Pseudogene Associated Recurrent Gene Fusion in Prostate Cancer.
Ontology highlight
ABSTRACT:
SUBMITTER: Chakravarthi BV
PROVIDER: S-EPMC6713813 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Non-coding RNAs play a vital role in diverse cellular processes. Pseudogenes, which are non-coding homologs of protein-coding genes, were once considered non-functional evolutional relics. However, recent studies have shown that pseudogene transcripts can regulate their parental transcripts by sequestering shared microRNAs (miRNAs), thus acting as competing endogenous RNAs (ceRNAs). In this study, we utilize an unbiased screen to identify the ferritin heavy chain 1 (FTH1) transcript and multiple FTH1 pseudogenes as targets of several oncogenic miRNAs in prostate cancer (PCa). We characterize the critical role of this FTH1 gene:pseudogene:miRNA network in regulating tumorigenesis in PCa, whereby oncogenic miRNAs downregulate the expression of FTH1 and its pseudogenes to drive oncogenesis. We further show that impairing miRNA binding and subsequent ceRNA crosstalk completely rescues the slow growth phenotype in vitro and in vivo. Our results also demonstrate the reciprocal regulation between the pseudogenes and intracellular iron levels, which are crucial for multiple physiological and pathophysiological processes. In summary, we describe an extensive gene:pseudogene network comprising multiple miRNAs and multiple pseudogenes derived from a single parental gene. The network could be regulated through multiple mechanisms to modulate iron storage in various signaling pathways, the deregulation of which results in PCa development and progression.
| S-EPMC5829750 | biostudies-literature
Project description:BackgroundThere is no cure for castration-recurrent prostate cancer (CRPC) and the mechanisms underlying this stage of the disease are unknown.MethodsWe analyzed the transcriptome of human LNCaP prostate cancer cells as they progress to CRPC in vivo using replicate LongSAGE libraries. We refer to these libraries as the LNCaP atlas and compared these gene expression profiles with current suggested models of CRPC.ResultsThree million tags were sequenced using in vivo samples at various stages of hormonal progression to reveal 96 novel genes differentially expressed in CRPC. Thirty-one genes encode proteins that are either secreted or are located at the plasma membrane, 21 genes changed levels of expression in response to androgen, and 8 genes have enriched expression in the prostate. Expression of 26, 6, 12, and 15 genes have previously been linked to prostate cancer, Gleason grade, progression, and metastasis, respectively. Expression profiles of genes in CRPC support a role for the transcriptional activity of the androgen receptor (CCNH, CUEDC2, FLNA, PSMA7), steroid synthesis and metabolism (DHCR24, DHRS7, ELOVL5, HSD17B4, OPRK1), neuroendocrine (ENO2, MAOA, OPRK1, S100A10, TRPM8), and proliferation (GAS5, GNB2L1, MT-ND3, NKX3-1, PCGEM1, PTGFR, STEAP1, TMEM30A), but neither supported nor discounted a role for cell survival genes.ConclusionsThe in vivo gene expression atlas for LNCaP was sequenced and support a role for the androgen receptor in CRPC.
| S-EPMC2956710 | biostudies-literature
Project description:Prostate cancer is the most common form of non-dermatological cancer among US men, with an increasing incidence due to the aging population. Patients diagnosed with clinically localized disease identified as intermediate or high-risk are often treated by radical prostatectomy. Approximately 33% of these patients will suffer recurrence after surgery. Identifying patients likely to experience recurrence after radical prostatectomy would lead to improved clinical outcomes, as these patients could receive adjuvant radiotherapy. Here, we report a new tool for prediction of prostate cancer recurrence based on the expression pattern of a small set of cooperation response genes (CRGs). CRGs are a group of genes downstream of cooperating oncogenic mutations previously identified in a colon cancer model that are critical to the cancer phenotype. We show that systemic dysregulation of CRGs is also found in prostate cancer, including a 4-gene signature (HBEGF, HOXC13, IGFBP2, and SATB1) capable of differentiating recurrent from non-recurrent prostate cancer. To develop a suitable diagnostic tool to predict disease outcomes in individual patients, multiple algorithms and data handling strategies were evaluated on a training set using leave-one-out cross-validation (LOOCV). The best-performing algorithm, when used in combination with a predictive nomogram based on clinical staging, predicted recurrent and non-recurrent disease outcomes in a blinded validation set with 83% accuracy, outperforming previous methods. Disease-free survival times between the cohort of prostate cancers predicted to recur and predicted not to recur differed significantly (p = 1.38x10-6). Therefore, this test allows us to accurately identify prostate cancer patients likely to experience future recurrent disease immediately following removal of the primary tumor.
