Hsa-miR-155-5p drives aneuploidy at early stages of cellular transformation
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Sara Pagotto1,2,*, Angelo Veronese1,2,*, Alessandra Soranno2, Paola Lanuti1,3, Mirco Di Marco1,2, Marco Vincenzo Russo1, Alice Ramassone1,2, Marco Marchisio1,3, Pasquale Simeone1,3, Paolo E. Guanciali Franchi2, Giandomenico Palka2, Renato Mariani Costantini1,2, Carlo M. Croce4,5 and Rosa Visone1,2
1Aging Research Center and Translational Medicine-CeSI-MeT, Chieti, 66100, Italy
2Department of Medical, Oral and Biotechnological Sciences, “G. d'Annunzio” University Chieti-Pescara, Chieti, 66100, Italy
3Department of Medicine and Aging Sciences, “G. d’Annunzio” University Chieti-Pescara, Chieti, 66100, Italy
4Department of Molecular Virology, Immunology, and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA
5Chronic Lymphocytic Leukemia Research Consortium, San Diego, California 92093, USA
*These authors contributed equally to this work
Rosa Visone, email: [email protected]
Keywords: miR-155; BUB1; CENP-F; ZW10; aneuploidy
Received: September 27, 2017 Accepted: November 16, 2017 Published: February 07, 2018
Hsa-miR-155-5p (miR-155) is overexpressed in most solid and hematological malignancies. It promotes loss of genomic integrity in cancer cells by targeting genes involved in microsatellite instability and DNA repair; however, the link between miR-155 and aneuploidy has been scarcely investigated. Here we describe a novel mechanism by which miR-155 causes chromosomal instability. Using osteosarcoma cells (U2OS) and normal human dermal fibroblast (HDF), two well-established models for the study of chromosome congression, we demonstrate that miR-155 targets the spindle checkpoint proteins BUB1, CENP-F, and ZW10, thus compromising chromosome alignment at the metaphase plate. In U2OS cells, exogenous miR-155 expression reduced the recruitment of BUB1, CENP-F, and ZW10 to the kinetochores which resulted in defective chromosome congression. In contrast, during in vitro transformation of HDF by enforced expression of SV40 Large T antigen and human telomerase (HDFLT/hTERT), inhibition of miR-155 reduced chromosome congression errors and aneuploidy at early passages. Using live-cell imaging we observed that miR-155 delays progression through mitosis, indicating an activated mitotic spindle checkpoint, which likely fails to reduce aneuploidy. Overall, this study provides insight into a mechanism that generates aneuploidy at early stages of cellular transformation, pointing to a role for miR-155 in chromosomal instability at tumor onset.
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