After 5-aza-2'-deoxycytidine treatment of prostate cancer cells, qRT-PCR was used to detect whether the expression of DACT-2 gene mRNA in the cells recovered.Results: Immunohistochemical results shown that the DACT-2 protein was strongly (3+) expressed in the cytoplasm of all 5 noncancerous tissues and 12.7% (12/95) prostate cancer (PCa) tissues. Whereas 68.4% (65/95) PCa samples and 18.9% (18/95) PCa tissues respectively displayed weakly (1+) expressed and moderately (2+) expressed. In addition, DACT-2 expression was negatively associated with Gleason score in tumor specimens (p=0.029). What's more, down-regulation and promoter methylation of DACT-2 were observed in 68.1% (32/47) frozen PCa tissues and all three prostate cancer cell lines. And, the expression of DACT-2 mRNA was restored by the treatment of demethylated drug 5-aza-2'-deoxycytidine in all prostate cancer lines. Prostate cancer cells invasion and migration were significantly suppressed by ectopic expression of DACT-2 in vitro.Conclusions: Our study provides evidence that DACT-2 may be a useful biomarker for distinguishing prostate tumor tissues from non-cancerous samples and a potential target for epigenetic silencing in primary prostate Cancer.

Effect of citrus peel extracts on the cellular quiescence of prostate cancer cells.

The re-entry of quiescent cancer cells to the cell cycle plays a key role in cancer recurrence, which can pose a high risk after primary treatment. Citrus peel extracts (CPEs) contain compounds that can potentially impair tumour growth; however the mechanism of action and effects on cell cycle regulation remain unclear. In this study, the capacity of an ethyl acetate : hexane extract (CPE/hexane) and water extract (CPE/water) to modulate the cell cycle re-entry of quiescent (PC-3 and LNCaP) prostate cancer cells was tested in an in vitro culture system. Cell cycle analysis showed that the quiescent PC-3 and LNCaP cancer cells in the presence of CPE/water were impaired in their ability to enter the S phase where only 2-3% reduction of G0/G1 cells was noted compared to 12-18% reduction of control cells. In contrast, the CPE/hexane did not show any cell cycle inhibition activity in both cell lines. A low DNA synthesis rate and weak apoptosis were observed in quiescent cancer cells treated with CPEs. Hesperidin and narirutin, the predominant flavonoids found in citrus fruits, were not responsible for the observed biological activity, implicating alternative bioactive compounds. Notably, citric acid was identified as one of the compounds present in CPEs that acts as a cell cycle re-entry inhibitor. Citric acid exhibited a higher cell toxicity effect on PC-3 prostate cancer cells than non-cancerous RWPE-1 prostate cells, suggesting specific benefits for cancer treatment. In conclusion, CPE containing citric acid together with various bioactive compounds may be used as a chemopreventive agent for post-therapy cancer patients.

Long non-coding RNA SAP30L-AS1 promotes prostate cancer growth through repressing SAP30L

Accumulating evidences have demonstrated the importance of long non-coding RNAs (lncRNAs) in initiation and progression of various cancers, including prostate cancer. LncRNA SAP30L-AS1 is previously identified in the plasma of prostate cancer patients. In this study, we further investigated the expression of SAP30L-AS1 in prostate cancer tissues and cell lines. Moreover, we explored the biological roles and mechanisms of action of SAP30L-AS1 in prostate cancer. The expression of SAP30L-AS1 is found to be increased in prostate cancer tissues and cell lines compared with adjacent noncancerous tissues and normal prostate epithelial cell line, respectively. Increased expression of SAP30L-AS1 is associated with greater Gleason score, advanced pathological T stage, and poor over survival of prostate cancer patients. Functional assays demonstrated that ectopic expression of SAP30L-AS1 promotes prostate cancer proliferation and inhibits prostate cancer apoptosis. SAP30L-AS1 knockdown represses prostate cancer proliferation and induces prostate cancer apoptosis. Furthermore, SAP30L-AS1 knockdown represses prostate cancer xenograft growth in vivo. Mechanistic investigation revealed that SAP30L-AS1 physically binds to the promoter of SAP30L and represses SAP30L expression. The expression of SAP30L is negatively associated with that of SAP30L-AS1 in prostate cancer tissues. Rescue assays demonstrated that overexpression of SAP30L attenuated the roles of SAP30L-AS1 in promoting prostate cancer proliferation and inhibiting prostate cancer apoptosis. In conclusion, SAP30L-AS1 is upregulated and has oncogenic roles in prostate cancer via repressing SAP30L. Our data suggest that SAP30L-AS1 may be a promising prognostic biomarker and therapeutic target for prostate cancer.

