Tumor Biology

, Volume 37, Issue 7, pp 9181–9187 | Cite as

MicroRNA-503 represses epithelial–mesenchymal transition and inhibits metastasis of osteosarcoma by targeting c-myb

  • Xinzhen Guo
  • Jie Zhang
  • Jianfeng Pang
  • Sheng He
  • Guojun Li
  • Yang Chong
  • Chao Li
  • Zhijian Jiao
  • Shiqian Zhang
  • Ming Shao
Original Article


Deregulated expression of miRNAs contributes to the development of osteosarcoma. Our previous study has showed that miR-503 was downregulated in osteosarcoma tissues. However, the mechanism of the miR-503 in osteosarcoma development still remains largely undefined. In our study, we found that miR-503 overexpression suppressed cell invasion and migration and inhibited epithelial-to-mesenchymal transition (EMT) of MG-63. Furthermore, we identified that c-myb, an oncogene, was a direct target of miR-503. Moreover, overexpression of c-myb could rescue miR-503-suppressed invasion and EMT. The expression of c-myb was upregulated in osteosarcoma cell lines. Therefore, we conclude that high miR-503 expression suppressed osteosarcoma cell mobility and EMT through targeting c-myb, and this may serve as a therapeutic target.


Osteosarcoma MicroRNA miR-503 c-myb EMT 



This work was supported by grants from the National Natural Science Foundation of Heilongjiang Province (Grant Numbers: H201308).

Compliance with ethical standards

Conflicts of interest


Supplementary material

13277_2016_4797_MOESM1_ESM.docx (14 kb)
Table S1 (DOCX 13 kb)