| S-EPMC5356893 | biostudies-literature
Project description:Beta-microseminoprotein (MSP)/MSMB is an immunoglobulin superfamily protein synthesized by prostate epithelial cells and secreted into seminal plasma. Variants in the promoter of the MSMB gene have been associated with the risk of prostate cancer (PCa) in several independent genome-wide association studies. Both MSMB and an adjacent gene, NCOA4, are subjected to transcriptional control via androgen response elements. The gene product of NCOA4 interacts directly with the androgen receptor as a co-activator to enhance AR transcriptional activity. Here, we provide evidence for the expression of full-length MSMB-NCOA4 fusion transcripts regulated by the MSMB promoter. The predominant MSMB-NCOA4 transcript arises by fusion of the 5'UTR and exons 1-2 of the MSMB pre-mRNA, with exons 2-10 of the NCOA4 pre-mRNA, producing a stable fusion protein, comprising the essential domains of NCOA4. Analysis of the splice sites of this transcript shows an unusually strong splice acceptor at NCOA4 exon 2 and the presence of Alu repeats flanking the exons potentially involved in the splicing event. Transfection experiments using deletion clones of the promoter coupled with luciferase reporter assays define a core MSMB promoter element located between -27 and -236 of the gene, and a negative regulatory element immediately upstream of the start codon. Computational network analysis reveals that the MSMB gene is functionally connected to NCOA4 and the androgen receptor signaling pathway. The data provide an example of how GWAS-associated variants may have multiple genetic and epigenetic effects.
| S-EPMC3956317 | biostudies-literature
Project description:Pseudogenes, non-coding homologs of protein-coding genes, were once considered non-functional evolutional relics. Recent studies have shown that pseudogene transcripts can regulate their parental transcripts by sequestering shared microRNAs, thus acting as competing endogenous RNAs (ceRNAs). In this study, we utilize an unbiased screen to identify the ferritin heavy chain 1 (FTH1) transcript and multiple FTH1 pseudogenes as targets of several oncogenic miRNAs in prostate cancer. We characterize the critical role of this FTH1 gene:pseudogene:microRNA network in regulating tumorigenesis in prostate cancer, and show that impairing microRNA binding and subsequent ceRNA crosstalk results in complete phenotype rescue. Our results also demonstrate that pseudogenes are able to regulate intracellular iron levels, which are crucial for multiple physiological and pathophysiological processes. In summary, we describe a novel and extensive gene:pseudogene ceRNA network comprising multiple microRNAs and multiple pseudogenes derived from a single parental gene, which regulates iron storage and tumorigenesis in prostate cancer.
