Tumor Biology

, Volume 37, Issue 11, pp 14961–14967 | Cite as

The predictive potential and oncogenic effects of HOXC8 expression on osteosarcoma

  • Li Cheng
  • Xiaojie Wei
  • Keqi Zhao
  • Fenzan Wu
  • Wenjie Lu
  • Songlin Tong
  • Guanzhen Yu
Original Article


Homeobox C8 (HOXC8) has been implicated in cell growth, migration, and metastasis of various cancers, yet its role in osteosarcoma remains to be explored. In the present study, resected osteosarcoma specimens from 50 patients were enrolled to evaluate the expression of HOXC8 protein by immunohistochemistry (IHC). In vitro and in vivo assays were used to determine the effect of HOXC8 on cell growth, migration, and tumor growth. HOXC8 expression was observed in 31 (62.0 %) of the 50 primary tumors and significantly associated with poorly or un-differentiated specimens (P = 0.031) and larger tumor size (P = 0.049). Survival analysis demonstrated that HOXC8 is a candidate predictive factor in predicting patients’ outcome and chemotherapeutic effect. HOXC8 knockdown led to inhibition of tumor cell proliferation and migration in vitro by inhibiting MMP-9 expression and tumor growth in vivo. Our results strongly suggest that HOXC8 is involved in the tumorigenesis of osteosarcoma and might serve as a novel predictor for patients’ outcome.


Osteosarcoma HOXC8 Prognosis Immunohistochemistry Chemotherapeutic effect 


Compliance with ethical standards

The Institutional Review Board of Changzheng Hospital approved the use of the tissues and clinical information. An informed consent was obtained from each patient or their guardians. All animal experiments were approved by the Animal Ethics Committee of the Second Military Medical University.

Conflict of interest

We declare no conflicts of interest with any other person or units.


