Skip to main content

Advertisement

Log in

Clinical significance of hypoxia-inducible factor 1 and VEGF-A in osteosarcoma

  • Original Article
  • Published:
International Journal of Clinical Oncology Aims and scope Submit manuscript

Abstract

Background

Although the function of hypoxia-inducible factor 1 (HIF1) in many kinds of solid tumor has been revealed, the significance of HIF1 in osteosarcoma is still controversial and not well understood.

Methods

Immunohistochemistry was used to detect HIF1 expression. The correlation between HIF1 and clinicopathology factors was analyzed by use of chi-squared tests. The prognostic value of HIF1 was evaluated by univariate and multivariate analysis. Moreover, the function of HIF1 in osteosarcoma cells was further investigated in in-vitro experiments by regulating HIF1 and vascular endothelial growth factor-A (VEGF-A) expression.

Results

Expression of HIF1 was high for 56.82 % of the samples in our investigation. HIF1 expression was significantly associated with positive metastasis (P = 0.037). By use of the Kaplan–Meier method, high expression of HIF1 was proved to be related to poorer overall survival (P = 0.007). By use of a Cox-regression model, HIF1 was identified as an independent prognostic biomarker (P = 0.019). We also proved that HIF1 can promote osteosarcoma invasion in hypoxia by inducing VEGF-A expression.

Conclusions

HIF1 was identified as an independent prognostic biomarker in osteosarcoma. It can promote osteosarcoma cell invasion by inducing VEGF-A expression, indicating that HIF1 is a potential drug target in osteosarcoma.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Luetke A, Meyers PA, Lewis I et al (2014) Osteosarcoma treatment—where do we stand? A state of the art review. Cancer Treat Rev 40:523–532

    Article  PubMed  Google Scholar 

  2. Ottaviani G, Jaffe N (2009) The epidemiology of osteosarcoma. Cancer Treat Res 152:3–13

    Article  PubMed  Google Scholar 

  3. Bielack S, Carrle D, Casali PG (2009) Osteosarcoma: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol 20(Suppl 4):137–139

    PubMed  Google Scholar 

  4. Moore DD, Luu HH (2014) Osteosarcoma. Cancer Treat Res 162:65–92

    Article  PubMed  Google Scholar 

  5. Guijarro MV, Ghivizzani SC, Gibbs CP (2014) Animal models in osteosarcoma. Front Oncol 4:189

    Article  PubMed Central  PubMed  Google Scholar 

  6. Yao Y, Dong Y, Lin F et al (2009) The expression of CRM1 is associated with prognosis in human osteosarcoma. Oncol Rep 21:229–235

    CAS  PubMed  Google Scholar 

  7. Jaffe N (2009) Adjuvant chemotherapy in osteosarcoma: an odyssey of rejection and vindication. Cancer Treat Res 152:219–237

    Article  PubMed  Google Scholar 

  8. Baumhoer D, Smida J, Zillmer S et al (2012) Strong expression of CXCL12 is associated with a favorable outcome in osteosarcoma. Mod Pathol 25:522–528

  9. Szuhai K, Cleton-Jansen AM, Hogendoorn PC et al (2012) Molecular pathology and its diagnostic use in bone tumors. Cancer Genet 205:193–204

    Article  CAS  PubMed  Google Scholar 

  10. Zeng W, Wan R, Zheng Y et al (2011) Hypoxia, stem cells and bone tumor. Cancer Lett 313:129–136

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. Schofield CJ, Ratcliffe PJ (2004) Oxygen sensing by HIF hydroxylases. Nat Rev Mol Cell Biol 5:343–354

    Article  CAS  PubMed  Google Scholar 

  12. Brahimi-Horn MC, Pouyssegur J (2009) HIF at a glance. J Cell Sci 122:1055–1057

    Article  CAS  PubMed  Google Scholar 

  13. Ivan M, Kondo K, Yang H et al (2001) HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for o2 sensing. Science 292:464–468

    Article  CAS  PubMed  Google Scholar 

  14. Jiang BH, Semenza GL, Bauer C et al (1996) Hypoxia-inducible factor 1 levels vary exponentially over a physiologically relevant range of o2 tension. Am J Physiol 271:C1172–C1180

    CAS  PubMed  Google Scholar 

  15. Iyer NV, Kotch LE, Agani F et al (1998) Cellular and developmental control of o2 homeostasis by hypoxia-inducible factor 1 alpha. Genes Dev 12:149–162