  1. 1.
    Hu K, Liao D, Wu W, Han AJ, Shi HJ, Wang F, et al. Targeting the anaphase-promoting complex/cyclosome (apc/c)-bromodomain containing 7 (brd7) pathway for human osteosarcoma. Oncotarget. 2014;5:3088–100.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Tsai HC, Su HL, Huang CY, Fong YC, Hsu CJ, Tang CH. Ctgf increases matrix metalloproteinases expression and subsequently promotes tumor metastasis in human osteosarcoma through down-regulating mir-519d. Oncotarget. 2014;5:3800–12.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Tang J, Shen L, Yang Q, Zhang C. Overexpression of metadherin mediates metastasis of osteosarcoma by regulating epithelial-mesenchymal transition. Cell Prolif. 2014;47:427–34.CrossRefPubMedGoogle Scholar
  4. 4.
    Montanaro L, Mazzini G, Barbieri S, Vici M, Nardi-Pantoli A, Govoni M, et al. Different effects of ribosome biogenesis inhibition on cell proliferation in retinoblastoma protein- and p53-deficient and proficient human osteosarcoma cell lines. Cell Prolif. 2007;40:532–49.CrossRefPubMedGoogle Scholar
  5. 5.
    Han G, Wang Y, Bi W. C-myc overexpression promotes osteosarcoma cell invasion via activation of mek-erk pathway. Oncol Res. 2012;20:149–56.CrossRefPubMedGoogle Scholar
  6. 6.
    Ye Z, Jingzhong L, Yangbo L, Lei C, Jiandong Y. Propofol inhibits proliferation and invasion of osteosarcoma cells by regulation of microrna-143 expression. Oncol Res. 2014;21:201–7.CrossRefGoogle Scholar
  7. 7.
    Yan K, Gao J, Yang T, Ma Q, Qiu X, Fan Q, et al. MicroRNA-34a inhibits the proliferation and metastasis of osteosarcoma cells both in vitro and in vivo. PLoS One. 2012;7:e33778.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Zhao G, Cai C, Yang T, Qiu X, Liao B, Li W, et al. MicroRNA-221 induces cell survival and cisplatin resistance through pi3k/akt pathway in human osteosarcoma. PLoS One. 2013;8:e53906.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Namlos HM, Meza-Zepeda LA, Baroy T, Ostensen IH, Kresse SH, Kuijjer ML, et al. Modulation of the osteosarcoma expression phenotype by micrornas. PLoS One. 2012;7:e48086.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Ji F, Zhang H, Wang Y, Li M, Xu W, Kang Y, et al. MicroRNA-133a, downregulated in osteosarcoma, suppresses proliferation and promotes apoptosis by targeting bcl-xl and mcl-1. Bone. 2013;56:220–6.CrossRefPubMedGoogle Scholar
  11. 11.
    Liang J, Zhang Y, Jiang G, Liu Z, Xiang W, Chen X, et al. Mir-138 induces renal carcinoma cell senescence by targeting ezh2 and is downregulated in human clear cell renal cell carcinoma. Oncol Res. 2013;21:83–91.CrossRefPubMedGoogle Scholar
  12. 12.
    Zhou J, Song S, Cen J, Zhu D, Li D, Zhang Z. MicroRNA-375 is downregulated in pancreatic cancer and inhibits cell proliferation in vitro. Oncol Res. 2012;20:197–203.CrossRefPubMedGoogle Scholar
  13. 13.
    Fei B, Wu H. Mir-378 inhibits progression of human gastric cancer mgc-803 cells by targeting mapk1 in vitro. Oncol Res. 2012;20:557–64.CrossRefPubMedGoogle Scholar
  14. 14.
    Bier A, Giladi N, Kronfeld N, Lee HK, Cazacu S, Finniss S, et al. MicroRNA-137 is downregulated in glioblastoma and inhibits the stemness of glioma stem cells by targeting rtvp-1. Oncotarget. 2013;4:665–76.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Li H, Yang BB. Stress response of glioblastoma cells mediated by mir-17-5p targeting pten and the passenger strand mir-17-3p targeting mdm2. Oncotarget. 2012;3:1653–68.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    McCubrey JA, Steelman LS, Chappell WH, Abrams SL, Franklin RA, Montalto G, et al. Ras/raf/mek/erk and pi3k/pten/akt/mtor cascade inhibitors: how mutations can result in therapy resistance and how to overcome resistance. Oncotarget. 2012;3:1068–111.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Lee HK, Finniss S, Cazacu S, Bucris E, Ziv-Av A, Xiang C, et al. Mesenchymal stem cells deliver synthetic microRNA mimics to glioma cells and glioma stem cells and inhibit their cell migration and self-renewal. Oncotarget. 2013;4:346–61.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Yu X, Li Z. MicroRNAs regulate vascular smooth muscle cell functions in atherosclerosis (review). Int J Mol Med. 2014;34:923–33.PubMedGoogle Scholar
  19. 19.
    Yang WB, Chen PH, Hsu TS, Fu TF, Su WC, Liaw H, et al. Sp1-mediated microRNA-182 expression regulates lung cancer progression. Oncotarget. 2014;5:740–53.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Akiyoshi S, Fukagawa T, Ueo H, Ishibashi M, Takahashi Y, Fabbri M, et al. Clinical significance of mir-144-zfx axis in disseminated tumour cells in bone marrow in gastric cancer cases. Br J Cancer. 2012;107:1345–53.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Luo J, Cai Q, Wang W, Huang H, Zeng H, He W, et al. A microRNA-7 binding site polymorphism in hoxb5 leads to differential gene expression in bladder cancer. PLoS One. 2012;7:e40127.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Kulkarni S, Augoff K, Rivera L, McCue B, Khoury T, Groman A, et al. Increased expression levels of wave3 are associated with the progression and metastasis of triple negative breast cancer. PLoS One. 2012;7:e42895.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Huang S, Xie Y, Yang P, Chen P, Zhang L. Hcv core protein-induced down-regulation of microRNA-152 promoted aberrant proliferation by regulating wnt1 in hepg2 cells. PLoS One. 2014;9:e81730.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Li Z, Lei H, Luo M, Wang Y, Dong L, Ma Y, et al. DNA methylation downregulated mir-10b acts as a tumor suppressor in gastric cancer. Gastric Cancer Off J Int Gastric Cancer Assoc Jpn Gastric Cancer Assoc. 2015;18:43–54.Google Scholar
  25. 25.