  1. 1.
    Klein MJ, Siegal GP. Osteosarcoma: anatomic and histologic variants. Am J Clin Pathol. 2006;125:555–81.CrossRefPubMedGoogle Scholar
  2. 2.
    Vander Griend RA. Osteosarcoma and its variants. Orthop Clin North Am. 1996;27:575–81.PubMedGoogle Scholar
  3. 3.
    Ottaviani G, Jaffe N. The etiology of osteosarcoma. Cancer Treat Res. 2009;152:15–32.CrossRefPubMedGoogle Scholar
  4. 4.
    Chou AJ, Gorlick R. Chemotherapy resistance in osteosarcoma: current challenges and future directions. Expert Rev Anticancer Ther. 2006;6:1075–85.CrossRefPubMedGoogle Scholar
  5. 5.
    Fagioli F, Aglietta M, Tienghi A, Ferrari S, Brach del Prever A, Vassallo E, Palmero A, Biasin E, Bacci G, Picci P, et al. High-dose chemotherapy in the treatment of relapsed osteosarcoma: an Italian sarcoma group study. J Clin Oncol Off J Am Soc Clin Oncol. 2002;20:2150–6.CrossRefGoogle Scholar
  6. 6.
    Anderson ME. Update on Survival in Osteosarcoma. Orthop Clin North Am. 2016;47:283–92.CrossRefPubMedGoogle Scholar
  7. 7.
    Li S, Sun W, Wang H, Zuo D, Hua Y, Cai Z. Research progress on the multidrug resistance mechanisms of osteosarcoma chemotherapy and reversal. Tumour Biol. 2015;36:1329–38.CrossRefPubMedGoogle Scholar
  8. 8.
    Gehring WJ, Hiromi Y. Homeotic genes and the homeobox. Annu Rev Genet. 1986;20:147–73.CrossRefPubMedGoogle Scholar
  9. 9.
    Yueh YG, Gardner DP, Kappen C. Evidence for regulation of cartilage differentiation by the homeobox gene Hoxc-8. Proc Natl Acad Sci U S A. 1998;95:9956–61.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Lu S, Liu R, Su M, Wei Y, Yang S, He S, Wang X, Qiang F, Chen C, Zhao S et al. Overexpression of HOXC8 is associated with poor prognosis in epithelial ovarian cancer. Reprod Sci. 2016;23:944–54.Google Scholar
  11. 11.
    Xu P, Zhang X, Ni W, Fan H, Xu J, Chen Y, Zhu J, Gu X, Yang L, Ni R, et al. Upregulated HOXC8 expression is associated with poor prognosis and oxaliplatin resistance in hepatocellular carcinoma. Dig Dis Sci. 2015;60:3351–63.CrossRefPubMedGoogle Scholar
  12. 12.
    Li Y, Chao F, Huang B, Liu D, Kim J, Huang S. HOXC8 promotes breast tumorigenesis by transcriptionally facilitating cadherin-11 expression. Oncotarget. 2014;5:2596–607.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    YB D, Dong B, Shen LY, Yan WP, Dai L, Xiong HC, Liang Z, Kang XZ, Qin B, Chen KN. The survival predictive significance of HOXC6 and HOXC8 in esophageal squamous cell carcinoma. J Surg Res. 2014;188:442–50.CrossRefGoogle Scholar
  14. 14.
    Adwan H, Zhivkova-Galunska M, Georges R, Eyol E, Kleeff J, Giese NA, Friess H, Bergmann F, Berger MR. Expression of HOXC8 is inversely related to the progression and metastasis of pancreatic ductal adenocarcinoma. Br J Cancer. 2011;105:288–95.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Manohar CF, Salwen HR, Furtado MR, Cohn SL. Up-regulation of HOXC6, HOXD1, and HOXD8 homeobox gene expression in human neuroblastoma cells following chemical induction of differentiation. Tumour Biol. 1996;17:34–47.CrossRefPubMedGoogle Scholar
  16. 16.
    Li Y, Guo Z, Chen H, Dong Z, Pan ZK, Ding H, Su SB, Huang S. HOXC8-dependent cadherin 11 expression facilitates breast cancer cell migration through trio and Rac. Genes cancer. 2011;2:880–8.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Yu G, Fang W, Xia T, Chen Y, Gao Y, Jiao X, Huang S, Wang J, Li Z, Xie K. Metformin potentiates rapamycin and cisplatin in gastric cancer in mice. Oncotarget. 2015;6:12748–62.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Poos K, Smida J, Nathrath M, Maugg D, Baumhoer D, Neumann A, Korsching E. Structuring osteosarcoma knowledge: an osteosarcoma-gene association database based on literature mining and manual annotation. Database (Oxford). 2014. doi: 10.1093/database/bau042.
  19. 19.
    Xi Y, Chen Y. Oncogenic and therapeutic targeting of PTEN loss in bone malignancies. J Cell Biochem. 2015;116:1837–47.CrossRefPubMedGoogle Scholar
  20. 20.
    Ren Z, Liang S, Yang J, Han X, Shan L, Wang B, Mu T, Zhang Y, Yang X, Xiong S, et al. Coexpression of CXCR4 and MMP9 predicts lung metastasis and poor prognosis in resected osteosarcoma. Tumour Biol. 2015;37:5089–96.CrossRefPubMedGoogle Scholar
  21. 21.
    Alami Y, Castronovo V, Belotti D, Flagiello D, Clausse N. HOXC5 and HOXC8 expression are selectively turned on in human cervical cancer cells compared to normal keratinocytes. Biochem Biophys Res Commun. 1999;257:738–45.CrossRefPubMedGoogle Scholar
  22. 22.
    Waltregny D, Alami Y, Clausse N, de Leval J, Castronovo V. Overexpression of the homeobox gene HOXC8 in human prostate cancer correlates with loss of tumor differentiation. Prostate. 2002;50:162–9.CrossRefPubMedGoogle Scholar
  23. 23.
    Ma Q, Zhou Y, Ma B, Chen X, Wen Y, Liu Y, Fan Q, Qiu X. The clinical value of CXCR4, HER2 and CD44 in human osteosarcoma: a pilot study. Oncol Lett. 2012;3:797–801.PubMedPubMedCentralGoogle Scholar
  24. 24.
    Salas S, Jiguet-Jiglaire C, Campion L, Bartoli C, Frassineti F, Deville JL, Maues De Paula A, Forest F, Jezequel P, Gentet JC, et al. Correlation between ERK1 and STAT3 expression and chemoresistance in patients with conventional osteosarcoma. BMC Cancer. 2014;14:606.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2016

Authors and Affiliations

  • Li Cheng
    • 1
  • Xiaojie Wei
    • 1
  • Keqi Zhao
    • 1
  • Fenzan Wu
    • 1
  • Wenjie Lu
    • 1
  • Songlin Tong
    • 1
  • Guanzhen Yu
    • 2
  1. 1.Department of Orthopaedics, Cixi People’s HospitalWenzhou Medical UniversityNingboChina
  2. 2.Department of OncologyChangzheng HospitalShanghaiChina

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