Abstract
WIN55,212-2 (WIN) is a synthetic agonist of cannabinoid receptors that displays promising antitumour properties. The aim of this study is to demonstrate that WIN is able to block the migratory ability of osteosarcoma cells and characterize the mechanisms involved. Using wound healing assay and zymography, we showed that WIN affects cell migration and reduces the activity of the metalloproteases MMP2 and MMP9. This effect seemed to be independent of secreted protein acidic and rich in cysteine (SPARC), a matricellular protein involved in tissue remodeling and extracellular matrix deposition. SPARC release was indeed prevented by WIN, and SPARC silencing by RNA interference did not influence the effect of the cannabinoid on cell migration. WIN also increased the release of extracellular vesicles and dramatically upregulated miR-29b1, a key miRNA that modulates cell proliferation and migration. Interestingly, reduced cell migration was observed in stably miR-29b1-transfected cells, similarly to WIN-treated cells. Finally, we show the absence of SPARC in the extracellular vesicles released by osteosarcoma cells and no changes in SPARC level in miR-29b1 overexpressing cells. Overall, these findings suggest that WIN markedly affects cell migration, dependently on miR-29b1 and independently of SPARC, and can thus be considered as a potential innovative therapeutic agent in the treatment of osteosarcoma.
Highlights
Osteosarcoma (OS) is a primary malignant bone tumour that most often affects males with two incidence peaks, one of which is between 10 and 40 years of age and the other in the elderly [1,2]
We demonstrate here that WIN markedly reduced the migratory ability of osteosarcoma MG63 cells, and this effect was accompanied by a dramatic reduction in the extracellular activity and intracellular levels of MMP2 and MMP9 metalloproteases
Fragmentary data in the literature demonstrate that WIN can inhibit the epithelial mesenchymal transition and migration in different cancer cell models [33,34] In an attempt to clarify the mechanism of the anti-migratory effect of WIN in osteosarcoma cells, our study focuses on a possible involvement of the matricellular protein secreted protein acidic and rich in cysteine (SPARC) and a hypothetical role exerted by miR-29b1
Summary
Osteosarcoma (OS) is a primary malignant bone tumour that most often affects males with two incidence peaks, one of which is between 10 and 40 years of age and the other in the elderly [1,2]. The tumour can respond to chemotherapy treatment, in patients with metastatic disease, the prognosis remains adverse [4]. Numerous studies have explored the anti-proliferative effects of these compounds in various tumours [8]. MiR-Let-7d has been demonstrated to be a target of cannabinoid receptors [14], and the anticancer activity of WIN was related to the miR-27a-mediated repression of specificity protein (Sp) transcription factor in colon cancer cells [15]
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