title: Jak2-Stat5a/b Signaling Induces Epithelial-to-Mesenchymal Transition and Stem-Like Cell Properties in Prostate Cancer.
abstract: Active Stat5a/b predicts early recurrence and disease-specific death in prostate cancer (PC), which both typically are caused by development of metastatic disease. Herein, we demonstrate that Stat5a/b induces epithelial-to-mesenchymal transition (EMT) of PC cells, as shown by Stat5a/b regulation of EMT marker expression (Twist1, E-cadherin, N-cadherin, vimentin, and fibronectin) in PC cell lines, xenograft tumors in vivo, and patient-derived PCs ex vivo using organ explant cultures. Jak2-Stat5a/b signaling induced functional end points of EMT as well, indicated by disruption of epithelial cell monolayers and increased migration and adhesion of PC cells to fibronectin. Knockdown of Twist1 suppressed Jak2-Stat5a/b-induced EMT properties of PC cells, which were rescued by re-introduction of Twist1, indicating that Twist1 mediates Stat5a/b-induced EMT in PC cells. While promoting EMT, Jak2-Stat5a/b signaling induced stem-like properties in PC cells, such as sphere formation and expression of cancer stem cell markers, including BMI1. Mechanistically, both Twist1 and BMI1 were critical for Stat5a/b induction of stem-like features, because genetic knockdown of Twist1 suppressed Stat5a/b-induced BMI1 expression and sphere formation in stem cell culture conditions, which were rescued by re-introduction of BMI1. By using human prolactin knock-in mice, we demonstrate that prolactin-Stat5a/b signaling promoted metastases formation of PC cells in vivo. In conclusion, our data support the concept that Jak2-Stat5a/b signaling promotes metastatic progression of PC by inducing EMT and stem cell properties in PC cells.
authors.affiliation: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Pooja G
authors.initials: PG
authors.lastname: Talati
authors.affiliation: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Lei
authors.initials: L
authors.lastname: Gu
authors.affiliation: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Elyse M
authors.initials: EM
authors.lastname: Ellsworth
authors.affiliation: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Melanie A
authors.initials: MA
authors.lastname: Girondo
authors.affiliation: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Marco
authors.initials: M
authors.lastname: Trerotola
authors.affiliation: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: David T
authors.initials: DT
authors.lastname: Hoang
authors.affiliation: Division of Biostatistics, Department of Pharmacology and Experimental Therapeutics, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Leiby
authors.affiliation: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Ayush
authors.initials: A
authors.lastname: Dagvadorj
authors.affiliation: Department of Pathology, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Peter A
authors.initials: PA
authors.lastname: McCue
authors.affiliation: Department of Urology, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Costas D
authors.initials: CD
authors.lastname: Lallas
authors.affiliation: Department of Urology, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Edouard J
authors.initials: EJ
authors.lastname: Trabulsi
authors.affiliation: Department of Urology, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Leonard
authors.initials: L
authors.lastname: Gomella
authors.affiliation: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania; Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Andrew E
authors.initials: AE
authors.lastname: Aplin
authors.affiliation: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania; Prostate Cancer Discovery and Development Program, Wistar Institute, Philadelphia, Pennsylvania.
authors.forename: Lucia
authors.initials: L
authors.lastname: Languino
authors.affiliation: Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Fatatis
authors.affiliation: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania; Department of Pathology, Thomas Jefferson University, Philadelphia, Pennsylvania; Department of Medical Oncology, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Hallgeir
authors.initials: H
authors.lastname: Rui
authors.affiliation: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania; Department of Urology, Thomas Jefferson University, Philadelphia, Pennsylvania; Prostate Cancer Discovery and Development Program, Wistar Institute, Philadelphia, Pennsylvania; Department of Medical Oncology, Thomas Jefferson University, Philadelphia, Pennsylvania. Electronic address: mnevalainen@mcw.edu.
authors.forename: Marja T
authors.initials: MT
authors.lastname: Nevalainen
mesh_terms: D000818:Animals; D015820:Cadherins / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition; D006801:Humans; D053614:Janus Kinase 2 / Q000378:metabolism*; D008297:Male; D051379:Mice; D014411:Neoplastic Stem Cells / Q000473:pathology; D009687:Nuclear Proteins / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D012008:Recurrence; D050799:STAT5 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D051879:Twist-Related Protein 1 / Q000378:metabolism
chemical_list: D015820:Cadherins; D009687:Nuclear Proteins; D050799:STAT5 Transcription Factor; C494092:STAT5A protein, human; C494095:STAT5B protein, human; C103173:TWIST1 protein, human; D025521:Tumor Suppressor Proteins; D051879:Twist-Related Protein 1; C507924:JAK2 protein, human; D053614:Janus Kinase 2