MicroRNA-497 impairs the growth of chemoresistant neuroblastoma cells by targeting cell cycle, survival and vascular permeability genes
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Aroa Soriano1, Laia París-Coderch1, Luz Jubierre1, Alba Martínez2, Xiangyu Zhou3, Olga Piskareva4, Isabella Bray4, Isaac Vidal1, Ana Almazán-Moga1, Carla Molist1, Josep Roma1, José R. Bayascas3, Oriol Casanovas2, Raymond L. Stallings4, José Sánchez de Toledo1, Soledad Gallego1, Miguel F. Segura1
1Laboratory of Translational Research in Child and Adolescent Cancer, Vall d’Hebron Research Institute (VHIR)-UAB, Barcelona, Spain
2Tumor Angiogenesis Group, Catalan Institute of Oncology-IDIBELL, L’Hospitalet de Llobregat, Barcelona, Spain
3Institut de Neurociències and Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Barcelona, Spain
4Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland and National Children’s Research Centre Our Lady’s Children’s Hospital, Dublin, Ireland
Miguel F. Segura, e-mail: [email protected]
Aroa Soriano, e-mail: [email protected]
Keywords: microRNA, neuroblastoma, epigenetic therapy, vascular permeability
Received: July 13, 2015 Accepted: January 01, 2016 Published: January 25, 2016
Despite multimodal therapies, a high percentage of high-risk neuroblastoma (NB) become refractory to current treatments, most of which interfere with cell cycle and DNA synthesis or function, activating the DNA damage response (DDR). In cancer, this process is frequently altered by deregulated expression or function of several genes which contribute to multidrug resistance (MDR). MicroRNAs are outstanding candidates for therapy since a single microRNA can modulate the expression of multiple genes of the same or different pathways, thus hindering the development of resistance mechanisms by the tumor. We found several genes implicated in the MDR to be overexpressed in high-risk NB which could be targeted by microRNAs simultaneously. Our functional screening identified several of those microRNAs that reduced proliferation of chemoresistant NB cell lines, the best of which was miR-497. Low expression of miR-497 correlated with poor patient outcome. The overexpression of miR-497 reduced the proliferation of multiple chemoresistant NB cell lines and induced apoptosis in MYCN-amplified cell lines. Moreover, the conditional expression of miR-497 in NB xenografts reduced tumor growth and inhibited vascular permeabilization. MiR-497 targets multiple genes related to the DDR, cell cycle, survival and angiogenesis, which renders this molecule a promising candidate for NB therapy.
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