2017-07-26 | GSE101837 | GEO
Project description:TMPRSS2-ERG gene fusions are the predominant molecular subtype of prostate cancer. Here, we explored the role of TMPRSS2-ERG gene fusion product using in vitro and in vivo model systems. Transgenic mice expressing the ERG gene fusion product under androgen-regulation develop mouse prostatic intraepithelial neoplasia (PIN), a precursor lesion of prostate cancer. Introduction of the ERG gene fusion product into primary or immortalized benign prostate epithelial cells induced an invasion-associated transcriptional program but did not increase cellular proliferation or anchorage-independent growth. These results suggest that TMPRSS2-ERG may not be sufficient for transformation in the absence of secondary molecular lesions. Transcriptional profiling of ERG knockdown in the TMPPRSS2-ERG-positive prostate cancer cell line VCaP revealed decreased expression of genes over-expressed in prostate cancer versus PIN and genes overexpressed in ETS-positive versus -negative prostate cancers in addition to inhibiting invasion. ERG knockdown in VCaP cells also induced a transcriptional program consistent with prostate differentiation. Importantly, VCaP cells and benign prostate cells overexpressing ERG directly engage components of the plasminogen activation pathway to mediate cellular invasion, potentially representing a downstream ETS target susceptible to therapeutic intervention. Our results support previous work suggesting that TMPRSS2-ERG fusions mediate invasion, consistent with the defining histologic distinction between PIN and prostate cancer.
| S-EPMC2244693 | biostudies-literature
Project description:The transmembrane protease serine 2:v‑ets erythroblastosis virus E26 oncogene homolog (TMPRSS2:ERG) gene fusion is common in prostate cancer, while its functional role is not fully understood. The present study aimed to investigate the significance of the TMPRSS2:ERG gene fusion in human prostate cancers using bioinformatics tools. Comprehensive alteration analysis of TMPRSS2 and ERG in 148 different human cancer studies was performed by cBioPortal, and the mRNA expression level of the ERG gene was evaluated using Oncomine analysis. Furthermore, lentiviral short hairpin (sh)RNA‑mediated knockdown of TMPRSS2:ERG was performed to study the impact of ERG silencing on cell proliferation and cell cycle distribution in prostate cancer cells. The results demonstrated that the TMPRSS2 and ERG genes were mostly altered in prostate cancer, and the most frequent alteration was gene fusion. Oncomine analysis demonstrated that the ERG gene was significantly upregulated in prostate clinical samples compared with the normal prostate gland in four independent datasets, and a positive association was observed between potassium inwardly‑rectifying channel subfamily J member 15, down syndrome critical region gene 4, potassium inwardly‑rectifying channel subfamily J member 6 and ERG gene expression. There were 272 mutations of the ERG gene identified in the cBioPortal database; among the mutations, 2 missense mutations (R367C and P401H) were regarded as functional mutations (functional impact score >1.938). Furthermore, the present study successfully knocked down ERG gene expression through a lentiviral‑mediated gene silencing approach in VCaP prostate cancer cells. The ERG mRNA and protein expression levels were both suppressed significantly, and a cell‑cycle arrest at G0/G1 phase was observed after ERG gene silencing. In conclusion, these bioinformatics analyses provide novel insights for TMPRSS2:ERG fusion gene study in prostate cancer. Target inhibition of ERG expression could significantly cause cell growth arrest in prostate cancer cells, which could be a potentially valuable target for prostate cancer treatment. However, the precise mechanism of these results remains unclear; therefore, further studies are required.
| S-EPMC5647090 | biostudies-literature
Project description:BackgroundRecent studies have indicated that prostate cancer patients with the TMPRSS2-ERG gene fusion have a higher risk of recurrence. To identify markers associated with TMPRSS2-ERG fusion and prognostic of biochemical recurrence, we analysed a cohort of 139 men with prostate cancer for 502 molecular markers.MethodsRNA from radical prostatectomy tumour specimens was analysed using cDNA-mediated, annealing, selection, extension and ligation (DASL) to determine mRNAs associated with TMPRSS2-ERG T1/E4 fusion and prognostic of biochemical recurrence. Differentially expressed mRNAs in T1/E4-positive tumours were determined using significance analysis of microarrays (false discovery rate (FDR) <5%). Univariate and multivariate Cox regression determined genes, gene signatures and clinical factors prognostic of recurrence (P-value <0.05, log-rank test). Analysis of two prostate microarray studies (GSE1065 and GSE8402) validated the findings.ResultsIn the 139 patients from this study and from a 455-patient Swedish cohort, 15 genes in common were differentially regulated in T1/E4 fusion-positive tumours (FDR <0.05). The most significant mRNAs in both cohorts coded ERG. Nine genes were found prognostic of recurrence in this study and in a 596-patient Minnesota cohort. A molecular recurrence score was significant in prognosticating recurrence (P-value 0.000167) and remained significant in multivariate analysis of a mixed clinical model considering Gleason score and TMPRSS2-ERG fusion status.ConclusionsTMPRSS2-ERG T1/E4 fusion-positive tumours had differentially regulated mRNAs observed in multiple studies, the most significant one coded for ERG. Several mRNAs were consistently associated with biochemical recurrence and have potential clinical utility but will require further validation for successful translation.
