title: BTG2 loss and miR-21 upregulation contribute to prostate cell transformation by inducing luminal markers expression and epithelial-mesenchymal transition.
abstract: Prostate cancer is one of the leading causes of cancer-related death in men. Despite significant advances in prostate cancer diagnosis and management, the molecular events involved in the transformation of normal prostate cells into cancer cells have not been fully understood. It is generally accepted that prostate cancer derives from the basal compartment while expressing luminal markers. We investigated whether downregulation of the basal protein B-cell translocation gene 2 (BTG2) is implicated in prostate cancer transformation and progression. Here we show that BTG2 loss can shift normal prostate basal cells towards luminal markers expression, a phenotype also accompanied by the appearance of epithelial-mesenchymal transition (EMT) traits. We also show that the overexpression of microRNA (miR)-21 suppresses BTG2 levels and promotes the acquisition of luminal markers and EMT in prostate cells. Furthermore, by using an innovative lentiviral vector able to compete with endogenous mRNA through the overexpression of the 3'-untranslated region of BTG2, we demonstrate that in prostate tumor cells, the levels of luminal and EMT markers can be reduced by derepression of BTG2 from microRNA-mediated control. Finally, we show that the loss of BTG2 expression confers to non-tumorigenic prostate cells ability to grow in an orthotopic murine model, thus demonstrating the central role of BTG2 downregulaton in prostate cancer biology.
authors.affiliation: Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Coppola
authors.forename: M
authors.initials: M
authors.lastname: Musumeci
authors.forename: M
authors.initials: M
authors.lastname: Patrizii
authors.forename: A
authors.initials: A
authors.lastname: Cannistraci
authors.forename: A
authors.initials: A
authors.lastname: Addario
authors.forename: M
authors.initials: M
authors.lastname: Maugeri-Saccà
authors.forename: M
authors.initials: M
authors.lastname: Biffoni
authors.forename: F
authors.initials: F
authors.lastname: Francescangeli
authors.forename: M
authors.initials: M
authors.lastname: Cordenonsi
authors.forename: S
authors.initials: S
authors.lastname: Piccolo
authors.forename: L
authors.initials: L
authors.lastname: Memeo
authors.forename: A
authors.initials: A
authors.lastname: Pagliuca
authors.forename: G
authors.initials: G
authors.lastname: Muto
authors.forename: A
authors.initials: A
authors.lastname: Zeuner
authors.forename: R
authors.initials: R
authors.lastname: De Maria
authors.forename: D
authors.initials: D
authors.lastname: Bonci
mesh_terms: D000818:Animals; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000473:pathology*; D002478:Cells, Cultured; D058750:Epithelial-Mesenchymal Transition; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D017874:Immediate-Early Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D011467:Prostate / Q000378:metabolism / Q000473:pathology*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; D017874:Immediate-Early Proteins; C524940:MIRN21 microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D025521:Tumor Suppressor Proteins; C070114:BTG2 protein, human