title: A microRNA/Runx1/Runx2 network regulates prostate tumor progression from onset to adenocarcinoma in TRAMP mice.
abstract: While decades of research have identified molecular pathways inducing and promoting stages of prostate cancer malignancy, studies addressing dynamic changes of cancer-related regulatory factors in a prostate tumor progression model are limited. Using the TRAMP mouse model of human prostate cancer, we address mechanisms of deregulation for the cancer-associated transcription factors, Runx1 and Runx2 by identifying microRNAs with reciprocal expression changes at six time points during 33 weeks of tumorigenesis. We molecularly define transition stages from PIN lesions to hyperplasia/neoplasia and progression to adenocarcinoma by temporal changes in expression of human prostate cancer markers, including the androgen receptor and tumor suppressors, Nkx3.1 and PTEN. Concomitant activation of PTEN, AR, and Runx factors occurs at early stages. At late stages, PTEN and AR are downregulated, while Runx1 and Runx2 remain elevated. Loss of Runx-targeting microRNAs, miR-23b-5p, miR-139-5p, miR-205-5p, miR-221-3p, miR-375-3p, miR-382-5p, and miR-384-5p, contribute to aberrant Runx expression in prostate tumors. Our studies reveal a Runx/miRNA interaction axis centered on PTEN-PI3K-AKT signaling. This regulatory network translates to mechanistic understanding of prostate tumorigenesis that can be developed for diagnosis and directed therapy.
authors.affiliation: Department of Biochemistry and University of Vermont Cancer Center, University of Vermont College of Medicine, Burlington, VT 05405, USA.
authors.forename: Nicholas H
authors.initials: NH
authors.lastname: Farina
authors.affiliation: Department of Biochemistry and University of Vermont Cancer Center, University of Vermont College of Medicine, Burlington, VT 05405, USA.
authors.forename: Areg
authors.initials: A
authors.lastname: Zingiryan
authors.affiliation: Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
authors.forename: Jacqueline A
authors.initials: JA
authors.lastname: Akech
authors.affiliation: Department of Biochemistry and University of Vermont Cancer Center, University of Vermont College of Medicine, Burlington, VT 05405, USA.
authors.forename: Cody J
authors.initials: CJ
authors.lastname: Callahan
authors.affiliation: Prostate Cancer Discovery and Development Program, Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Huimin
authors.initials: H
authors.lastname: Lu
authors.affiliation: Department of Biochemistry and University of Vermont Cancer Center, University of Vermont College of Medicine, Burlington, VT 05405, USA.
authors.forename: Janet L
authors.initials: JL
authors.lastname: Stein
authors.affiliation: Prostate Cancer Discovery and Development Program, Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Lucia R
authors.initials: LR
authors.lastname: Languino
authors.affiliation: Department of Biochemistry and University of Vermont Cancer Center, University of Vermont College of Medicine, Burlington, VT 05405, USA.
authors.forename: Gary S
authors.initials: GS
authors.lastname: Stein
authors.affiliation: Department of Biochemistry and University of Vermont Cancer Center, University of Vermont College of Medicine, Burlington, VT 05405, USA.
authors.forename: Jane B
authors.initials: JB
authors.lastname: Lian
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology; D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics*; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics*; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics*; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D034622:RNA Interference; D015398:Signal Transduction / Q000235:genetics
chemical_list: D050659:Core Binding Factor Alpha 1 Subunit; D050676:Core Binding Factor Alpha 2 Subunit; D035683:MicroRNAs; C493726:Runx1 protein, mouse; C493716:Runx2 protein, mouse
keywords: AR; PTEN; TRAMP; miRNA targeting Runx; prostate cancer progression