miR-181b-p53 negative feedback axis regulates osteosarcoma cell proliferation and invasion

Abstract

Osteosarcoma (OS) is one of the most common malignant tumors in young adults and as a high distant metastasis rate. The p53 protein, a potent prognostic biomarker for patients with OS, is altered in ~50% of OS cases. p53 was reported to exert its effects through regulating the transcription of microRNAs (miRNAs/miRs) and other genes. In the present study, the expression of miR-181b, a critical OS oncomiR, was shown to be significantly upregulated whereas p53 expression was downregulated within OS tissues and cells; in tissue samples, miR-181b and p53 were negatively correlated. p53 inhibited the transcription of miR-181b via targeting its promoter region, whereas miR-181b bound the TP53 3′-untranslated region (UTR) to inhibit p53 expression. miR-181b silencing considerably increased p53, p21, and epithelial-Cadherin protein levels but decreased Cyclin D1 protein levels in OS cells. In addition, miR-181b inhibition reduced OS cell proliferation and invasion. In contrast, p53 knockdown had the opposite effects on these proteins and OS cell proliferation and invasion. Above all, p53 knockdown significantly attenuated the effects of miR-181b inhibition. Moreover, OS cell xenograft assays further confirmed the roles of the miR-181b/p53 axis in OS growth. In conclusion, miR-181b and p53 are negatively regulated by one another and therefore form a negative feedback axis that regulates the proliferation and invasion abilities of OS cells. Targeting miR-181b to inhibit its abnormal upregulation might be a potent strategy for OS treatment.