The tumor suppressor miR-124 inhibits cell proliferation and invasion by targeting B7-H3 in osteosarcoma
- 318 Downloads
Our previous studies have shown that the expression level of B7 homolog 3 (B7-H3) was correlated with clinical staging and prognosis of osteosarcoma (OS) patients, and its silencing inhibited the proliferation and invasion of OS cells in vitro. However, its overexpression mechanism behind was far from elucidated. On the basis of bioinformatics and the preliminary screening data, we hypothesized that miR-124 might play an important role in OS development and as a lead candidate for modulating B7-H3 expression. In this study, we found that miR-124 was downregulated significantly in OS tumor tissue, compared to normal adjacent tissues (NATs). Lower miR-124 expression levels were associated with advanced Ennecking stage, lower tumor differentiation, and common pulmonary metastasis. The 5-year overall survival rate in the miR-124 upregulated group was 61.5 %, while with low miR-124 expression, only 11.8 % survived. Further studies in vitro showed that B7-H3 was a direct target of miR-124. Overexpression of miR-124 decreased B7-H3 mRNA and protein level and inhibited B7-H3 3′-UTR reporter activity. Treatment of OS cells with miR-124 mimics induced the inhibition of cell growth and invasion in vitro, which could be abrogated by transfected by B7-H3 expression vector. Our findings highlight the potential application of miR-124 as a novel onco-miRNA in OS, and its oncogenic effects are mediated chiefly through downregulation of B7-H3, thus suggesting a model for identifying miR-124 that can be exploited to improve the therapeutic potential efficacy of mAb targeting to B7-H3.
KeywordsOsteosarcoma miR-124 B7-H3 Proliferation Invasion
This program was financially supported by the National Natural Science Foundation of China (81402228), Hebei Natural Science Foundation (H2015206216), HeBei Province Medical Foundation (ZL20140334), and HeBei Province Education Foundation (QN2014049).
Compliance with ethical standards
Conflicts of interest
The conception and design were initiated by FBK and LW; NS, JW, and WC performed clinical data acquisition and drafted the manuscript; DL contributed in the statistical analysis; BES directed the study and helped revised the paper. All authors read and approved the final manuscript.
- 5.Atkins MB, Larkin J. Immunotherapy combined or sequenced with targeted therapy in the treatment of solid tumors: current perspectives. J Natl Cancer Inst. 2016;108(6).Google Scholar
- 15.Li T, Mo X, Fu L, Xiao B, Guo J: Molecular mechanisms of long noncoding RNAs on gastric cancer. Oncotarget 2016.Google Scholar
- 25.Wang L, Cao NN, Wang S, Man HW, Li PF, Shan BE: Roles of coinhibitory molecules B7-H3 and B7-H4 in esophageal squamous cell carcinoma. Tumour biology: the journal of the International Society for Oncodevelopmental Biology and Medicine 2015.Google Scholar
- 26.Salunke AA, Shah J, Gupta N, Pandit J. Pathologic fracture in osteosarcoma: association with poorer overall survival. European journal of surgical oncology: the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology. 2016.Google Scholar
- 34.Kuninty PR, Schnittert J, Storm G, Prakash J. MicroRNA targeting to modulate tumor microenvironment. Frontiers in oncology. 2016.Google Scholar
- 36.Qu Y, Pan S, Kang M, Dong R, Zhao J. MicroRNA-150 functions as a tumor suppressor in osteosarcoma by targeting IGF2BP1. Tumour biology: the journal of the International Society for Oncodevelopmental Biology and Medicine. 2015.Google Scholar
- 37.Bao Y, Chen B, Wu Q, Hu K, Xi X, Zhu W, Zhong X, Chen J: Overexpression of miR-664 is associated with enhanced osteosarcoma cell migration and invasion ability via targeting SOX7. Clinical and experimental medicine 2015.Google Scholar
- 38.Feng T, Shao F, Wu Q, Zhang X, Xu D, Qian K, Xie Y, Wang S, Xu N, Wang Y et al. miR-124 downregulation leads to breast cancer progression via LncRNA-MALAT1 regulation and CDK4/E2F1 signal activation. Oncotarget. 2016.Google Scholar
- 39.Shi XB, Ma AH, Xue L, Li M, Nguyen HG, Yang JC, Tepper CG, Gandour-Edwards R, Evans CP, Kung HJ et al: miR-124 and androgen receptor signaling inhibitors repress prostate cancer growth by downregulating androgen receptor splice variants, EZH2, and Src. Cancer Res 2015, 75(24):5309–5317.Google Scholar
- 41.Kim J, Bae JS. Tumor-associated macrophages and neutrophils in tumor microenvironment. Mediat Inflamm. 2016;2016:6058147.Google Scholar
- 43.Nunes-Xavier CE, Karlsen KF, Tekle C, Pedersen C, Oyjord T, Hongisto V, Nesland JM, Tan M, Sahlberg KK, Fodstad O. Decreased expression of B7-H3 reduces the glycolytic capacity and sensitizes breast cancer cells to AKT/mTOR inhibitors. Oncotarget. 2016;7(6):6891–901.PubMedPubMedCentralGoogle Scholar
- 45.Yin K, Yin W, Wang Y, Zhou L, Liu Y, Yang G, Wang J, Lu J. MiR-206 suppresses epithelial mesenchymal transition by targeting TGF-beta signaling in estrogen receptor positive breast cancer cells. Oncotarget. 2016.Google Scholar