ELAVL3 stabilizes MYCN mRNA and provides a therapeutic target in neuroendocrine prostate cancer [RIPseq-ELAVL3&R1D]
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE236365 | GEO | 2023/10/23
REPOSITORIES: GEO
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Project description:Here we demonstrated that the RNA-binding protein ELAVL3 is specifically upregulated in NEPC, and that overexpression of ELAVL3 alone sufficiently induce neuroendocrine phenotype in prostate adenocarcinoma. We performed RIP-seq of ELAVL3-V5 from 2 prostate cancer cell lines.
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Project description:Here we demonstrated that the RNA-binding protein ELAVL3 is specifically upregulated in NEPC, and that overexpression of ELAVL3 alone sufficiently induce neuroendocrine phenotype in prostate adenocarcinoma. Pharmacological inhibition of ELAVL3 with pyrvinium pamoate, an FDA-approved drug, effectively suppressed tumor growth, reduced the risk of metastases, and improved the survival of NEPC mice models.
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Project description:Here we demonstrated that the RNA-binding protein ELAVL3 is specifically upregulated in NEPC, and that overexpression of ELAVL3 alone sufficiently induce neuroendocrine phenotype in prostate adenocarcinoma. Pharmacological inhibition of ELAVL3 with pyrvinium pamoate, an FDA-approved drug, effectively suppressed tumor growth, reduced the risk of metastases, and improved the survival of NEPC mice models.
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Project description:Neuronal Elavl-like (nElavl) RNA binding proteins have three paralogs (Elavl2, Elavl3 and Elavl4) in the mouse genome. This family of RNABPs have been implicated in a variety of post-transcriptional RNA processing mechanisms, including regulation of mRNA stability, alternative splicing, and translational regulation. In this study, using mouse exon arrays, we identify significant differences (p<0.01) in 119 transcripts between wild-type and Elavl3/Elavl4 double knockout forebrain tissue at postnatal day 0. A total of 10 samples were analyzed. These samples consisted of 5 littermate pairs of wild-type and Elavl3/Elavl4 double knockout mice.
2013-01-05 | E-GEOD-43287 | biostudies-arrayexpress
Project description:Neuronal Elavl-like (nElavl) RNA binding proteins have three paralogs (Elavl2, Elavl3 and Elavl4) in the mouse genome. This family of RNABPs have been implicated in a variety of post-transcriptional RNA processing mechanisms, including regulation of mRNA stability, alternative splicing, and translational regulation. In this study, using mouse exon arrays, we identify significant differences (p<0.01) in 119 transcripts between wild-type and Elavl3/Elavl4 double knockout forebrain tissue at postnatal day 0.
2013-01-05 | GSE43287 | GEO
Project description:Introduction: Neuroendocrine prostate cancer (NEPC) is an aggressive subtype of prostate cancer, exhibiting rapid progression and is unresponsive to hormone therapy. Reliable prognostic assays and more effective treatments are critically required. However, the research of NEPC has been hampered by a lack of clinically relevant in vivo models. Recently, we successfully developed a first-in-field patient tissue-derived xenograft model of complete neuroendocrine transdifferentiation from prostate adenocarcinoma. By comparing gene expression profiles of the parental adenocarcinoma line (LTL331) and the NEPC subline (LTL331R), we identified DEK, a gene not previously reported in prostate cancer, as a potential biomarker and target for NEPC. Methods: DEK protein expression in patient tissue-derived xenograft models and clinical samples was assessed by immunohistochemistry. The function of DEK was determined by siRNA-induced reduction of DEK expression in PC-3 cells, a cell line with NEPC characteristics, followed by functional assays and gene expression profiling analysis. Results: Elevated DEK protein expression was observed in all clinical NEPC cases, which is distinct from their benign counterparts (0%), hormonal naïve prostate cancer (2.45%) and castration resistant prostate cancer (29.55%). Increased DEK expression is an independent clinical risk factor and is associated with shorter disease free survival in hormonal naïve prostate cancer patients. Reduction of DEK expression in PC-3 cells led to a marked reduction in cell proliferation, cell migration and invasion. Conclusions: The results suggest that DEK may play an important role in the progression of prostate cancer, especially NEPC and provide a potential biomarker to aid risk stratification of prostate cancer and a novel therapeutic target for treating NEPC. The function of DEK was determined by siRNA-induced reduction of DEK expression in PC-3 cells, a cell line with NEPC characteristics, followed by functional assays and gene expression profiling analysis.
