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Transcriptional Profiling of Lineage Depleted Dek-KO Murine Bone Marrow Treated with Exogenous DEK

ABSTRACT: Nuclear protein DEK is an endogenous DNA-binding chromatin factor regulating hematopoiesis. DEK is one of only two known secreted nuclear chromatin factors, but whether and how extracellular DEK regulates hematopoiesis is not known. We demonstrate that extracellular DEK greatly enhances ex vivo expansion of cytokine-stimulated human and mouse hematopoietic stem cells, and regulates hematopoiesis in vivo and in vitro. These effects are mediated through chemokine receptor CXCR2 and heparan sulfate proteoglycans, and are associated with enhanced phosphorylation of ERK1/2, AKT and p38 MAPK. Thus, DEK acts as a hematopoietic cytokine, with potential for clinical applicability.

ORGANISM(S): Mus musculus

PROVIDER: GSE126875 | GEO | 2019/02/22

REPOSITORIES: GEO

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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.

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Transcriptional Profiling of Lineage Depleted Dek-KO Murine Bone Marrow Treated with Exogenous DEK

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