There are remarkable disparities among patients of different races with prostate cancer; however, the mechanism underlying this difference remains unclear. Here, we present a comprehensive landscape ...of the transcriptome profiles of 14 primary prostate cancers and their paired normal counterparts from the Chinese population using RNA-seq, revealing tremendous diversity across prostate cancer transcriptomes with respect to gene fusions, long noncoding RNAs （long ncRNA）, alternative splicing and somatic mutations. Three of the 14 tumors （21.4%） harbored a TM- PRSS2-ERG fusion, and the low prevalence of this fusion in Chinese patients was further confirmed in an additional tumor set （10/54=18.5%）. Notably, two novel gene fusions, CTAGE5-KHDRBS3 （20/54=37%） and USP9Y-TTTY15 （19/54=35.2%）, occurred frequently in our patient cohort. Further systematic transcriptional profiling identified nu- merous long ncRNAs that were differentially expressed in the tumors. An analysis of the correlation between expres- sion of long ncRNA and genes suggested that long ncRNAs may have functions beyond transcriptional regulation. This study yielded new insights into the pathogenesis of prostate cancer in the Chinese population.
Purpose To understand the role of MALAT-1 in prostate cancer we evaluated its expression in prostate cancer tissues and cell lines. We also studied the therapeutic effects of MALAT-1 silencing on ...castration resistant prostate cancer cells in vitro and in vivo. Materials and Methods Quantitative reverse transcriptase-polymerase chain reaction was used to detect MALAT-1 expression in prostate cancer tissues and cell lines. siRNA against MALAT-1 was designed and the silencing effect was examined by quantitative reverse transcriptase-polymerase chain reaction. The biological effects of MALAT-1 siRNA on cells were investigated by examining cell proliferation using a cell counting kit and cell colony assays as well as cell migration by in vitro scratch assay, cell invasion by Transwell® invasion assay and cell cycle by flow cytometry. We further investigated the effect of therapeutic siRNA targeting MALAT-1 on castration resistant prostate cancer in vivo. Results MALAT-1 was up-regulated in human prostate cancer tissues and cell lines. Higher MALAT-1 expression correlated with high Gleason score, prostate specific antigen, tumor stage and castration resistant prostate cancer. MALAT-1 down-regulation by siRNA inhibited prostate cancer cell growth, invasion and migration, and induced castration resistant prostate cancer cell cycle arrest in the G0/G1 phases. Importantly, intratumor delivery of therapeutic siRNA targeting MALAT-1 elicited delayed tumor growth and reduced metastasis of prostate cancer xenografts in castrated male nude mice, followed by the concomitant prolongation of survival of tumor bearing mice. Conclusions MALAT-1 may be needed to maintain prostate tumorigenicity and it is involved in prostate cancer progression. Thus, MALAT-1 may serve as a potential therapeutic target for castration resistant prostate cancer.
Abstract Objective Emerging evidences implicate long noncoding RNAs (lncRNAs) are deregulated in cancer development. The purpose of the current study is to investigate the role of new lncRNA, named ...PlncRNA-1, in prostate cancer (CaP) pathogenesis. Materials and methods In this study, real-time q-PCR was used to demonstrate the expression of PlncRNA-1 in 16 pairs CaP tissues and matched normal tissues, 14 pairs CaP tissues and BPH tissues, 4 CaP cell lines, including LNCaP, LNCaP-AI, PC3, and C4-2, and 2 normal prostate epithelial cell lines RWPE-1 and PWR-1E. After PlncRNA-1 was suppressed by siRNA in LNCaP and LNCaP-AI cell lines, cell proliferation and apoptosis were assessed using CCK-8 and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL). After PlncRNA-1 and AR was suppressed by siRNA in LNCaP and LNCaP-AI cell lines, real-time q-PCR and Western blotting were used to measure reciprocal regulation of PlncRNA-1 and AR. Results We showed that expression PlncRNA-1, was significantly higher in CaP cells relative to normal prostate epithelial cells, as well as higher in human CaPs compared with normal tissues and benign prostatic hyperplasia (BPH). Silencing of PlncRNA-1 significantly reduced cell proliferation and induced apoptosis in CaP cell lines LNCaP and LNCaP-AI. Mechanistically, PlncRNA-1 suppression by siRNA resulted in a decrease of androgen receptor (AR) mRNA, protein and AR downstream target. Of note, blockade of AR signaling with siRNA also resulted in a suppression of PlncRNA-1 expression in CaP cell lines. Conclusions Our study suggests reciprocal regulation of PlncRNA-1 and androgen receptor contribute to CaP pathogenesis and that PlncRNA-1 is a potential therapy target.