2015-01-15 | E-GEOD-61214 | biostudies-arrayexpress
Project description:Increased treatment of metastatic castration resistant prostate cancer (mCRPC) with second-generation anti-androgen therapies (ADT) has coincided with a greater incidence of lethal, aggressive variant prostate cancer (AVPC) tumors that have lost androgen receptor (AR) signaling. AVPC tumors may also express neuroendocrine markers, termed neuroendocrine prostate cancer (NEPC). Recent evidence suggests kinase signaling may be an important driver of NEPC. To identify targetable kinases in NEPC, we performed global phosphoproteomics comparing AR-negative to AR-positive prostate cancer cell lines and identified multiple altered signaling pathways, including enrichment of RET kinase activity in the AR-negative cell lines. Clinical NEPC and NEPC patient derived xenografts displayed upregulated RET transcript and RET pathway activity. Pharmacologically inhibiting RET kinase in NEPC models dramatically reduced tumor growth and cell viability in mouse and human NEPC models. Our results suggest that targeting RET in NEPC tumors with high RET expression may be a novel treatment option.
2020-05-29 | PXD012970 | Pride
Project description:Increased treatment of metastatic castration resistant prostate cancer (mCRPC) with second-generation anti-androgen therapies (ADT) has coincided with a greater incidence of lethal, aggressive variant prostate cancer (AVPC) tumors that have lost androgen receptor (AR) signaling. AVPC tumors may also express neuroendocrine markers, termed neuroendocrine prostate cancer (NEPC). Recent evidence suggests kinase signaling may be an important driver of NEPC. To identify targetable kinases in NEPC, we performed global phosphoproteomics comparing AR-negative to AR-positive prostate cancer cell lines and identified multiple altered signaling pathways, including enrichment of RET kinase activity in the AR-negative cell lines. Clinical NEPC and NEPC patient derived xenografts displayed upregulated RET transcript and RET pathway activity. Pharmacologically inhibiting RET kinase in NEPC models dramatically reduced tumor growth and cell viability in mouse and human NEPC models. Our results suggest that targeting RET in NEPC tumors with high RET expression may be a novel treatment option.
2020-05-29 | PXD012971 | Pride
Project description:Neuroendocrine prostate cancer (NEPC) is proliferative, invasive, and untreatable. Its molecular pathogenesis remains poorly understood but appears to require TP53 and RB1 aberration. In this study we modeled the development of NEPC from conventional prostatic adenocarcinoma using a unique patient-derived xenograft and identified up-regulation of the placental gene PEG10. We found that the androgen receptor and the E2F/RB pathway dynamically regulate distinct post-transcriptional and post-translational isoforms of PEG10 at different stages of NEPC development. In vitro, PEG10 promoted cell cycle progression from G0/G1 in the context of TP53 loss, and regulated Snail expression via TGF-β signaling to promote invasion. Finally we show in vivo proof of principal using antisense oligonucleotide that PEG10 is a novel therapeutic target for NEPC. Six patient-derived xenograft tumors from the LTL331 xenograft lineage (PMID: 24356420; http://www.livingtumorcentre.com/) after differing lengths of time post-host castration. No replicates.
2015-01-05 | E-GEOD-59985 | biostudies-arrayexpress
Project description:Neuroendocrine prostate cancer (NEPC) is proliferative, invasive, and untreatable. Its molecular pathogenesis remains poorly understood but appears to require TP53 and RB1 aberration. In this study we modeled the development of NEPC from conventional prostatic adenocarcinoma using a unique patient-derived xenograft and identified up-regulation of the placental gene PEG10. We found that the androgen receptor and the E2F/RB pathway dynamically regulate distinct post-transcriptional and post-translational isoforms of PEG10 at different stages of NEPC development. In vitro, PEG10 promoted cell cycle progression from G0/G1 in the context of TP53 loss, and regulated Snail expression via TGF-? signaling to promote invasion. Finally we show in vivo proof of principal using antisense oligonucleotide that PEG10 is a novel therapeutic target for NEPC. 14 patient-derived xenograft tumors from the LTL331 xenograft lineage (PMID: 24356420; http://www.livingtumorcentre.com/) after differing lengths of time post-host castration. Three replicates present for days 1-3 post-host castration.
2015-01-05 | E-GEOD-59984 | biostudies-arrayexpress