Identification of microRNAs implicated in the late differentiation stages of normal B cells suggests a central role for miRNA targets ZEB1 and TP53
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Giorgio Malpeli1,2, Stefano Barbi2, Simonetta Zupo3, Gabriele Tosadori4, Giovanni Scardoni4, Anna Bertolaso2, Silvia Sartoris5, Stefano Ugel5, Caterina Vicentini2,10, Matteo Fassan6, Annalisa Adamo7, Mauro Krampera7, Maria Teresa Scupoli8, Carlo Maria Croce9, Aldo Scarpa2,10
1Department of Surgical Sciences, Dentistry, Gynecology and Pediatrics, Section of Surgery, University of Verona, Verona, Italy
2Department of Diagnostics and Public Health, Section of Pathological Anatomy, University of Verona, Verona, Italy
3Laboratory of Molecular Diagnostics, IRCCS-AOU San Martino-IST, Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy
4Center for BioMedical Computing (CBMC), University of Verona, Verona, Italy
5Department of Medicine, Section of Immunology, University of Verona, Verona, Italy
6Department of Medicine, Surgical Pathology and Cytopathology Unit, University of Padua, Padua, Italy
7Department of Medicine, Section of Hematology, Stem Cell Research Laboratory, University of Verona, Italy
8Department of Medicine, Section of Hematology, University of Verona, Italy
9Department of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
10Applied Research on Cancer-Network (ARC-NET), University of Verona, Verona, Italy
Giorgio Malpeli, email: [email protected]
Keywords: B cell development, follicle, germinal centre, microRNAs, network analysis
Received: June 17, 2016 Accepted: December 12, 2016 Published: January 17, 2017
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.
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