    Yu X, Li Z, Shen J, Wu WK, Liang J, Weng X, et al. MicroRNA-10b promotes nucleus pulposus cell proliferation through rhoc-akt pathway by targeting hoxd10 in intervetebral disc degeneration. PLoS One. 2013;8:e83080.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Li Z, Yu X, Shen J, Wu WK, Chan MT. MicroRNA expression and its clinical implications in ewing’s sarcoma. Cell Prolif. 2015;48:1–6.CrossRefPubMedGoogle Scholar
  27. 27.
    Chong Y, Zhang J, Guo X, Li G, Zhang S, Li C, et al. MicroRNA-503 acts as a tumor suppressor in osteosarcoma by targeting l1cam. PLoS One. 2014;9:e114585.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Huang J, Gao K, Lin J, Wang Q. MicroRNA-100 inhibits osteosarcoma cell proliferation by targeting cyr61. Tumour Biol J Int Soc Oncodev Biol Med. 2014;35:1095–100.CrossRefGoogle Scholar
  29. 29.
    Wang X, Sun J, Fu C, Wang D, Bi Z: Microrna-214 regulates osteosarcoma survival and growth by directly targeting phosphatase and tensin homolog. Mol Med Rep. 2014.Google Scholar
  30. 30.
    Cheng C, Chen ZQ, Shi XT. MicroRNA-320 inhibits osteosarcoma cells proliferation by directly targeting fatty acid synthase. Tumour Biol J Int Soc Oncodev Biol Med. 2014;35:4177–83.CrossRefGoogle Scholar
  31. 31.
    Wang Y, Shang Y: Epigenetic control of epithelial-to-mesenchymal transition and cancer metastasis. Exp Cell Res. 2012.Google Scholar
  32. 32.
    Koutsaki M, Spandidos DA, Zaravinos A. Epithelial-mesenchymal transition-associated mirnas in ovarian carcinoma, with highlight on the mir-200 family: prognostic value and prospective role in ovarian cancer therapeutics. Cancer Lett. 2014;351:173–81.CrossRefPubMedGoogle Scholar
  33. 33.
    Cai LM, Lyu XM, Luo WR, Cui XF, Ye YF, Yuan CC, Peng QX, Wu DH, Liu TF, Wang E, Marincola FM, Yao KT, Fang WY, Cai HB, Li X: Ebv-mir-bart7-3p promotes the emt and metastasis of nasopharyngeal carcinoma cells by suppressing the tumor suppressor pten. Oncogene 2014.Google Scholar
  34. 34.
    Tellez CS, Juri DE, Do K, Bernauer AM, Thomas CL, Damiani LA, et al. Emt and stem cell-like properties associated with mir-205 and mir-200 epigenetic silencing are early manifestations during carcinogen-induced transformation of human lung epithelial cells. Cancer Res. 2011;71:3087–97.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Hur K, Toiyama Y, Takahashi M, Balaguer F, Nagasaka T, Koike J, et al. MicroRNA-200c modulates epithelial-to-mesenchymal transition (emt) in human colorectal cancer metastasis. Gut. 2013;62:1315–26.CrossRefPubMedGoogle Scholar
  36. 36.
    Luo Z, Zhang L, Li Z, Jiang C, Dai Y, Liu X, et al. Mir-149 promotes epithelial-mesenchymal transition and invasion in nasopharyngeal carcinoma cells. Zhong Nan Da Xue Xue Bao Yi Xue Ban J Cent South Univ Med Sci. 2011;36:604–9.Google Scholar
  37. 37.
    Cesi V, Casciati A, Sesti F, Tanno B, Calabretta B, Raschella G. Tgfbeta-induced c-myb affects the expression of emt-associated genes and promotes invasion of er+ breast cancer cells. Cell Cycle. 2011;10:4149–61.CrossRefPubMedGoogle Scholar
  38. 38.
    Ren D, Wang M, Guo W, Zhao X, Tu X, Huang S, et al. Wild-type p53 suppresses the epithelial-mesenchymal transition and stemness in pc-3 prostate cancer cells by modulating mir145. Int J Oncol. 2013;42:1473–81.PubMedGoogle Scholar
  39. 39.
    Chen RX, Xia YH, Xue TC, Ye SL. Transcription factor c-myb promotes the invasion of hepatocellular carcinoma cells via increasing osteopontin expression. J Exp Clin Cancer Res. 2010;29:172.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Wolff L. Myb-induced transformation. Crit Rev Oncog. 1996;7:245–60.CrossRefPubMedGoogle Scholar
  41. 41.
    Ramsay R. Myb: getting involved in emt. Cell Cycle. 2012;11:433–4.CrossRefPubMedGoogle Scholar
  42. 42.
    Zhou Y, Ness SA. Myb proteins: angels and demons in normal and transformed cells. Front Biosci (Landmark Ed). 2011;16:1109–31.CrossRefGoogle Scholar
  43. 43.
    Yongchun Z, Linwei T, Xicai W, Lianhua Y, Guangqiang Z, Ming Y, Guangjian L, Yujie L, Yunchao H: Microrna-195 inhibits non-small cell lung cancer cell proliferation, migration and invasion by targeting myb. Cancer Lett. 2014Google Scholar
  44. 44.
    Lu H, Wang Y, Huang Y, Shi H, Xue Q, Yang S, et al. Expression and prognostic role of c-myb as a novel cell cycle protein in esophageal squamous cell carcinoma. Clin Transl Oncol Off Publ Fed Span Oncol Soc Natl Cancer Inst Mexico. 2013;15:796–801.Google Scholar
  45. 45.
    Biroccio A, Benassi B, D’Agnano I, D’Angelo C, Buglioni S, Mottolese M, et al. C-myb and bcl-x overexpression predicts poor prognosis in colorectal cancer: clinical and experimental findings. Am J Pathol. 2001;158:1289–99.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Kauraniemi P, Hedenfalk I, Persson K, Duggan DJ, Tanner M, Johannsson O, et al. Myb oncogene amplification in hereditary brca1 breast cancer. Cancer Res. 2000;60:5323–8.PubMedGoogle Scholar
  47. 47.
    Karafiat V, Dvorakova M, Krejci E, Kralova J, Pajer P, Snajdr P, et al. Transcription factor c-myb is involved in the regulation of the epithelial-mesenchymal transition in the avian neural crest. Cell Mol Life Sci. 2005;62:2516–25.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2016

Authors and Affiliations

  • Xinzhen Guo
    • 1
  • Jie Zhang
    • 1
  • Jianfeng Pang
    • 2
  • Sheng He
    • 3
  • Guojun Li
    • 1
  • Yang Chong
    • 1
  • Chao Li
    • 1
  • Zhijian Jiao
    • 1
  • Shiqian Zhang
    • 1
  • Ming Shao
    • 1
  1. 1.Department of Orthopedic SurgeryThe First Affiliated Hospital of Harbin Medical UniversityHarbinChina
  2. 2.Ming Shui County People’s HospitalSuihuaChina
  3. 3.Administration Center Hospital of NongkenBei’anChina

Personalised recommendations