MiR-4270 acts as a tumor suppressor by directly targeting Bcl-xL in human osteosarcoma cells

Clément Veys; Flavie Boulouard; Abderrahim Benmoussa; Manon Jammes; Emilie Brotin; Françoise Rédini; Laurent Poulain; Nicolas Gruchy; Christophe Denoyelle; Florence Legendre; Philippe Galera

doi:10.3389/fonc.2023.1220459

MiR-4270 acts as a tumor suppressor by directly targeting Bcl-xL in human osteosarcoma cells

Front Oncol. 2023 Aug 31:13:1220459. doi: 10.3389/fonc.2023.1220459. eCollection 2023.

Authors

Clément Veys¹, Flavie Boulouard^{1

2}, Abderrahim Benmoussa^{1

3}, Manon Jammes¹, Emilie Brotin^{4

5

6}, Françoise Rédini⁷, Laurent Poulain^{5

6}, Nicolas Gruchy^{1

2}, Christophe Denoyelle^{4

5

6}, Florence Legendre¹, Philippe Galera¹

Affiliations

¹ Normandie Univ., UNICAEN, BIOTARGEN, Caen, France.
² Department of Genetics, Normandy Center for Genomic and Personalized Medicine, Caen University Hospital, Caen, France.
³ Research Center of the UHC Sainte-Justine and Department of Nutrition, Université de Montréal, Montréal, QC, Canada.
⁴ Normandie Univ., UNICAEN, Federative Structure Normandie Oncology, US Platon, ImpedanCELL Platform, Caen, France.
⁵ Normandie Univ., UNICAEN, INSERM U1086 ANTICIPE, Biology and Innovative Therapeutics for Ovarian Cancer (BioTICLA), Caen, France.
⁶ UNICANCER, Comprehensive Cancer Center F. Baclesse, Caen, France.
⁷ UMR 1238 Phy-Os "Bone Sarcomas and Remodeling of Calcified Tissues", INSERM, Nantes University, Nantes, France.

Abstract

Chondrosarcomas and osteosarcomas are malignant bone tumors with a poor prognosis when unresectable or metastasized. Moreover, radiotherapy and chemotherapy could be ineffective. MiRNAs represent an alternative therapeutic approach. Based on high-throughput functional screening, we identified four miRNAs with a potential antiproliferative effect on SW1353 chondrosarcoma cells. Individual functional validations were then performed in SW1353 cells, as well as in three osteosarcoma cell lines. The antiproliferative and cytotoxic effects of miRNAs were evaluated in comparison with a positive control, miR-342-5p. The cytotoxic effect of four selected miRNAs was not confirmed on SW1353 cells, but we unambiguously revealed that miR-4270 had a potent cytotoxic effect on HOS and MG-63 osteosarcoma cell lines, but not on SaOS-2 cell line. Furthermore, like miR-342-5p, miR-4270 induced apoptosis in these two cell lines. In addition, we provided the first report of Bcl-xL as a direct target of miR-4270. MiR-4270 also decreased the expression of the anti-apoptotic protein Mcl-1, and increased the expression of the pro-apoptotic protein Bak. Our findings demonstrated that miR-4270 has tumor suppressive activity in osteosarcoma cells, particularly through Bcl-xL downregulation.

Keywords: Bcl-XL; apoptosis; chondrosarcoma; miR-342-5p; miR-4270; osteosarcoma.

Grants and funding

This work was supported by the Normandy Regional Council through the “Emergence” program (to CD, LP and PG) and the “RIN Recherche OncoThera” program (to LP and PG), by two grants to FL from the Normandy confederation of the “Ligue Contre le Cancer” (Orne and Seine Maritime committees), by the French Government and the European Community (European Regional Development Funds (ERDF)) to PG The xCELLigence apparatus (Core Facility Federative structure 4206 ICORE of Normandy University) was financed by the European Community (ERDF) and the Comprehensive Cancer Center F. Baclesse (Caen). These funding sources had no involvement in the study design, collection, analysis and interpretation of data, in the writing of the manuscript, or in the decision to submit the manuscript for publication.