Abstract Examining plasma RNA is an emerging non-invasive diagnosis technique. However, whether tumour-derived long non-coding RNAs (lncRNAs) in plasma can be used as a novel approach to detect human ...prostate cancer (PCa) has not yet been established. The study was divided into three parts: (1) the characteristics of PCa-related lncRNA fragments were systematically studied in the plasma or serum of 25 patients; (2) the source of the circulating lncRNA fragments was explored in vitro and in vivo ; and (3) the diagnostic performance of metastasis associated in lung adenocarcinoma transcript 1 (MALAT-1) derived (MD) miniRNA was validated in an independent cohort of 192 patients. The expression levels of lncRNAs were measured by quantitative real time polymerase chain reaction (qRT-PCR). The MD-miniRNA copies were calculated using a standard curve in an area under the ROC curve (AUC)-receiver operating characteristic (ROC) analysis. Genome-wide profiling revealed that MALAT-1 and prostate cancer gene 3 (PCA3) are overexpressed in PCa tissues. Plasma lncRNAs probably exist in the form of fragments in a stable form. MD-miniRNA enters cell culture medium at measurable levels, and MD-miniRNA derived from human PCa xenografts actually enters the circulation in vivo and can be measured to distinguish xenografted mice from controls. In addition, plasma MD-miniRNA levels are significantly elevated in PCa patients compared to non-PCa patients ( p < 0.001). At a cut-off of 867.8 MD-miniRNA copies per microlitre of plasma, the sensitivity is 58.6%, 58.6% and 43.5% and the specificity is 84.8%, 84.8% and 81.6% for discriminating PCa from non-PCa, positive biopsy from negative biopsy and positive biopsy from negative biopsy, respectively. We conclude that MD-miniRNA can be used as a novel plasma-based biomarker for PCa detection and can improve diagnostic accuracy by predicting prostate biopsy outcomes. Further large-scale studies are needed to confirm our findings.
Prostate cancer is a highly prevalent tumor affecting millions of men worldwide, but poor understanding of its pathogenesis has limited effective clinical management of patients. In addition to ...transcriptional profiling or transcriptomics, metabolomics is being increasingly utilized to discover key molecular changes underlying tumorigenesis. In this study, we integrated transcriptomics and metabolomics to analyze 25 paired human prostate cancer tissues and adjacent noncancerous tissues, followed by further validation of our findings in an additional cohort of 51 prostate cancer patients and 16 benign prostatic hyperplasia patients. We found several altered pathways aberrantly expressed at both metabolic and transcriptional levels, including cysteine and methionine metabolism, nicotinamide adenine dinucleotide metabolism, and hexosamine biosynthesis. Additionally, the metabolite sphingosine demonstrated high specificity and sensitivity for distinguishing prostate cancer from benign prostatic hyperplasia, particularly for patients with low prostate specific antigen level (0–10 ng/ml). We also found impaired sphingosine-1-phosphate receptor 2 signaling, downstream of sphingosine, representing a loss of tumor suppressor gene and a potential key oncogenic pathway for therapeutic targeting. By integrating metabolomics and transcriptomics, we have provided both a broad picture of the molecular perturbations underlying prostate cancer and a preliminary study of a novel metabolic signature, which may help to discriminate prostate cancer from normal tissue and benign prostatic hyperplasia.
Castration-resistant prostate cancer (CRPC) with neuroendocrine differentiation (NED) is a lethal disease for which effective therapies are urgently needed. The mechanism underlying development of ...CRPC with NED, however, remains largely uncharacterized. In this study, we explored and characterized the functional role of neurotensin (NTS) in cell line and animal models of CRPC with NED. NTS was acutely induced by androgen deprivation in animal models of prostate cancer (PCa) and activated downstream signaling leading to NED through activation of neurotensin receptor 1 (NTSR1) and neurotensin receptor 3 (NTSR3), but not neurotensin receptor 2 (NTSR2). Our findings also revealed the existence of a CK8
/CK14
subpopulation in the LNCaP cell line that expresses high levels of both NTSR1 and NTSR3, and displays an enhanced susceptibility to develop neuroendocrine-like phenotypes upon treatment with NTS. More importantly, NTSR1 pathway inhibition prevented the development of NED and castration resistance in vivo. We propose a novel role of NTS in the development of CRPC with NED, and a possible strategy to prevent the onset of NED by targeting the NTS signaling pathway.
With the rapidly increasing incidence of bladder cancer in China and worldwide, great efforts have been made to understand the detailed mechanism of bladder cancer tumorigenesis. Recently, the ...introduction of immune checkpoint inhibitor-based immunotherapy has changed the treatment strategy for bladder cancer, especially for advanced bladder cancer, and has improved the survival of patients. The ubiquitin-proteasome system, which affects many biological processes, plays an important role in bladder cancer. Several E3 ubiquitin ligases and deubiquitinases target immune checkpoints, either directly or indirectly. In this review, we summarize the recent progress in E3 ubiquitin ligases and deubiquitinases in bladder cancer tumorigenesis and further highlight the implications for bladder cancer immunotherapies.
