microRNA-758 inhibits the malignant phenotype of osteosarcoma cells by directly targeting HMGA1 and deactivating the Wnt/β-catenin pathway

American Journal of Cancer Research

Jia Ren¹  Mengjie Yang² 

[1] Department of Emergency, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, P. R. China;National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing 102206, P. R. China

关键词: High mobility group AT-hook 1;    malignant phenotype;    microRNA-758;    osteosarcoma;    Wnt/β;    -catenin pathway;   

DOI  :  

学科分类：肿瘤学

来源: e-Century Publishing Corporation

【 摘 要 】

microRNAs (miRNAs) are frequently aberrantly expressed in osteosarcoma (OS) and are implicated in its development. Dysregulation of miR-758 has been reported in various human malignancies. However, whether miR-758 is involved in the oncogenesis and progression of OS remains unclear. In this study, reverse transcription-quantitative polymerase chain reaction was performed to detect miR-758 expression in OS tissues and cell lines. A series of functional experiments were employed to explore the regulatory effects of miR-758 on the malignant behaviors of OS cells both in vitro and in vivo. The molecular mechanisms underlying the activity of miR-758 in OS cells were also investigated. miR-758 was significantly downregulated in OS tissues and cell lines, and a low miR-758 level was correlated with tumor size, clinical stage, and distant metastasis of patients with OS. OS patients with low miR-758 level exhibited poorer overall survival and worse disease-free survival rates compared to patients with high miR-758 level. In addition, functional assays revealed that miR-758 overexpression led to a significant decrease in OS cell growth and metastasis in vitro, whereas miR-758 inhibition had the opposite effect on OS cells. miR-758 reduced the tumorous growth of OS cells in vivo. Furthermore, high mobility group AT-hook 1 (HMGA1) was identified as a direct target of miR-758 in OS cells. HMGA1 was highly expressed in OS tissues, and its expression was inversely correlated with miR-758 expression. HMGA1 silencing exerted an effect similar to that induced by miR-758 upregulation in OS cells. Restored HMGA1 expression abolished the effects of miR-758 on the malignant phenotypes of OS cells. Moreover, miR-758 regulated the Wnt/β-catenin pathway in OS cells in vitro and in vivo. To the best of our knowledge, this is the first study to demonstrate that miR-758 may inhibit the aggressive behavior of OS cells in vitro and in vivo by directly targeting HMGA1 and regulating the Wnt/β-catenin pathway. These results will aid in elucidating the roles of miR-758 and suggest that the miR-758/HMGA1/Wnt/β-catenin pathway represents a potential therapeutic target in OS.

【 授权许可】

CC BY-NC