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The tumor suppressor miR-124 inhibits cell proliferation and invasion by targeting B7-H3 in osteosarcoma

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Tumor Biology

Abstract

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.

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Reference

  1. Benjamin RS. Osteosarcoma: better treatment through better trial design. The Lancet Oncology. 2015;16(1):12–3.

    Article  PubMed  Google Scholar 

  2. Berner K, Johannesen TB, Bruland OS. Clinical epidemiology of low-grade and dedifferentiated osteosarcoma in Norway during 1975 and 2009. Sarcoma. 2015;2015:917679.

    PubMed  PubMed Central  Google Scholar 

  3. Reed DE, Shokat KM. Targeting osteosarcoma. Proc Natl Acad Sci U S A. 2014;111(51):18100–1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Bagcchi S. Osteosarcoma survivors’ risk of second cancer. The Lancet Oncology. 2014;15(10):e425.

    Article  PubMed  Google Scholar 

  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).

  6. Batlevi CL, Matsuki E, Brentjens RJ, Younes A. Novel immunotherapies in lymphoid malignancies. Nature reviews Clinical oncology. 2016;13(1):25–40.

    Article  CAS  PubMed  Google Scholar 

  7. Bourzac K. Therapy: an immune one-two punch. Nature. 2015;528(7582):S134–6.

    Article  CAS  PubMed  Google Scholar 

  8. Kroemer G, Senovilla L, Galluzzi L, Andre F, Zitvogel L. Natural and therapy-induced immunosurveillance in breast cancer. Nat Med. 2015;21(10):1128–38.

    Article  CAS  PubMed  Google Scholar 

  9. You S. Differential sensitivity of regulatory and effector T cells to cell death: a prerequisite for transplant tolerance. Front Immunol. 2015;6:242.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Depoil D, Dustin ML. Force and affinity in ligand discrimination by the TCR. Trends Immunol. 2014;35(12):597–603.

    Article  CAS  PubMed  Google Scholar 

  11. Patel SP, Kurzrock R. PD-L1 expression as a predictive biomarker in cancer immunotherapy. Mol Cancer Ther. 2015;14(4):847–56.

    Article  CAS  PubMed  Google Scholar 

  12. Leung J, Suh WK. The CD28-B7 family in anti-tumor immunity: emerging concepts in cancer immunotherapy. Immune network. 2014;14(6):265–76.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Wang L, Zhang Q, Chen W, Shan B, Ding Y, Zhang G, Cao N, Liu L, Zhang Y. B7-H3 is overexpressed in patients suffering osteosarcoma and associated with tumor aggressiveness and metastasis. PLoS One. 2013;8(8):e70689.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Rupaimoole R, Calin GA, Lopez-Berestein G, Sood AK. miRNA deregulation in cancer cells and the tumor microenvironment. Cancer discovery. 2016;6(3):235–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Li T, Mo X, Fu L, Xiao B, Guo J: Molecular mechanisms of long noncoding RNAs on gastric cancer. Oncotarget 2016.

  16. Suzuki HI, Katsura A, Matsuyama H, Miyazono K. MicroRNA regulons in tumor microenvironment. Oncogene. 2015;34(24):3085–94.

    Article  CAS  PubMed  Google Scholar 

  17. Judice CC, Bourgard C, Kayano AC, Albrecht L, Costa FT. MicroRNAs in the host-apicomplexan parasites interactions: a review of immunopathological aspects. Frontiers in cellular and infection microbiology. 2016;6:5.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Xiao Y, Wang J, Yan W, Zhou Y, Chen Y, Zhou K, Wen J, Wang Y, Cai W. Dysregulated miR-124 and miR-200 expression contribute to cholangiocyte proliferation in the cholestatic liver by targeting IL-6/STAT3 signalling. J Hepatol. 2015;62(4):889–96.

    Article  CAS  PubMed  Google Scholar 

  19. Dueck A, Eichner A, Sixt M, Meister G. A miR-155-dependent microRNA hierarchy in dendritic cell maturation and macrophage activation. FEBS Lett. 2014;588(4):632–40.

    Article  CAS  PubMed  Google Scholar 

  20. O’Connell RM, Taganov KD, Boldin MP, Cheng G, Baltimore D. MicroRNA-155 is induced during the macrophage inflammatory response. Proc Natl Acad Sci U S A. 2007;104(5):1604–9.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Nygren MK, Tekle C, Ingebrigtsen VA, Makela R, Krohn M, Aure MR, Nunes-Xavier CE, Perala M, Tramm T, Alsner J, et al. Identifying microRNAs regulating B7-H3 in breast cancer: the clinical impact of microRNA-29c. Br J Cancer. 2014;110(8):2072–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Xu H, Cheung IY, Guo HF, Cheung NK. MicroRNA miR-29 modulates expression of immunoinhibitory molecule B7-H3: potential implications for immune based therapy of human solid tumors. Cancer Res. 2009;69(15):6275–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Zhao J, Lei T, Xu C, Li H, Ma W, Yang Y, Fan S, Liu Y. MicroRNA-187, down-regulated in clear cell renal cell carcinoma and associated with lower survival, inhibits cell growth and migration though targeting B7-H3. Biochem Biophys Res Commun. 2013;438(2):439–44.

