title: Dickkopf-related protein 3 promotes pathogenic stromal remodeling in benign prostatic hyperplasia and prostate cancer.
abstract: BACKGROUND
  Compartment-specific epithelial and stromal expression of the secreted glycoprotein Dickkopf-related protein (Dkk)-3 is altered in age-related proliferative disorders of the human prostate. This study aimed to determine the effect of Dkk-3 on prostate stromal remodeling that is stromal proliferation, fibroblast-to-myofibroblast differentiation and expression of angiogenic factors in vitro.
  
  
  METHODS
  Lentiviral-delivered overexpression and shRNA-mediated knockdown of DKK3 were applied to primary human prostatic stromal cells (PrSCs). Cellular proliferation was analyzed by BrdU incorporation ELISA. Expression of Dkk-3, apoptosis-related genes, cyclin-dependent kinase inhibitors and angiogenic factors were analyzed by qPCR, Western blot analysis or ELISA. Fibroblast-to-myofibroblast differentiation was monitored by smooth muscle cell actin and insulin-like growth factor binding protein 3 mRNA and protein levels. The relevance of Wnt/β-catenin and PI3K/AKT signaling pathways was assessed by cytoplasmic/nuclear β-catenin levels and phosphorylation of AKT.
  
  
  RESULTS
  Knockdown of DKK3 significantly attenuated PrSC proliferation as well as fibroblast-to-myofibroblast differentiation and increased the expression of the vessel stabilizing factor angiopoietin-1. DKK3 knockdown did not affect subcellular localization or levels of β-catenin but attenuated AKT phosphorylation in PrSCs. Consistently the PI3K/AKT inhibitor LY294002 mimicked the effects of DKK3 knockdown.
  
  
  CONCLUSIONS
  Dkk-3 promotes fibroblast proliferation and myofibroblast differentiation and regulates expression of angiopoietin-1 in prostatic stroma potentially via enhancing PI3K/AKT signaling. Thus, elevated Dkk-3 in the stroma of the diseased prostate presumably regulates stromal remodeling by enhancing proliferation and differentiation of stromal cells and contributing to the angiogenic switch observed in BPH and PCa. Therefore, Dkk-3 represents a potential therapeutic target for stromal remodeling in BPH and PCa.
authors.affiliation: Institute for Biomedical Aging Research, University of Innsbruck, Innsbruck, Austria. christoph.zenzmaier@i-med.ac.at
authors.forename: Christoph
authors.initials: C
authors.lastname: Zenzmaier
authors.forename: Natalie
authors.initials: N
authors.lastname: Sampson
authors.forename: Eugen
authors.initials: E
authors.lastname: Plas
authors.forename: Peter
authors.initials: P
authors.lastname: Berger
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D042683:Angiopoietin-1 / Q000378:metabolism; D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D010766:Phosphorylation; D011467:Prostate / Q000378:metabolism* / Q000473:pathology; D011470:Prostatic Hyperplasia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering; D015398:Signal Transduction / Q000502:physiology; D017154:Stromal Cells / Q000378:metabolism* / Q000473:pathology; D051176:beta Catenin / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D042683:Angiopoietin-1; C405061:Dkk3 protein, mouse; D018972:Insulin-Like Growth Factor Binding Protein 3; D036341:Intercellular Signaling Peptides and Proteins; D034741:RNA, Small Interfering; D051176:beta Catenin; D051057:Proto-Oncogene Proteins c-akt
keywords: angiogenic factors; angiopoietin; myofibroblast differentiation; proliferation