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Small Nucleolar RNAs Determine Resistance to Doxorubicin in Human Osteosarcoma

Authors :
Joanna Kopecka
Francesca Cordero
Ilaria Buondonno
Massimo Serra
Federica Di Nicolantonio
Martina Godel
Deborah Morena
Claudia Maria Hattinger
Riccardo Taulli
Preeta Ananthanarayanan
Chiara Riganti
Giulio Ferrero
Source :
International Journal of Molecular Sciences, Vol 21, Iss 4500, p 4500 (2020), International Journal of Molecular Sciences, Volume 21, Issue 12
Publication Year :
2020
Publisher :
MDPI AG, 2020.

Abstract

Doxorubicin (Dox) is one of the most important first-line drugs used in osteosarcoma therapy. Multiple and not fully clarified mechanisms, however, determine resistance to Dox. With the aim of identifying new markers associated with Dox-resistance, we found a global up-regulation of small nucleolar RNAs (snoRNAs) in human Dox-resistant osteosarcoma cells. We investigated if and how snoRNAs are linked to resistance. After RT-PCR validation of snoRNAs up-regulated in osteosarcoma cells with different degrees of resistance to Dox, we overexpressed them in Dox-sensitive cells. We then evaluated Dox cytotoxicity and changes in genes relevant for osteosarcoma pathogenesis by PCR arrays. SNORD3A, SNORA13 and SNORA28 reduced Dox-cytotoxicity when over-expressed in Dox-sensitive cells. In these cells, GADD45A and MYC were up-regulated, TOP2A was down-regulated. The same profile was detected in cells with acquired resistance to Dox. GADD45A/MYC-silencing and TOP2A-over-expression counteracted the resistance to Dox induced by snoRNAs. We reported for the first time that snoRNAs induce resistance to Dox in human osteosarcoma, by modulating the expression of genes involved in DNA damaging sensing, DNA repair, ribosome biogenesis, and proliferation. Targeting snoRNAs or down-stream genes may open new treatment perspectives in chemoresistant osteosarcomas.

Details

Language :
English
ISSN :
16616596 and 14220067
Volume :
21
Issue :
4500
Database :
OpenAIRE
Journal :
International Journal of Molecular Sciences
Accession number :
edsair.doi.dedup.....452ea283f1ad791336daa5b3da2864ca