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TIKI2 suppresses growth of osteosarcoma by targeting Wnt/β-catenin pathway

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Abstract

Osteosarcoma is the most bone-associated malignancy with high lethality. The current therapeutic strategy benefits little on the survival of patients. Studies have shown that aberrant activation of Wnt/β-catenin pathway is essential for the progression of osteosarcoma, implying that targeting this signaling may be an effective way of therapeutics. Recently, TIKI family has been identified as a new class of negative regulators for Wnt/β-catenin pathway. However, the implication of TIKIs with osteosarcoma has not been explored. Here, we constructed an adenoviral vector that expresses TIKI2 in osteosarcoma cells (Ad-TIKI2). TIKI2 expression was found to be reduced in osteosarcoma specimens and cell lines. In tested osteosarcoma cells, the activation of Wnt/β-catenin pathway was found to be inhibited by TIKI2 expression. Furthermore, the proliferation, colony formation ability, and invasion were all significantly suppressed in osteosarcoma cells infected with Ad-TIKI2. Finally, animal experiments further confirmed that TIKI2 restoration was able to inhibit the growth of osteosarcoma in vivo. Taken together, we provided evidence that reduced expression of TIKI family protein in osteosarcoma may participate in the progression of osteosarcoma and restoring its expression was able to impair the growth of osteosarcoma.

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References

  1. Bacci G, Briccoli A, Rocca M, Ferrari S, Donati D, Longhi A, Bertoni F, Bacchini P, Giacomini S, Forni C, Manfrini M, Galletti S (2003) Neoadjuvant chemotherapy for osteosarcoma of the extremities with metastases at presentation: recent experience at the Rizzoli Institute in 57 patients treated with cisplatin, doxorubicin, and a high dose of methotrexate and ifosfamide. Ann Oncol 14:1126–1134

    Article  CAS  PubMed  Google Scholar 

  2. Li C, Shi X, Zhou G, Liu X, Wu S, Zhao J (2013) The canonical Wnt-beta-catenin pathway in development and chemotherapy of osteosarcoma. Front Biosci (Landmark Ed) 18:1384–1391

    Article  CAS  Google Scholar 

  3. Hoang BH, Kubo T, Healey JH, Sowers R, Mazza B, Yang R, Huvos AG, Meyers PA, Gorlick R (2004) Expression of LDL receptor-related protein 5 (LRP5) as a novel marker for disease progression in high-grade osteosarcoma. Int J Cancer 109:106–111

    Article  CAS  PubMed  Google Scholar 

  4. Chen K, Fallen S, Abaan HO, Hayran M, Gonzalez C, Wodajo F, MacDonald T, Toretsky JA, Uren A (2008) Wnt10b induces chemotaxis of osteosarcoma and correlates with reduced survival. Pediatr Blood Cancer 51:349–355

    Article  CAS  PubMed  Google Scholar 

  5. Lu BJ, Wang YQ, Wei XJ, Rong LQ, Wei D, Yan CM, Wang DJ, Sun JY (2012) Expression of WNT-5a and ROR2 correlates with disease severity in osteosarcoma. Mol Med Rep 5:1033–1036

    CAS  PubMed Central  PubMed  Google Scholar 

  6. Hoang BH, Kubo T, Healey JH, Yang R, Nathan SS, Kolb EA, Mazza B, Meyers PA, Gorlick R (2004) Dickkopf 3 inhibits invasion and motility of Saos-2 osteosarcoma cells by modulating the Wnt-beta-catenin pathway. Cancer Res 64:2734–2739

    Article  CAS  PubMed  Google Scholar 

  7. Guo Y, Zi X, Koontz Z, Kim A, Xie J, Gorlick R, Holcombe RF, Hoang BH (2007) Blocking Wnt/LRP5 signaling by a soluble receptor modulates the epithelial to mesenchymal transition and suppresses met and metalloproteinases in osteosarcoma Saos-2 cells. J Orthop Res 25:964–971

    Article  CAS  PubMed  Google Scholar 

  8. Guo Y, Rubin EM, Xie J, Zi X, Hoang BH (2008) Dominant negative LRP5 decreases tumorigenicity and metastasis of osteosarcoma in an animal model. Clin Orthop Relat Res 466:2039–2045

    Article  PubMed Central  PubMed  Google Scholar 

  9. Kansara M, Tsang M, Kodjabachian L, Sims NA, Trivett MK, Ehrich M, Dobrovic A, Slavin J, Choong PF, Simmons PJ, Dawid IB, Thomas DM (2009) Wnt inhibitory factor 1 is epigenetically silenced in human osteosarcoma, and targeted disruption accelerates osteosarcomagenesis in mice. J Clin Invest 119:837–851

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Liu Y, Wang W, Xu J, Li L, Dong Q, Shi Q, Zuo G, Zhou L, Weng Y, Tang M, He T, Luo J (2013) Dihydroartemisinin inhibits tumor growth of human osteosarcoma cells by suppressing Wnt/beta-catenin signaling. Oncol Rep 30:1723–1730

