Etoposide-resistance in a neuroblastoma model cell line is associated with 13q14.3 mono-allelic deletion and miRNA-15a/16-1 down-regulation

Barbara Marengo, Paola Monti, Mariangela Miele, Paola Menichini, Laura Ottaggio, Giorgia Foggetti, Alessandra Pulliero, Alberto Izzotti, Andrea Speciale, Ombretta Garbarino, Nicola Traverso, Gilberto Fronza, Cinzia Domenicotti

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Abstract

Drug resistance is the major obstacle in successfully treating high-risk neuroblastoma. The aim of this study was to investigate the basis of etoposide-resistance in neuroblastoma. To this end, a MYCN-amplified neuroblastoma cell line (HTLA-230) was treated with increasing etoposide concentrations and an etoposide-resistant cell line (HTLA-ER) was obtained. HTLA-ER cells, following etoposide exposure, evaded apoptosis by altering Bax/Bcl2 ratio. While both cell populations shared a homozygous TP53 mutation encoding a partially-functioning protein, a mono-allelic deletion of 13q14.3 locus, where the P53 inducible miRNAs 15a/16-1 are located, and the consequent miRNA down-regulation were detected only in HTLA-ER cells. This event correlated with BMI-1 oncoprotein up-regulation which caused a decrease in p16 tumor suppressor content and a metabolic adaptation of HTLA-ER cells. These results, taken collectively, highlight the role of miRNAs 15a/16-1 as markers of chemoresistance.

Original languageEnglish
Article number13762
JournalScientific Reports
Volume8
Issue number1
DOIs
Publication statusPublished - Dec 1 2018

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    Marengo, B., Monti, P., Miele, M., Menichini, P., Ottaggio, L., Foggetti, G., Pulliero, A., Izzotti, A., Speciale, A., Garbarino, O., Traverso, N., Fronza, G., & Domenicotti, C. (2018). Etoposide-resistance in a neuroblastoma model cell line is associated with 13q14.3 mono-allelic deletion and miRNA-15a/16-1 down-regulation. Scientific Reports, 8(1), [13762]. https://doi.org/10.1038/s41598-018-32195-7