MYC-related microRNAs signatures in non-Hodgkin B-cell lymphomas and their relationships with core cellular pathways
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Giorgio Malpeli1,2, Stefano Barbi2, Gabriele Tosadori3, Corinna Greco4, Simonetta Zupo5, Serena Pedron2, Matteo Brunelli2, Anna Bertolaso2, Maria Teresa Scupoli6, Mauro Krampera4, Paul Takam Kamga3, Carlo Maria Croce7, George Adrian Calin8, Aldo Scarpa2,9 and Alberto Zamò10
1Department of Surgical Sciences, Dentistry, Gynecology and Pediatrics, Section of Surgery, University of Verona, Verona, Italy
2Department of Diagnostics and Public Health, University of Verona, Verona, Italy
3Center for BioMedical Computing, University of Verona, Verona, Italy
4Department of Medicine, Section of Hematology, Stem Cell Research Laboratory, University of Verona, Verona, Italy
5Laboratory of Molecular Diagnostics, IRCCS-AOU San Martino-IST, Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy
6Department of Medicine, Section of Hematology, University of Verona, Verona, Italy
7Department of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
8Department of Experimental Therapeutics and The Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
9Applied Research on Cancer-Network (ARC-NET), University of Verona, Verona, Italy
10Department of Oncology, University of Turin, Torino, Italy
Giorgio Malpeli, email: [email protected]
Keywords: microRNAs; MYC; non-Hodgkin B-cell lymphoma; cell lines; network analysis
Received: October 26, 2017 Accepted: April 28, 2018 Published: July 03, 2018
In order to investigate the role of microRNAs in the pathogenesis of different B-cell lymhoma subtypes, we have applied an array-based assay to a series of 76 mixed non-Hodgkin B-cell lymphomas, including Burkitt’s lymphoma (BL), diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, mantle cell lymphoma (MCL) and follicular lymphoma. Lymphomas clustered according to histological subtypes, driven by two miRNA clusters (the miR-29 family and the miR-17-92 cluster). Since the two miRNA clusters are known to be MYC-regulated, we investigated whether this would be supported in MYC-driven experimental models, and found that this signature separated BL cell lines and a MYC-translocated MCL cell lines from normal germinal center B-cells and other B-cell populations. Similar results were also reproduced in tissue samples comparing BL and reactive lymph node samples. The same series was then quantitatively analyzed for MYC expression by immunohistochemistry and MYC protein levels were compared with corresponding miRNA signatures. A specific metric was developed to summarize the levels of MYC-related microRNAs and the corresponding protein levels. We found that MYC-related signatures are directly related to MYC protein expression across the whole spectrum of B-cells and B-cell lymphoma, suggesting that the MYC-responsive machinery shows predominantly quantitative, rather than qualitative, modifications in B-cell lymphoma. Novel MYC-related miRNAs were also discovered by this approach. Finally, network analysis found that in BL MYC-related differentially expressed miRNAs could control, either positively or negatively, a limited number of hub proteins, including BCL2, CDK6, MYB, ZEB1, CTNNB1, BAX and XBP1.
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