title: miR-23b/SP1/c-myc forms a feed-forward loop supporting multiple myeloma cell growth.
abstract: Deregulated microRNA (miR)/transcription factor (TF)-based networks represent a hallmark of cancer. We report here a novel c-Myc/miR-23b/Sp1 feed-forward loop with a critical role in multiple myeloma (MM) and Waldenstrom's macroglobulinemia (WM) cell growth and survival. We have found miR-23b to be downregulated in MM and WM cells especially in the presence of components of the tumor bone marrow milieu. Promoter methylation is one mechanism of miR-23b suppression in myeloma. In gain-of-function studies using miR-23b mimics-transfected or in miR-23b-stably expressing MM and WM cell lines, we observed a significant decrease in cell proliferation and survival, along with induction of caspase-3/7 activity over time, thus supporting a tumor suppressor role for miR-23b. At the molecular level, miR-23b targeted Sp1 3'UTR and significantly reduced Sp1-driven nuclear factor-κB activity. Finally, c-Myc, an important oncogenic transcription factor known to stimulate MM cell proliferation, transcriptionally repressed miR-23b. Thus MYC-dependent miR-23b repression in myeloma cells may promote activation of oncogenic Sp1-mediated signaling, representing the first feed-forward loop with critical growth and survival role in myeloma.
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Fulciniti
authors.affiliation: Department of Experimental and Clinical Medicine, Magna Græcia University of Catanzaro, Salvatore Venuta Campus, Catanzaro, Italy.
authors.forename: N
authors.initials: N
authors.lastname: Amodio
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: R L
authors.initials: RL
authors.lastname: Bandi
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Cagnetta
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: M K
authors.initials: MK
authors.lastname: Samur
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: C
authors.identifier: http://orcid.org/0000-0001-8767-5905
authors.initials: C
authors.lastname: Acharya
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.|VA Boston Healthcare System, Harvard Medical School, Boston, MA, USA.
authors.forename: R
authors.initials: R
authors.lastname: Prabhala
authors.affiliation: Department of Biology, Ecology and Earth Science (DiBEST), University of Calabria, Arcavacata di Rende, Cosenza, Italy.
authors.forename: P
authors.initials: P
authors.lastname: D'Aquila
authors.affiliation: Department of Biology, Ecology and Earth Science (DiBEST), University of Calabria, Arcavacata di Rende, Cosenza, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Bellizzi
authors.affiliation: Department of Biology, Ecology and Earth Science (DiBEST), University of Calabria, Arcavacata di Rende, Cosenza, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Passarino
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Adamia
authors.affiliation: Department of Medical Sciences, University of Milan, Hematology 1, IRCCS Policlinico Foundation, Milan, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Neri
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: Z R
authors.initials: ZR
authors.lastname: Hunter
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: S P
authors.initials: SP
authors.lastname: Treon
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: K C
authors.initials: KC
authors.lastname: Anderson
authors.affiliation: Department of Experimental and Clinical Medicine, Magna Græcia University of Catanzaro, Salvatore Venuta Campus, Catanzaro, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Tassone
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.|VA Boston Healthcare System, Harvard Medical School, Boston, MA, USA.
authors.forename: N C
authors.initials: NC
authors.lastname: Munshi
mesh_terms: D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics; D019175:DNA Methylation; D004195:Disease Models, Animal; D015536:Down-Regulation; D015870:Gene Expression; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D020868:Gene Silencing; D017930:Genes, Reporter; D006801:Humans; D035683:MicroRNAs / Q000737:chemistry / Q000235:genetics*; D009101:Multiple Myeloma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011401:Promoter Regions, Genetic; D016271:Proto-Oncogene Proteins c-myc / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D012333:RNA, Messenger / Q000737:chemistry / Q000235:genetics; D016329:Sp1 Transcription Factor / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
chemical_list: C552430:MIRN23a microRNA, human; D035683:MicroRNAs; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D016329:Sp1 Transcription Factor; D053148:Caspase 3