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Open AccessArticle

Small Nucleolar RNAs Determine Resistance to Doxorubicin in Human Osteosarcoma

1
Department of Oncology, University of Torino, 1026 Torino, Italy
2
Department of Computer Science, University of Torino, 10149 Torino, Italy
3
Department of Clinical and Biological Sciences, University of Torino, 10043 Orbassano, Italy
4
Laboratory of Experimental Oncology, Pharmacogenomics and Pharmacogenetics Research Unit, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy
5
Candiolo Cancer Institute, FPO–IRCCS, 10060 Candiolo, Italy
*
Authors to whom correspondence should be addressed.
These authors equally contributed to this work.
Int. J. Mol. Sci. 2020, 21(12), 4500; https://doi.org/10.3390/ijms21124500
Received: 31 May 2020 / Revised: 19 June 2020 / Accepted: 21 June 2020 / Published: 24 June 2020
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. View Full-Text
Keywords: osteosarcoma; doxorubicin; chemoresistance; small nucleolar RNAs osteosarcoma; doxorubicin; chemoresistance; small nucleolar RNAs
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MDPI and ACS Style

Godel, M.; Morena, D.; Ananthanarayanan, P.; Buondonno, I.; Ferrero, G.; Hattinger, C.M.; Di Nicolantonio, F.; Serra, M.; Taulli, R.; Cordero, F.; Riganti, C.; Kopecka, J. Small Nucleolar RNAs Determine Resistance to Doxorubicin in Human Osteosarcoma. Int. J. Mol. Sci. 2020, 21, 4500.

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