miR-99b-5p, miR-380-3p, and miR-485-3p are novel chemosensitizing miRNAs in high-risk neuroblastoma

Holliday, H; Yang, J; Dodson, E; Nikolic, I; Kamili, A; Wheatley, M; Deng, N; Alexandrou, S; Davis, TP; Kavallaris, M; Caldon, CE; McCarroll, J; De Preter, K; Mestdagh, P; Marshall, GM; Simpson, KJ; Fletcher, J; Swarbrick, A

Author(s): Holliday, H; Yang, J; Dodson, E; Nikolic, I; Kamili, A; Wheatley, M; Deng, N; Alexandrou, S; Davis, TP; Kavallaris, M; Caldon, CE; McCarroll, J; De Preter, K; Mestdagh, P; Marshall, GM; Simpson, KJ; Fletcher, J; Swarbrick, A;
Details: Publication Year 2022-03-02,Volume 30,Issue #3,Page 1119-1134
Journal Title: Molecular Therapy
Publication Type: Research article
Abstract: Neuroblastoma is a deadly childhood cancer arising in the developing sympathetic nervous system. High-risk patients are currently treated with intensive chemotherapy, which is curative in only 50% of children and leaves some surviving patients with life-long side effects. microRNAs (miRNAs) are critical regulators of neural crest development and are deregulated during neuroblastoma tumorigenesis, making miRNA-based drugs an attractive therapeutic avenue. A functional screen of >1,200 miRNA mimics was conducted in neuroblastoma cell lines to discover miRNAs that sensitized cells to low doses (30% inhibitory concentration [IC(30)]) of doxorubicin and vincristine chemotherapy used in the treatment of the disease. Three miRNAs, miR-99b-5p, miR-380-3p, and miR-485-3p, had potent chemosensitizing activity with doxorubicin in multiple models of high-risk neuroblastoma. These miRNAs underwent genomic loss in a subset of neuroblastoma patients, and low expression predicted poor survival outcome. In vitro functional assays revealed each of these miRNAs enhanced the anti-proliferative and pro-apoptotic effects of doxorubicin. We used RNA sequencing (RNA-seq) to show that miR-99b-5p represses neuroblastoma dependency genes LIN28B and PHOX2B both in vitro and in patient-derived xenograft (PDX) tumors. Luciferase reporter assays demonstrate that PHOX2B is a direct target of miR-99b-5p. We anticipate that restoring the function of the tumor-suppressive miRNAs discovered here may be a valuable therapeutic strategy for the treatment of neuroblastoma patients.
Keywords: Child; Doxorubicin/pharmacology/therapeutic use; Gene Expression Regulation, Neoplastic; Humans; *MicroRNAs/genetics/metabolism; *Neuroblastoma/drug therapy/genetics; chemotherapy; doxorubicin; high-throughput screen; miR-380-3p; miR-485-3p; miR-99b-5p; miRNA; miRNA-based therapy; nanoparticle; neuroblastoma
Department(s): Laboratory Research
PubMed ID: 34998954
Publisher's Version: https://doi.org/10.1016/j.ymthe.2022.01.004
Open Access at Publisher's Site: https://doi.org/10.1016/j.ymthe.2022.01.004
Terms of Use/Rights Notice: Refer to copyright notice on published article.

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