Tumor Biology

, Volume 37, Issue 5, pp 6493–6499 | Cite as

Regulation of osteosarcoma cell invasion through osteopontin modification by miR-4262

Original Article


Osteopontin (OPN) is a phosphorylated glycoprotein that plays a critical role in the invasion of osteosarcoma (OS), the most common primary malignant bone tumor. Since microRNAs (miRNAs) have been well documented as key players in the tumorigenesis, cancer cell growth, and metastases, determination of the involved miRNAs that may regulate OPN-mediated OS cell invasion appears to be one important question in the current understanding and therapeutic strategies for OS. Here, we found that the levels of miR-4262 were significantly decreased and the levels of OPN were significantly increased in OS specimens, compared to the paired adjacent non-tumor tissue. Moreover, miR-4262 and OPN inversely correlated in OS specimens. The 5-year survival of the patients with lower miR-4262 levels in the resected OS was worse than that of patients with high miR-4262 levels. Bioinformatics analyses showed that miR-4262 targeted the 3′-UTR of OPN mRNA to inhibit its translation, which was proved by luciferase reporter assay. Furthermore, miR-4262 overexpression inhibited OPN-mediated cell invasion, while miR-4262 depletion increased OPN-mediated cell invasion in OS cells, in both a transwell cell invasion assay and a scratch wound healing assay. Together, our data suggest that suppression of miR-4262 in OS cells may promote OPN-mediated cancer invasion, highlighting miR-4262 as an intriguing therapeutic target to prevent OS metastases.


Osteosarcoma (OS) Osteopontin (OPN) miR-4262 Cancer cell invasion 


Conflicts of interest



  1. 1.
    Lu J, Song G, Tang Q, Zou C, Han F, Zhao Z, et al. Irx1 hypomethylation promotes osteosarcoma metastasis via induction of CXCL14/NF-kappaB signaling. J Clin Invest. 2015;125:1839–56.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Kansara M, Tsang M, Kodjabachian L, Sims NA, Trivett MK, Ehrich M, et al. Wnt inhibitory factor 1 is epigenetically silenced in human osteosarcoma, and targeted disruption accelerates osteosarcomagenesis in mice. J Clin Invest. 2009;119:837–51.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Johnston NI, Gunasekharan VK, Ravindranath A, O’Connell C, Johnston PG, El-Tanani MK. Osteopontin as a target for cancer therapy. Front Biosci. 2008;13:4361–72.CrossRefPubMedGoogle Scholar
  4. 4.
    Rangaswami H, Bulbule A, Kundu GC. Osteopontin: role in cell signaling and cancer progression. Trends Cell Biol. 2006;16:79–87.CrossRefPubMedGoogle Scholar
  5. 5.
    Weber GF. The metastasis gene osteopontin: a candidate target for cancer therapy. Biochim Biophys Acta. 2001;1552:61–85.CrossRefPubMedGoogle Scholar
  6. 6.
    Furger KA, Menon RK, Tuck AB, Bramwell VH, Chambers AF. The functional and clinical roles of osteopontin in cancer and metastasis. Curr Mol Med. 2001;1:621–32.CrossRefPubMedGoogle Scholar
  7. 7.
    Kiss T, Ecsedi S, Vizkeleti L, Koroknai V, Emri G, Kovacs N, et al. The role of osteopontin expression in melanoma progression. Tumour Biol. 2015;36:7841–7.CrossRefPubMedGoogle Scholar
  8. 8.
    Mardani M, Andisheh-Tadbir A, Khademi B, Fattahi MJ, Shafiee S, Asad-Zadeh M. Serum levels of osteopontin as a prognostic factor in patients with oral squamous cell carcinoma. Tumour Biol. 2014;35:3827–9.CrossRefPubMedGoogle Scholar
  9. 9.
    Li Y, Xie Y, Cui D, Ma Y, Sui L, Zhu C, et al. Osteopontin promotes invasion, migration and epithelial-mesenchymal transition of human endometrial carcinoma cell HEC-1A through AKT and ERK1/2 signaling. Cell Physiol Biochem. 2015;37:1503–12.CrossRefPubMedGoogle Scholar
  10. 10.
    Shen Z, Chen B, Hou X, Chen P, Zhao G, Fan J. Polymorphism −433 C > T of the osteopontin gene is associated with the susceptibility to develop gliomas and their prognosis in a Chinese cohort. Cell Physiol Biochem. 2014;34:1190–8.CrossRefPubMedGoogle Scholar
  11. 11.
    Liu SJ, Zhang DQ, Sui XM, Zhang L, Cai ZW, Sun LQ, et al. The inhibition of in vivo tumorigenesis of osteosarcoma (OS)-732 cells by antisense human osteopontin RNA. Cell Mol Biol Lett. 2008;13:11–9.CrossRefPubMedGoogle Scholar
  12. 12.
    Liu SJ, Hu GF, Liu YJ, Liu SG, Gao H, Zhang CS, et al. Effect of human osteopontin on proliferation, transmigration and expression of MMP-2 and MMP-9 in osteosarcoma cells. Chin Med J (Engl). 2004;117:235–40.Google Scholar
  13. 13.
    Di Leva G, Croce CM. Mirna profiling of cancer. Curr Opin Genet Dev. 2013;23:3–11.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Pereira DM, Rodrigues PM, Borralho PM, Rodrigues CM. Delivering the promise of miRNA cancer therapeutics. Drug Discov Today. 2013;18:282–9.CrossRefPubMedGoogle Scholar
  15. 15.
    Mei Q, Li F, Quan H, Liu Y, Xu H. Busulfan inhibits growth of human osteosarcoma through miR-200 family microRNAs in vitro and in vivo. Cancer Sci. 2014;105:755–62.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Wang F, Xiao W, Sun J, Han D, Zhu Y. MiRNA-181c inhibits EGFR-signaling-dependent MMP9 activation via suppressing Akt phosphorylation in glioblastoma. Tumour Biol. 2014;35:8653–8.CrossRefPubMedGoogle Scholar
  17. 17.
    Liu G, Jiang C, Li D, Wang R, Wang W. MiRNA-34a inhibits EGFR-signaling-dependent MMP7 activation in gastric cancer. Tumour Biol. 2014;35:9801–6.CrossRefPubMedGoogle Scholar
  18. 18.
    Bao H, Gao F, Xie G, Liu Z. Angiotensin-converting enzyme 2 inhibits apoptosis of pulmonary endothelial cells during acute lung injury through suppressing miR-4262. Cell Physiol Biochem. 2015;37:759–67.CrossRefPubMedGoogle Scholar
  19. 19.
    Ponten J, Saksela E. Two established in vitro cell lines from human mesenchymal tumours. Int J Cancer. 1967;2:434–47.CrossRefPubMedGoogle Scholar
  20. 20.
    Liang CC, Park AY, Guan JL. In vitro scratch assay: a convenient and inexpensive method for analysis of cell migration in vitro. Nat Protoc. 2007;2:329–33.CrossRefPubMedGoogle Scholar
  21. 21.
    Simoes AE, Pereira DM, Gomes SE, Brito H, Carvalho T, French A, et al. Aberrant MEK5/ERK5 signalling contributes to human colon cancer progression via NF-kappaB activation. Cell death & disease. 2015;6:e1718.CrossRefGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  1. 1.The Third Department of OrthopedicsCangzhou Central HospitalCangzhouChina
  2. 2.Department of Ocular fundusCangzhou Ophthalmologic HospitalCangzhouChina
  3. 3.Department of Human ResourceCangzhou Central HospitalCangzhouChina

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