In-depth delineation of lipid metabolism in prostate cancer (PCa) is significant to open new insights into prostate tumorigenesis and progression, and provide potential biomarkers with greater ...accuracy for improved diagnosis. Here, we performed lipidomics and transcriptomics in paired prostate cancer tumor (PCT) and adjacent nontumor (ANT) tissues, followed by external validation of biomarker candidates. We identified major dysregulated pathways involving lipogenesis, lipid uptake and phospholipids remodeling, correlated with widespread lipid accumulation and lipid compositional reprogramming in PCa. Specifically, cholesteryl esters (CEs) were most prominently accumulated in PCa, and significantly associated with cancer progression and metastasis. We showed that overexpressed scavenger receptor class B type I (SR-BI) may contribute to CEs accumulation. In discovery set, CEs robustly differentiated PCa from nontumor (area under curve (AUC) of receiver operating characteristics (ROC), 0.90-0.94). In validation set, CEs potently distinguished PCa and non-malignance (AUC, 0.84-0.91), and discriminated PCa and benign prostatic hyperplasia (BPH) (AUC, 0.90-0.96), superior to serum prostate-specific antigen (PSA) (AUC = 0.83). Cholesteryl oleate showed highest AUCs in distinguishing PCa from non-malignance or BPH (AUC = 0.91 and 0.96). Collectively, our results unravel the major lipid metabolic aberrations in PCa and imply the potential role of CEs, particularly, cholesteryl oleate, as molecular biomarker for PCa detection.
The prognosis of bladder urothelial carcinoma (BLCA) varies greatly among patients, and conventional pathological predictors are generally inadequate and often inaccurate to predict the heterogeneous ...behavior of BLCA. This study aims to investigate the prognostic value and function of TOP2A in BLCA.
TOP2A expression level was examined by RNA-sequencing, quantitative real time polymerase chain reaction and immunohistochemistry from 10, 40 and 209 BLCA samples, respectively. Public databases were analyzed for validation. Cell proliferation, migration, invasion assays were performed to explore potential functions of TOP2A in BLCA. Flow cytometry was performed for cell cycle and apoptosis analysis. Univariable and multivariable Cox regression models were performed to identify independent risk factors for the prognosis of BLCA.
We found TOP2A was significantly upregulated in BLCA samples, especially for high-grade and advanced stage tumors, compared with matched normal epithelial tissue. Univariable COX regression analysis revealed high TOP2A expression was significantly associated with poorer cancer-specific, progression-free and recurrence-free survival, but not independently of clinical characteristics in the multivariable models. Knockdown of TOP2A remarkably inhibited the proliferation of BLCA cells and non-cancerous urothelial cells. Furthermore, migration and invasion capacity of BLCA cells were strongly suppressed after TOP2A knockdown. Moreover, flow cytometry suggested TOP2A had anti-apoptotic function, and knockdown of TOP2A could induce resistance to doxorubicin in J82 cells.
In our study, TOP2A was overexpressed in BLCA and could serve as a prognostic biomarker for BLCA. Moreover, TOP2A is functionally important for the proliferation, invasion and survival of BLCA cells.
Background
To examine the microbial profiles in parenchyma tissues in bladder cancer.
Methods
Tissue samples of cancerous bladder mucosa were collected from patients diagnosed with bladder cancer (22 ...carcinoma tissues and 12 adjacent normal tissues). The V3‐V4 region of the bacterial 16S rRNA gene was PCR amplified, followed by sequencing on an Illumina MiSeq platform. Bioinformatics analysis for microbial classification and functional assessment was performed to assess bladder microbiome diversity and variations.
Results
The predominant phylum in both tissues was Proteobacteria. The cancerous tissues exhibited lower species richness and diversity. Beta diversity significantly differed between the cancerous and normal tissues. Lower relative abundances of the microbial genera Lactobacillus, Prevotella_9, as well as Ruminococcaceae were observed, whereas those of Cupriavidus spp., an unknown genus of family Brucellaceae, and Acinetobacter, Anoxybacillus, Escherichia‐Shigella, Geobacillus, Pelomonas, Ralstonia, and Sphingomonas were higher in the cancerous tissues. These findings indicate that these genera may be potentially utilized as biomarkers for bladder cancer. PICRUSt analysis revealed that several pathways involved in the metabolism of harmful chemical compounds were enriched in the cancer tissues, thereby providing evidence that environmental factors are strongly associated with bladder cancer etiology.
Conclusion
This is the first study that has described and analyzed the dysbiotic motifs of urinary microbiota in the parenchymatous tissues of bladder cancer via 16S rRNA gene sequencing. Our results suggest that changes in the bladder microbiome may serve as biomarkers for bladder cancer, possibly assisting in disease screening and monitoring.
This is the first study describing and analyzing the dysbiosis signatures of urinary microbiota within the parenchyma in bladder cancer using a 16S rRNA gene sequencing method. The study reveals previously undescribed bacterial diversity present in human bladder. The bladder microbiome changes could be a biomarker of bladder cancer that could be used to help in screening for the disease. Analysis of the inferred bladder cancer metagenome identified the strongest association with the harmful chemical products that may be metabolized.
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