title: MicroRNA-497 impairs the growth of chemoresistant neuroblastoma cells by targeting cell cycle, survival and vascular permeability genes.
abstract: 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.
authors.affiliation: Laboratory of Translational Research in Child and Adolescent Cancer, Vall d'Hebron Research Institute (VHIR)-UAB, Barcelona, Spain.
authors.forename: Aroa
authors.initials: A
authors.lastname: Soriano
authors.affiliation: Laboratory of Translational Research in Child and Adolescent Cancer, Vall d'Hebron Research Institute (VHIR)-UAB, Barcelona, Spain.
authors.forename: Laia
authors.initials: L
authors.lastname: París-Coderch
authors.affiliation: Laboratory of Translational Research in Child and Adolescent Cancer, Vall d'Hebron Research Institute (VHIR)-UAB, Barcelona, Spain.
authors.forename: Luz
authors.initials: L
authors.lastname: Jubierre
authors.affiliation: Tumor Angiogenesis Group, Catalan Institute of Oncology-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Alba
authors.initials: A
authors.lastname: Martínez
authors.affiliation: Institut de Neurociències and Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Xiangyu
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland and National Children's Research Centre Our Lady's Children's Hospital, Dublin, Ireland.
authors.forename: Olga
authors.initials: O
authors.lastname: Piskareva
authors.affiliation: Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland and National Children's Research Centre Our Lady's Children's Hospital, Dublin, Ireland.
authors.forename: Isabella
authors.initials: I
authors.lastname: Bray
authors.affiliation: Laboratory of Translational Research in Child and Adolescent Cancer, Vall d'Hebron Research Institute (VHIR)-UAB, Barcelona, Spain.
authors.forename: Isaac
authors.initials: I
authors.lastname: Vidal
authors.affiliation: Laboratory of Translational Research in Child and Adolescent Cancer, Vall d'Hebron Research Institute (VHIR)-UAB, Barcelona, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Almazán-Moga
authors.affiliation: Laboratory of Translational Research in Child and Adolescent Cancer, Vall d'Hebron Research Institute (VHIR)-UAB, Barcelona, Spain.
authors.forename: Carla
authors.initials: C
authors.lastname: Molist
authors.affiliation: Laboratory of Translational Research in Child and Adolescent Cancer, Vall d'Hebron Research Institute (VHIR)-UAB, Barcelona, Spain.
authors.forename: Josep
authors.initials: J
authors.lastname: Roma
authors.affiliation: Institut de Neurociències and Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: José R
authors.initials: JR
authors.lastname: Bayascas
authors.affiliation: Tumor Angiogenesis Group, Catalan Institute of Oncology-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Oriol
authors.initials: O
authors.lastname: Casanovas
authors.affiliation: Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland and National Children's Research Centre Our Lady's Children's Hospital, Dublin, Ireland.
authors.forename: Raymond L
authors.initials: RL
authors.lastname: Stallings
authors.affiliation: Laboratory of Translational Research in Child and Adolescent Cancer, Vall d'Hebron Research Institute (VHIR)-UAB, Barcelona, Spain.
authors.forename: José
authors.initials: J
authors.lastname: Sánchez de Toledo
authors.affiliation: Laboratory of Translational Research in Child and Adolescent Cancer, Vall d'Hebron Research Institute (VHIR)-UAB, Barcelona, Spain.
authors.forename: Soledad
authors.initials: S
authors.lastname: Gallego
authors.affiliation: Laboratory of Translational Research in Child and Adolescent Cancer, Vall d'Hebron Research Institute (VHIR)-UAB, Barcelona, Spain.
authors.forename: Miguel F
authors.initials: MF
authors.lastname: Segura
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002199:Capillary Permeability / Q000235:genetics*; D002453:Cell Cycle / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D002470:Cell Survival / Q000235:genetics*; D004318:Doxycycline / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics*; D009389:Neovascularization, Pathologic / Q000235:genetics*; D009447:Neuroblastoma / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
chemical_list: C559640:MIRN497 microRNA, human; D035683:MicroRNAs; D004318:Doxycycline
keywords: epigenetic therapy; microRNA; neuroblastoma; vascular permeability
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