Oncotarget 7(27):42241-42251(2016) 

miR-145 promotes osteosarcoma growth by reducing expression of the transcription factor friend leukemia virus integration 1

Juyu Tang, Kanghua Li


Osteosarcoma (OS) is the most common malignant bone tumor in children and young adults. miR-145 is a microRNA highly expressed in vascularized tissues and has been widely studied in cancers. In this study, we explored the expression and function of miR-145 in OS. We found that miR-145 was consistently under-expressed in OS tissues and cell lines as compared to normal bone tissues and osteoblast cells. Ectopic expression of miR-145 in OS cells inhibited their proliferation and migration and induced apoptosis. miR-145 targets a putative microRNA regulatory element (MRE) in the 3′-UTR of friend leukemia virus integration 1 gene (FLI-1), and its abundance was inversely related to FLI-1 expression in OS tissues and cell lines. miR-145 decreased expression FLI-1 protein and mRNA, but mutation of the miR-145 MRE sequence in the FLI-1 3′-UTR abolished the activity of miR-145 in a reporter assay. Restored expression of FLI-1 diminished miR-145-mediated suppression of tumor progression. These results suggest that miR-145 acts as a tumor suppressor by directly reducing expression of FLI-1, and that the miR-145/FLI-1 pathway is important for tumor progression in OS.To explore the expression of miR-145 and FLI-1 in OS carcinogenesis, we examined 13 pairs of OS and matched normal tissues using TaqMan RT-PCR analysis. Relative to matched normal tissues, more than half of the OS tissues exhibited under-expression of miR-145 mRNA and all of the OS tissues had high expression of FLI-1 mRNA (Figure 1A & 1C). Expression of miR-145 in OS tissues was lower than in normal tissues (Figure 1C). We next explored the expression of miR-145 and FLI-1 in four OS cell lines (HOS, Saos-2, U2OS, and MG-63). Compared with the normal human osteoblast cell line (NHOst), miR-145 expression was reduced in the four OS cell lines (Figure 1B). Interestingly, expression of FLI-1 mRNA in all of the four OS cell lines was higher than in the NHOst cells (Figure 1D). These results suggested that the under-expression of miR-145 and over-expression of FLI-1 mRNA are common features of OS tissues and cell lines.Thirteen fresh specimens of osteosarcoma and matched normal tissues were collected from the Department of Orthopedics, Xiang Ya Hospital of the Central South University. The matched normal tissues were obtained 5 cm distant from the tumor margin, which were confirmed by pathologists. No patients underwent any therapy before study recruitment. Use of the tissue samples and all experiments were approved by the Institutional Ethics Committee.This work was supported by the fund from the Department of Education Foundation in Hunan Province (12C0356).CONFLICTS OF INTERESTThe authors declare no potential conflicts of interest.
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