    Article  CAS  PubMed  Google Scholar 

  24. Kang FB, Wang L, Jia HC, Li D, Li HJ, Zhang YG, Sun DX. B7-H3 promotes aggression and invasion of hepatocellular carcinoma by targeting epithelial-to-mesenchymal transition via JAK2/STAT3/Slug signaling pathway. Cancer Cell Int. 2015;15:45.

    Article  PubMed  PubMed Central  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.

  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.

  27. Bishop MW, Janeway KA, Gorlick R. Future directions in the treatment of osteosarcoma. Curr Opin Pediatr. 2016;28(1):26–33.

    Article  CAS  PubMed  Google Scholar 

  28. Chapoval AI, Ni J, Lau JS, Wilcox RA, Flies DB, Liu D, Dong H, Sica GL, Zhu G, Tamada K, et al. B7-H3: a costimulatory molecule for T cell activation and IFN-gamma production. Nat Immunol. 2001;2(3):269–74.

    Article  CAS  PubMed  Google Scholar 

  29. Luo L, Chapoval AI, Flies DB, Zhu G, Hirano F, Wang S, Lau JS, Dong H, Tamada K, Flies AS, et al. B7-H3 enhances tumor immunity in vivo by costimulating rapid clonal expansion of antigen-specific CD8+ cytolytic T cells. J Immunol. 2004;173(9):5445–50.

    Article  CAS  PubMed  Google Scholar 

  30. Wang L, Kang FB, Shan BE. B7-H3-mediated tumor immunology: friend or foe? Int J Cancer. 2014;134(12):2764–71.

    Article  CAS  PubMed  Google Scholar 

  31. Arigami T, Uenosono Y, Hirata M, Yanagita S, Ishigami S, Natsugoe S. B7-H3 expression in gastric cancer: a novel molecular blood marker for detecting circulating tumor cells. Cancer Sci. 2011;102(5):1019–24.

    Article  CAS  PubMed  Google Scholar 

  32. Bachawal SV, Jensen KC, Wilson KE, Tian L, Lutz AM, Willmann JK. Breast cancer detection by B7-H3-targeted ultrasound molecular imaging. Cancer Res. 2015;75(12):2501–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Yuan H, Wei X, Zhang G, Li C, Zhang X, Hou J. B7-H3 over expression in prostate cancer promotes tumor cell progression. J Urol. 2011;186(3):1093–9.

    Article  CAS  PubMed  Google Scholar 

  34. Kuninty PR, Schnittert J, Storm G, Prakash J. MicroRNA targeting to modulate tumor microenvironment. Frontiers in oncology. 2016.

  35. Arora A, Singh S, Bhatt AN, Pandey S, Sandhir R, Dwarakanath BS. Interplay between metabolism and oncogenic process: role of microRNAs. Translational oncogenomics. 2015;7:11–27.

    PubMed  PubMed Central  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.

  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.

  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.

  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.

  40. Zu L, Xue Y, Wang J, Fu Y, Wang X, Xiao G, Hao M, Sun X, Wang Y, Fu G, et al. The feedback loop between miR-124 and TGF-beta pathway plays a significant role in non-small cell lung cancer metastasis. Carcinogenesis. 2016;37(3):333–43.

    Article  CAS  PubMed  Google Scholar 

  41. Kim J, Bae JS. Tumor-associated macrophages and neutrophils in tumor microenvironment. Mediat Inflamm. 2016;2016:6058147.

    Google Scholar 

  42. Quail DF, Joyce JA. Microenvironmental regulation of tumor progression and metastasis. Nat Med. 2013;19(11):1423–37.

    Article  CAS  PubMed  PubMed Central  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.

    PubMed  PubMed Central  Google Scholar 

  44. Liu H, Wang H, Liu X, Yu T. miR-1271 inhibits migration, invasion and epithelial-mesenchymal transition by targeting ZEB1 and TWIST1 in pancreatic cancer cells. Biochem Biophys Res Commun. 2016;472(2):346–52.

    Article  CAS  PubMed  Google 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.

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Acknowledgments

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).

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Correspondence to Bao-en Shan.

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Authors’ contributions

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.

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Wang L and Kang FB contributed equally to this work.

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Wang, L., Kang, Fb., Sun, N. et al. The tumor suppressor miR-124 inhibits cell proliferation and invasion by targeting B7-H3 in osteosarcoma. Tumor Biol. 37, 14939–14947 (2016). https://doi.org/10.1007/s13277-016-5386-2

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  • DOI: https://doi.org/10.1007/s13277-016-5386-2

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