Downregulation of miR-22 Contributes to Epithelial-Mesenchymal Transition in Osteosarcoma by Targeting Twist1.

The epithelial-mesenchymal transition (EMT) is a vital step in osteosarcoma (OS) progression toward metastasis, but the specific molecular events governing this process are incompletely characterized, with miRNAs having increasingly been found to regulate the EMT. In this study, We assessed levels of miR-22 and its target, Twist1, via real-time PCR (qRT-PCR). We further used functional proliferation assays, measures of cell morphology, and western blotting to assess the functional relevance of miR-22 in OS and confirmed Twist1 as a miR-22 target via luciferase reporter assay. We observed a significant decrease in miR-22 levels in OS tumor samples relative to normal tissue, with such downregulating being significantly associated with tumor histological grade. When overexpressed, miR-22 impaired OS cell proliferation and EMT progression. We found Twist1 to be a direct miR-22 target, with levels of miR-22 and Twist1 mRNA being inversely correlated in patient samples. When overexpressed, miR-22 suppressed Twist1 translation and thereby attenuated the EMT in OS cells. These results clearly demonstrate that miR-22 can regulate the EMT in OS cells via targeting Twist1, thus highlighting a potentially novel pathway that can be therapeutically targeted in order to treat OS.

MiR-200c regulates tumor growth and chemosensitivity to cisplatin in osteosarcoma by targeting AKT2.

MicroRNAs (miRNAs) expression aberration has been discovered in almost all human cancers, thus offering a group of potential diagnostic markers, prognostic factors and therapeutic targets in tumorigenesis. Now our data showed that miR-200c, which is downregulated in osteosarcoma tissues, drives chemosensitivity to cisplatin in osteosarcoma. We demonstrated that AKT2 is a direct target of miR-200c, Spearman's rank correlation analysis showed that the expression levels of AKT2 and miR-200c in 35 pairs of osteosarcoma specimens were inversely correlated. Moreover, miR-200c inhibited cell proliferation and cell migration. Taken together, for the first time, our results demonstrate that miR-200c plays a significant role in osteosarcoma tumor growth and chemosensitivity by regulating AKT2, which may provide a novel therapeutic strategy for treatment of osteosarcoma.

MiR-100 Inhibits Osteosarcoma Cell Proliferation, Migration, and Invasion and Enhances Chemosensitivity by Targeting IGFIR.

MicroRNAs are highly conserved noncoding RNA that negatively modulate protein expression at a posttranscriptional and/or translational level. MicroRNAs play an important role in the development and progression of human cancers, including osteosarcoma. Recent studies have shown that miR-100 was downregulated in many cancers; however, the role of miR-100 in human osteosarcoma has not been totally elucidated. In this study, we demonstrate that the expression of miR-100 was significantly downregulated in human osteosarcoma tissues compared to the adjacent tissues. Enforced expression of miR-100 inhibited cell proliferation, migration, and invasion abilities of osteosarcoma cells, U-2OS, and MG-63. Additionally, miR-100 also sensitized osteosarcoma cells to cisplatin and promoted apoptosis. Furthermore, overexpression of miR-100 decreased the expression of insulin-like growth factor I receptor and inhibited PI3K/AKT and MAPK/ERK signaling. In human clinical specimens, insulin-like growth factor I receptor was inversely correlated with miR-100 in osteosarcoma tissues. Collectively, our results demonstrate that miR-100 is a tumor suppressor microRNA and indicate its potential application for the treatment of osteosarcoma in future.