    CAS  PubMed  Google Scholar 

  11. Lin CH, Guo Y, Ghaffar S, McQueen P, Pourmorady J, Christ A, Rooney K, Ji T, Eskander R, Zi X, Hoang BH (2013) Dkk-3, a secreted wnt antagonist, suppresses tumorigenic potential and pulmonary metastasis in osteosarcoma. Sarcoma 2013:147541

    Article  PubMed Central  PubMed  Google Scholar 

  12. Xu J, Zhu X, Wu L, Yang R, Yang Z, Wang Q, Wu F (2012) MicroRNA-122 suppresses cell proliferation and induces cell apoptosis in hepatocellular carcinoma by directly targeting Wnt/beta-catenin pathway. Liver Int 32:752–760

    Article  CAS  PubMed  Google Scholar 

  13. Yan K, Gao J, Yang T, Ma Q, Qiu X, Fan Q, Ma B (2012) MicroRNA-34a inhibits the proliferation and metastasis of osteosarcoma cells both in vitro and in vivo. PLoS One 7:e33778

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  14. Nakashima N, Huang CL, Liu D, Ueno M, Yokomise H (2010) Intratumoral Wnt1 expression affects survivin gene expression in non-small cell lung cancer. Int J Oncol 37:687–694

    CAS  PubMed  Google Scholar 

  15. Wilkins JA, Sansom OJ (2008) C-Myc is a critical mediator of the phenotypes of Apc loss in the intestine. Cancer Res 68:4963–4966

    Article  CAS  PubMed  Google Scholar 

  16. Cruciat CM, Niehrs C (2013) Secreted and transmembrane wnt inhibitors and activators. Cold Spring Harb Perspect Biol 5:a015081

    Article  PubMed  Google Scholar 

  17. Zhang X, Abreu JG, Yokota C, MacDonald BT, Singh S, Coburn KL, Cheong SM, Zhang MM, Ye QZ, Hang HC, Steen H, He X (2012) Tiki1 is required for head formation via Wnt cleavage-oxidation and inactivation. Cell 149:1565–1577

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Wang B, Liu J, Ma LN, Xiao HL, Wang YZ, Li Y, Wang Z, Fan L, Lan C, Yang M, Hu L, Wei Y, Bian XW, Chen D, Wang J (2013) Chimeric 5/35 adenovirus-mediated Dickkopf-1 overexpression suppressed tumorigenicity of CD44(+) gastric cancer cells via attenuating Wnt signaling. J Gastroenterol 48:798–808

    Article  CAS  PubMed  Google Scholar 

  19. McQueen P, Ghaffar S, Guo Y, Rubin EM, Zi X, Hoang BH (2011) The Wnt signaling pathway: implications for therapy in osteosarcoma. Expert Rev Anticancer Ther 11:1223–1232

    Article  CAS  PubMed  Google Scholar 

  20. Navarro D, Agra N, Pestana A, Alonso J, Gonzalez-Sancho JM (2010) The EWS/FLI1 oncogenic protein inhibits expression of the Wnt inhibitor DICKKOPF-1 gene and antagonizes beta-catenin/TCF-mediated transcription. Carcinogenesis 31:394–401

    Article  CAS  PubMed  Google Scholar 

  21. Zhang F, Chen A, Chen J, Yu T, Guo F (2011) SiRNA-mediated silencing of beta-catenin suppresses invasion and chemosensitivity to doxorubicin in MG-63 osteosarcoma cells. Asian Pac J Cancer Prev 12:239–245

    PubMed  Google Scholar 

  22. Li C, Cheng Q, Liu J, Wang B, Chen D, Liu Y (2012) Potent growth-inhibitory effect of TRAIL therapy mediated by double-regulated oncolytic adenovirus on osteosarcoma. Mol Cell Biochem 364:337–344

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Spine Surgery, Norman Bethune First Hospital of Jilin University, 71 Xinmin Street, Changchun, 130021, China

    Ruhui Li, Lidi Liu, Lijun Wang & Shaokun Zhang

  2. Department of Joint Surgery, Norman Bethune First Hospital of Jilin University, Changchun, 130021, China

    Jianguo Liu

  3. Department of Ophthalmology, Norman Bethune Second Hospital of Jilin University, Changchun, 130041, China

    Hong Wu

Authors
  1. Ruhui Li
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  2. Jianguo Liu
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  3. Hong Wu
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  4. Lidi Liu
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  5. Lijun Wang
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  6. Shaokun Zhang
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Correspondence to Shaokun Zhang.

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Ruhui Li and Jianguo Liu equally contribute to this work.

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Li, R., Liu, J., Wu, H. et al. TIKI2 suppresses growth of osteosarcoma by targeting Wnt/β-catenin pathway. Mol Cell Biochem 392, 109–116 (2014). https://doi.org/10.1007/s11010-014-2023-5

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  • DOI: https://doi.org/10.1007/s11010-014-2023-5

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