| S-EPMC2822948 | biostudies-literature
Project description:PURPOSE:We assessed the feasibility and cancer detection rate of fluciclovine (18F) positron emission tomography-ultrasound fusion targeted biopsy vs standard template biopsy in the same patient with biochemical failure after nonsurgical therapy for prostate cancer. MATERIALS AND METHODS:A total of 21 patients with a mean ± SD prostate specific antigen of 7.4 ± 6.8 ng/ml and biochemical failure after nonoperative prostate cancer treatment underwent fluciclovine (18F) positron emission tomography-computerized tomography (mean 364.1 ± 37.7 MBq) and planning transrectal prostate ultrasound with 3-dimensional image reconstruction. Focal prostatic activity on positron emission tomography was delineated and co-registered with planning ultrasound. During the subsequent biopsy session computer generated 12-core template biopsies were performed and then fluciclovine defined targets were revealed and biopsied. Histological analysis of template and targeted cores were completed. RESULTS:Template biopsy was positive for malignancy in 6 of 21 patients (28.6%), including 10 of 124 regions and 11 of 246 cores, vs targeted biopsy in 10 of 21 (47.6%), including 17 of 50 regions and 40 of 125 cores. Five of 21 patients had positive findings on targeted biopsy only and 1 of 21 had positive findings on template biopsy only. An additional case was upgraded from Grade Group 2 to 3 on targeted biopsy. Extraprostatic disease was detected in 8 of 21 men (38.1%) with histological confirmation in all 3 who underwent lesion biopsy. CONCLUSIONS:Fluciclovine positron emission tomography real-time ultrasound fusion guidance for biopsy is feasible in patients with biochemical failure after nonsurgical therapy for prostate cancer. It identifies more recurrent prostate cancer using fewer cores compared with template biopsy in the same patient. Further study is required to determine in what manner targeted biopsy may augment template biopsy of recurrent prostate cancer.
| S-EPMC6800044 | biostudies-literature
Project description:Approximately 50% of prostate cancers are associated with gene fusions of the androgen-regulated gene TMPRSS2 to the oncogenic erythroblast transformation-specific (ETS) transcription factor ERG. The three-dimensional proximity of TMPRSS2 and ERG genes, in combination with DNA breaks, facilitates the formation of TMPRSS2-ERG gene fusions. However, the origins of DNA breaks that underlie gene fusion formation in prostate cancers are far from clear. We demonstrate a role for inflammation-induced oxidative stress in the formation of DNA breaks leading to recurrent TMPRSS2-ERG gene fusions. The transcriptional status and epigenetic features of the target genes influence this effect. Importantly, inflammation-induced de novo genomic rearrangements are blocked by homologous recombination (HR) and promoted by non-homologous end-joining (NHEJ) pathways. In conjunction with the association of proliferative inflammatory atrophy (PIA) with human prostate cancer, our results support a working model in which recurrent genomic rearrangements induced by inflammatory stimuli lead to the development of prostate cancer.
| S-EPMC5147555 | biostudies-literature