Further exploration on the downstream network of miR-34a identified that blocking plasminogen activator inhibitor-1 (PAI-1) expression could restrain OS dedifferentiation into cancer stem-like cells by downregulating SRY-related-HMG box (Sox) 2.
Treatment of U2OS cells with cisplatin induced cell apoptosis by upregulation of c-Myc -dependent Bim expression; Osteosarcoma U2OS cells transfected with miR-34a mimics (miR-34a/U2OS) induced cell apoptosis and inhibited cell survival, and increased the sensitivity of U2OS cells to cisplatin.
The data of the present study indicated that the inhibitory role of miR‑34a on tumor growth and metastasis of osteosarcoma may function by reducing the maintenance of osteosphere self‑renewal capacity, elimination of tumorigenic ability and invasion of osteosarcoma in vitro.
And the expression of C-IAP2 and Bcl-2 protein was drastically inhibited, and the activities of caspase-3 and caspase-9 were significantly increased after transfecting miR-34a onto osteosarcoma MG-63 cells.
Independent actions of the model drugs DNA-intercalating doxorubicin, RNA-interfering miR-34a and protein-inhibiting sorafenib on DNA replication, RNA translation and protein kinase signaling in highly metastatic, human osteosarcoma 143B cells were demonstrated by the increase of γH2A.X foci formation, reduction of c-MET expression and inhibition of Erk1/2 phosphorylation, respectively, and optimal effects were found for triple-drug combination.
Validating the coordinating role of miR-34a in microtubule destabilization, when miR-34a was combined with either microtubule inhibitors or chemotherapy, STMN1 phosphorylation was suppressed and there was greater cytotoxicity in osteosarcoma cells.
The angiotensin II type 1 receptor (AGTR1) gene, is one of the targets of miR-34a-5p in OS and thus negatively correlates with OS chemoresistance by systematic investigations of a multi-drug sensitive (G-292) and resistant (SJSA-1) OS cell lines.
Specifically, in this study, using systematic observations of multi-drug sensitive (G-292 and MG63.2) and resistant (SJSA-1 and MNNG/HOS) osteosarcoma (OS) cell lines, we showed that miR-34a-5p promotes the multi-drug resistance of OS through the receptor tyrosine kinase CD117, a direct target of miR-34a-5p.
Inhibition of OS cell growth and invasion were associated with release of high levels of mature miR-34a from pre-miR-34a prodrug and consequently reduction of protein levels of many miR-34a target genes including SIRT1, BCL2, c-MET, and CDK6.