title: Identification of microRNAs implicated in the late differentiation stages of normal B cells suggests a central role for miRNA targets ZEB1 and TP53.
abstract: In the late B cell differentiation stages, miRNAs expression modifications promoting or inhibiting key pathways are only partially defined. We isolated 29 CD19+ human B cell samples at different stages of differentiation: B cells from peripheral blood; naïve, germinal center (GC) and subepithelial (SE) B cells from tonsils. SE cells were further split in activated and resting B cell. The miRNA expression profile of these B cells was assessed by microarray analysis and selected miRNAs were validated by quantitative RT-PCR and in situ hybridization on normal tonsils. The comparison of all samples showed changes in 107 miRNAs in total. Among 48 miRNAs differentially expressed in naïve, GC and SE cells, we identified 8 miRNAs: mir-323, mir-138, mir-9*, mir-211, mir-149, mir-373, mir-135a and mir-184, strictly specific to follicular cells that had never been implicated before in late stages of B cell development. Moreover, we unveiled 34 miRNAs able to discriminate between CD5- activated B cells and resting B cells. The miRNAs profile of CD5- resting B cells showed a higher similarity to naïve CD5+ than CD5- activated B cells. Finally, network analysis on shortest paths connecting gene targets suggested ZEB1 and TP53 as key miRNA targets during the follicular differentiation pathway. These data confirm and extend our knowledge on the miRNAs-related regulatory pathways involved in the late B cell maturation.
authors.affiliation: Department of Surgical Sciences, Dentistry, Gynecology and Pediatrics, Section of Surgery, University of Verona, Verona, Italy.|Department of Diagnostics and Public Health, Section of Pathological Anatomy, University of Verona, Verona, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Malpeli
authors.affiliation: Department of Diagnostics and Public Health, Section of Pathological Anatomy, University of Verona, Verona, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Barbi
authors.affiliation: Laboratory of Molecular Diagnostics, IRCCS-AOU San Martino-IST, Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy.
authors.forename: Simonetta
authors.initials: S
authors.lastname: Zupo
authors.affiliation: Center for BioMedical Computing (CBMC), University of Verona, Verona, Italy.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Tosadori
authors.affiliation: Center for BioMedical Computing (CBMC), University of Verona, Verona, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Scardoni
authors.affiliation: Department of Diagnostics and Public Health, Section of Pathological Anatomy, University of Verona, Verona, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Bertolaso
authors.affiliation: Department of Medicine, Section of Immunology, University of Verona, Verona, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Sartoris
authors.affiliation: Department of Medicine, Section of Immunology, University of Verona, Verona, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Ugel
authors.affiliation: Department of Diagnostics and Public Health, Section of Pathological Anatomy, University of Verona, Verona, Italy.|Applied Research on Cancer-Network (ARC-NET), University of Verona, Verona, Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Vicentini
authors.affiliation: Department of Medicine, Surgical Pathology and Cytopathology Unit, University of Padua, Padua, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Fassan
authors.affiliation: Department of Medicine, Section of Hematology, Stem Cell Research Laboratory, University of Verona, Italy.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Adamo
authors.affiliation: Department of Medicine, Section of Hematology, Stem Cell Research Laboratory, University of Verona, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Krampera
authors.affiliation: Department of Medicine, Section of Hematology, University of Verona, Italy.
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Scupoli
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
authors.forename: Carlo Maria
authors.initials: CM
authors.lastname: Croce
authors.affiliation: Department of Diagnostics and Public Health, Section of Pathological Anatomy, University of Verona, Verona, Italy.|Applied Research on Cancer-Network (ARC-NET), University of Verona, Verona, Italy.
authors.forename: Aldo
authors.initials: A
authors.lastname: Scarpa
mesh_terms: D001402:B-Lymphocytes / Q000166:cytology / Q000502:physiology*; D002454:Cell Differentiation / Q000502:physiology; D053263:Gene Regulatory Networks; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D009367:Neoplasm Staging; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D000071799:Zinc Finger E-box-Binding Homeobox 1 / Q000235:genetics* / Q000378:metabolism
chemical_list: D035683:MicroRNAs; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1
keywords: B cell development; follicle; germinal centre; microRNAs; network analysis