SOCS6 Functions as a Tumor Suppressor by Inducing Apoptosis and Inhibiting Angiogenesis in Human Prostate Cancer.

Our previous studies revealed that the downregulation of Suppressor of cytokine signaling 6 (SOCS6) was correlated with malignant progression of human prostate cancer (PCa). In the current study, we aimed to investigate the tumor suppressive roles of SOCS6 and the underlying mechanisms in PCa. SOCS6 expression in PCa and non-cancerous prostate tissues was compared by immunohistochemistry. Statistical associations of SOCS6 expression with various clinicopathological features and patients prognosis were evaluated. In addition, we investigated SOCS6's functions by overexpressing it in vitro (cell apoptosis, migration and invasion assays) and in vivo (tumor formation, angiogenesis and apoptosis). Moreover, SOCS6-regulated genes were identified by nextgeneration RNA-sequencing analysis, followed by pathway enrichment analysis and in vitro experimental validation. SOCS6 downregulation was significantly associated with advanced clinical stage (P=0.029) and positive lymph node metastasis (P=0.013) in PCa patients. We also identified SOCS6 as an independent prognostic factor for disease-free survival in PCa patients (P=0.045). Moreover, overexpression of SOCS6 inhibited PCa cell invasion, migration, tumor xenografts growth and angiogenesis, but induced PCa cell apoptosis (P values <0.05). Mechanically, we revealed that SOCS6 expression may induce cell apoptosis coincident with down-regulation of Bcl2 and Hspa1a, and may suppress tumor angiogenesis with downregulation of F7, Fak3 and Frzb. These findings suggest that the reduced expression of SOCS6 may be predictive of unfavorable prognosis in PCa. Thus, SOCS6 may serve as a tumor suppressor and a novel therapeutic target for this cancer.

Prostate Cancer Differentiation and Aggressiveness: Assessment With a Radiomic-Based Model vs. PI-RADS v2.

BackgroundMultiparametric MRI (mp‐MRI) combined with machine‐aided approaches have shown high accuracy and sensitivity in prostate cancer (PCa) diagnosis. However, radiomics‐based analysis has not been thoroughly compared with Prostate Imaging and Reporting and Data System version 2 (PI‐RADS v2) scores.PurposeTo develop and validate a radiomics‐based model for differentiating PCa and assessing its aggressiveness compared with PI‐RADS v2 scores.Study TypeRetrospective.PopulationIn all, 182 patients with biopsy‐proven PCa and 199 patients with a biopsy‐proven absence of cancer were enrolled in our study.Field Strength/SequenceConventional and diffusion‐weighted MR images (b values = 0, 1000 sec/mm2) were acquired on a 3.0T MR scanner.AssessmentA total of 396 features and 385 features were extracted from apparent diffusion coefficient (ADC) images and T2WI, respectively. A predictive model was constructed for differentiating PCa from non‐PCa and high‐grade from low‐grade PCa. The diagnostic performance of each radiomics‐based model was compared with that of the PI‐RADS v2 scores.Statistical TestsA radiomics‐based predictive model was constructed by logistic regression analysis. 70% of the patients were assigned to the training group, and the remaining were assigned to the validation group. The diagnostic efficacy was analyzed with receiver operating characteristic (ROC) in both the training and validation groups.ResultsFor PCa versus non‐PCa, the validation model had an area under the ROC curve (AUC) of 0.985, 0.982, and 0.999 with T2WI, ADC, and T2WI&ADC features, respectively. For low‐grade versus high‐grade PCa, the validation model had an AUC of 0.865, 0.888, and 0.93 with T2WI, ADC, and T2WI&ADC features, respectively. PI‐RADS v2 had an AUC of 0.867 in differentiating PCa from non‐PCa and an AUC of 0.763 in differentiating high‐grade from low‐grade PCa.Data ConclusionBoth the T2WI‐ and ADC‐based radiomics models showed high diagnostic efficacy and outperformed the PI‐RADS v2 scores in distinguishing cancerous vs. noncancerous prostate tissue and high‐grade vs. low‐grade PCa. Level of Evidence: 3 Technical Efficacy: Stage 2J. Magn. Reson. Imaging 2019;49:875–884.