Tumor Biology

, Volume 36, Issue 8, pp 5965–5970 | Cite as

Depletion of ALX1 causes inhibition of migration and induction of apoptosis in human osteosarcoma

Research Article

Abstract

Osteosarcoma is the most common primary malignant tumor in children and young adults, and the molecular regulation of the invasion of osteosarcoma (OS) remains unknown. In this study, we found that increased expression of ALX1 was associated with the progression of osteosarcoma and that ALX1 protein levels were significantly elevated in matched distant metastases. High ALX1 levels also predict shorter overall survival of osteosarcoma patients. We investigated the therapeutic potential of targeting ALX1 expression using the technique of RNA silencing via short hairpin RNA (shRNA). Synthetic shRNA duplexes against ALX1 were introduced to downregulate the expression of ALX1 in a highly malignant osteosarcoma cell line, U2OS. The results obtained indicated that shRNA targeting of ALX1 could lead to an efficient and specific inhibition of endogenous ALX1 activity. Furthermore, we found that depletion of ALX1 caused a dramatic cell cycle arrest, followed by massive apoptotic cell death, and eventually resulted in a significant decrease in migration and invasion of the osteosarcoma cell line studied.

Keywords

Osteosarcoma ALX1 depletion Migration Apoptosis 

Notes

Conflicts of interest

No potential conflicts of interest were disclosed.

References

  1. 1.
    Siclari VA, Qin L. Targeting the osteosarcoma cancer stem cell. J Orthop Surg Res. 2010;5:78.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Gorlick R, Meyers PA. Osteosarcoma necrosis following chemotherapy: innate biology versus treatment-specific. J Pediatr Hematol Oncol. 2003;25:840–1.CrossRefPubMedGoogle Scholar
  3. 3.
    Pakos EE, Nearchou AD, Grimer RJ, Koumoullis HD, Abudu A, Bramer JA, et al. Prognostic factors and outcomes for osteosarcoma: an international collaboration. Eur J Cancer. 2009;45:2367–75.CrossRefPubMedGoogle Scholar
  4. 4.
    Klein MJ, Siegal GP. Osteosarcoma: anatomic and histologic variants. Am J Clin Pathol. 2006;125:555–81.CrossRefPubMedGoogle Scholar
  5. 5.
    Simmons LW, Lovegrove M and Almbro M. Female effects, but no intrinsic male effects on paternity outcome in crickets. J Evol Biol 2014.Google Scholar
  6. 6.
    Allred DC, Clark GM, Elledge R, Fuqua SA, Brown RW, Chamness GC, et al. Association of p53 protein expression with tumor cell proliferation rate and clinical outcome in node-negative breast cancer. J Natl Cancer Inst. 1993;85:200–6.CrossRefPubMedGoogle Scholar
  7. 7.
    Yuan H, Kajiyama H, Ito S, Yoshikawa N, Hyodo T, Asano E, et al. ALX1 induces snail expression to promote epithelial-to-mesenchymal transition and invasion of ovarian cancer cells. Cancer Res. 2013;73:1581–90.CrossRefPubMedGoogle Scholar
  8. 8.
    Li H, Chen X, Gao Y, Wu J, Zeng F, Song F. XBP1 induces snail expression to promote epithelial-to-mesenchymal transition and invasion of breast cancer cells. Cell Signal. 2015;27:82–9.CrossRefPubMedGoogle Scholar
  9. 9.
    Wang Q, Cai J, Wang J, Xiong C and Zhao J. MiR-143 inhibits EGFR-signaling-dependent osteosarcoma invasion. Tumour Biol 2014.Google Scholar
  10. 10.
    Savage SA, Mirabello L. Using epidemiology and genomics to understand osteosarcoma etiology. Sarcoma. 2011;2011:548151.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Nathan SS, Pereira BP, Zhou YF, Gupta A, Dombrowski C, Soong R, et al. Elevated expression of Runx2 as a key parameter in the etiology of osteosarcoma. Mol Biol Rep. 2009;36:153–8.CrossRefPubMedGoogle Scholar
  12. 12.
    Li H, Song F, Chen X, Li Y, Fan J, Wu X. Bmi-1 regulates epithelial-to-mesenchymal transition to promote migration and invasion of breast cancer cells. Int J Clin Exp Pathol. 2014;7:3057–64.PubMedPubMedCentralGoogle Scholar
  13. 13.
    Li H, Chen X, Gao Y, Wu J, Zeng F, Song F. XBP1 induces snail expression to promote epithelial- to-mesenchymal transition and invasion of breast cancer cells. Cell Signal. 2015;27:82–9.CrossRefPubMedGoogle Scholar
  14. 14.
    Endo-Munoz L, Evdokiou A, Saunders NA. The role of osteoclasts and tumour-associated macrophages in osteosarcoma metastasis. Biochim Biophys Acta. 1826;2012:434–42.Google Scholar
  15. 15.
    Perbal B, Zuntini M, Zambelli D, Serra M, Sciandra M, Cantiani L, et al. Prognostic value of CCN3 in osteosarcoma. Clin Cancer Res. 2008;14:701–9.CrossRefPubMedGoogle Scholar
  16. 16.
    Chen CC, Lau LF. Functions and mechanisms of action of CCN matricellular proteins. Int J Biochem Cell Biol. 2009;41:771–83.CrossRefPubMedGoogle Scholar
  17. 17.
    Mann KK, Wallner B, Lossos IS, Miller Jr WH. Darinaparsin: a novel organic arsenical with promising anticancer activity. Expert Opin Investig Drugs. 2009;18:1727–34.CrossRefPubMedGoogle Scholar
  18. 18.
    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
  19. 19.
    Liu Y, Wang W, Xu J, Li L, Dong Q, Shi Q, et al. Dihydroartemisinin inhibits tumor growth of human osteosarcoma cells by suppressing Wnt/beta-catenin signaling. Oncol Rep. 2013;30:1723–30.PubMedGoogle Scholar
  20. 20.
    Zhao Q, Wang C, Zhu J, Wang L, Dong S, Zhang G, et al. RNAi-mediated knockdown of cyclooxygenase2 inhibits the growth, invasion and migration of SaOS2 human osteosarcoma cells: a case control study. J Exp Clin Cancer Res. 2011;30:26.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Wu YF, Liang XJ, Liu YY, Gong W, Liu JX, Wang XP, et al. +Antisense oligonucleotide targeting survivin inhibits growth by inducing apoptosis in human osteosarcoma cells MG-63. Neoplasma. 2010;57:501–6.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  1. 1.Department of Orthopaedics, Xinqiao HospitalThird Military Medical UniversityChongqingChina

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