Project description:Extracellular microRNAs (miRNAs) embedded in circulating exosomes may serves as prognostic biomarkers in cancer. This study was performed to identify and evaluate plasma exosomal miRNAs for prognostication in castration resistant prostate cancer (CRPC). RNA sequencing was performed to identify candidate exosomal miRNAs associated with overall survival in a screening cohort of 23 CRPC patients. Candidate miRNAs were further evaluated for prognosis using qRT-PCR in a follow-up cohort of 100 patients. Cox regression and Kaplan–Meier survival curve analysis were used to evaluate prognostic value of miRNA candidates with and without incorporation of clinical prognostic factors (age, Gleason score and time from androgen deprivation therapy to clinical progression). In the screening cohort, we obtained ~6.80 million mappable RNA reads per patient. Of those with normalized read counts ? 5, 43% were mapped to miRNAs for a total of 375 known and 57 novel miRNAs. Cox regression analysis identified an association of miR-1290, -1246, and -375 with overall survival (FDR<0.1). Of those, higher levels of miR-1290 and -375 were verified to be significantly associated with poor overall survival (p<0.004) in the follow-up cohort. The miR-1290/-375-based prediction model showed better performance with time-dependent area under the curve (AUC) =72% compared to clinical variable-based model with AUC=65%. Plasma exosomal miR-1290 and miR-375 are promising prognostic biomarkers for CRPC patients. Prospective validation is needed for further development of these candidate miRNAs.
Project description:To identify changes at multiple omic levels between hormone naive and castration resistant prostate cancer. Using orthograft murine tumour models of human cell lines injected into the prostate of CD-1 Nude mice grown under castration resistant (castrate) or hormone naive (non-castrate) conditions.
Project description:Benign prostate tissue and prostate cancer tissue (untreated, androgen deprivation therapy responding, or castrate-resistant) was collected from patients at the time of transurethral resection of the prostate surgery.
Project description:Benign prostate tissue and prostate cancer tissue (untreated, androgen deprivation therapy responding, or castrate-resistant) was collected from patients at the time of transurethral resection of the prostate surgery. 24 samples, technical replicates.
Project description:The prostate cancer cell line PC-3 was transfected with pre-miR-375 or control. After 48 hours the cells were lysed and immunoprecipitation was performed using anti-panAgo (...) or isotype anti-IgG antibodies overnight. RNA of total lysates and immunoprecipitation fractions was extracted using miRNeasy kit (Qiagen) and libraries were generated using the Stranded Total RNA Sample Prep Kit (Takara Clontech). The experiment was performed in order to identify potential targets of miR-375 in prostate cancer.
Project description:shRNAs targeting METTL3 used to deplete METTL3 in castrate-resistant LNCaP:C42 prostate cancer cells and the effect on gene expression and splicing determined.
Project description:Prostate cancer is the second leading cause of cancer death in the United States and Europe. Diagnosis and risk estimation of cancer recurrence is often critical with the common clinicopathologic parameters of prostate-specific antigen, tumor stage and grade. Therefore it is mandatory to develop new diagnostic and prognostic markers for prostate cancer. miRNAs have been shown to be novel markers in a series of other cancer types. We show for the first time, that good overall classification of normal and malignant prostate tissue was possible with combination of just two miRNAs (hsa-miR-205, hsa-miR-183). Further, hsa-miR-96 is shown to be associated with the recurrence-free interval after radical prostatectomy.
Project description:Altered patterns of transcription factor (TF) binding are now accepted as a hallmark of many aggressive cancers including prostate and breast cancers1,2. This implies that underlying global changes in chromatin accessibility may drive cancer progression, as previously hypothesized3-5. In addition there are epigenetic readers such as bromodomain containing protein 4 (BRD4), which have been shown to associate with these TFs6-8 and also to contribute to aggressive cancers of many types8,9 including prostate cancer (PC)6,10. Here we show for the first time that formaldehyde-assisted isolation of regulatory elements followed by sequencing (FAIRE-seq) applied to human prostate tumors tissue can define castrate-resistant prostate cancer (CRPC) and can be used to inform the discovery of gene-level classifiers for therapy. In addition, we show that the androgen receptor (AR) overexpression alone is a primary driver for chromatin relaxation and that this effect can be reversed using bromodomain inhibitors. We also report that bromodomain-containing proteins (BRDs) are overexpressed in advanced CRPCs and that ATAD2 and BRD2 have prognostic value. In conclusion, this is the first study demonstrating a major impact of BRDs on chromatin accessibility in CRPC in patient samples. Consequently, targeting bromodomains provides a compelling rational for combination therapy in which BRD-mediated TF binding is enhanced or modified as cancer progresses. FAIRE-seq study for LNCaP and VCaP prostate cancer cell lines hormone starved or treated with R1881, and human prostate tissue samples from benign prostate hyperplasia (BPH), primary prostate cancer (PC), and castrate resistant prostate cancer (CRPC) patients.
Project description:Cancer cells often adapt a stem-like state resulting in lineage plasticity and phenotypic heterogeneity. We assessed the dynamics of lineage determination and cellular subpopulation expansion in treatment-resistant adenocarcinoma, amphicrine, and small cell neuroendocrine castrate resistant prostate cancers.
Project description:Cancer cells often adapt a stem-like state resulting in lineage plasticity and phenotypic heterogeneity. We assessed the dynamics of lineage determination and cellular subpopulation expansion in treatment-resistant adenocarcinoma, amphicrine, and small cell neuroendocrine castrate resistant prostate cancers.