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  16. Loor G, Schumacker PT (2008) Role of hypoxia-inducible factor in cell survival during myocardial ischemia-reperfusion. Cell Death Differ 15:686–690

    Article  CAS  PubMed  Google Scholar 

  17. Kappler M, Taubert H, Eckert AW (2011) Oxygen sensing, homeostasis, and disease. N Engl J Med 365:1845–1846 (author reply 1846)

  18. Semenza GL (2014) Oxygen sensing, hypoxia-inducible factors, and disease pathophysiology. Ann Rev Pathol 9:47–71

    Article  CAS  Google Scholar 

  19. Shan B, Gerez J, Haedo M et al (2012) RSUME is implicated in HIF-1-induced VEGF-A production in pituitary tumour cells. Endocr Relat Cancer 19:13–27

    Article  CAS  PubMed  Google Scholar 

  20. Enneking WF (1986) A system of staging musculoskeletal neoplasms. Clin Orthop Relat Res 9–24

  21. Xia LM, Huang WJ, Wang B et al (2009) Transcriptional up-regulation of FoxM1 in response to hypoxia is mediated by HIF-1. J Cell Biochem 106:247–256

    Article  CAS  PubMed  Google Scholar 

  22. Elbashir SM, Harborth J, Lendeckel W et al (2001) Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature 411:494–498

    Article  CAS  PubMed  Google Scholar 

  23. Sowter HM, Raval RR, Moore JW et al (2003) Predominant role of hypoxia-inducible transcription factor (hif)-1alpha versus Hif-2alpha in regulation of the transcriptional response to hypoxia. Cancer Res 63:6130–6134

    CAS  PubMed  Google Scholar 

  24. Takei Y, Kadomatsu K, Yuzawa Y et al (2004) A small interfering RNA targeting vascular endothelial growth factor as cancer therapeutics. Cancer Res 64:3365–3370

    Article  CAS  PubMed  Google Scholar 

  25. Kappler M, Rot S, Taubert H et al (2007) The effects of knockdown of wild-type survivin, survivin-2b or survivin-delta3 on the radiosensitization in a soft tissue sarcoma cells in vitro under different oxygen conditions. Cancer Gene Ther 14:994–1001

    Article  CAS  PubMed  Google Scholar 

  26. Feige E, Yokoyama S, Levy C et al (2011) Hypoxia-induced transcriptional repression of the melanoma-associated oncogene MITF. Proc Natl Acad Sci USA 108:E924–E933

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  27. Busca R, Berra E, Gaggioli C et al (2005) Hypoxia-inducible factor 1{alpha} is a new target of microphthalmia-associated transcription factor (mitf) in melanoma cells. J Cell Biol 170:49–59

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  28. Zelzer E, Mamluk R, Ferrara N et al (2004) VEGFA is necessary for chondrocyte survival during bone development. Development 131:2161–2171

    Article  CAS  PubMed  Google Scholar 

  29. Weijts BG, Bakker WJ, Cornelissen PW et al (2012) E2F7 and E2F8 promote angiogenesis through transcriptional activation of VEGFA in cooperation with HIF1. EMBO J 31:3871–3884

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  30. Semenza GL (2003) Targeting HIF-1 for cancer therapy. Nat Rev Cancer 3:721–732

    Article  CAS  PubMed  Google Scholar 

  31. Dang CV, Semenza GL (1999) Oncogenic alterations of metabolism. Trends Biochem Sci 24:68–72

    Article  CAS  PubMed  Google Scholar 

  32. Yang QC, Zeng BF, Dong Y et al (2007) Overexpression of hypoxia-inducible factor-1alpha in human osteosarcoma: correlation with clinicopathological parameters and survival outcome. Jpn J Clin Oncol 37:127–134

    Article  PubMed  Google Scholar 

  33. Mizobuchi H, Garcia-Castellano JM, Philip S et al (2008) Hypoxia markers in human osteosarcoma: an exploratory study. Clin Orthop Relat Res 466:2052–2059

    Article  PubMed Central  PubMed  Google Scholar 

  34. Mayes PA, Campbell L, Ricci MS et al (2005) Modulation of trail-induced tumor cell apoptosis in a hypoxic environment. Cancer Biol Ther 4:1068–1074

    Article  CAS  PubMed  Google Scholar 

  35. Mathupala SP, Rempel A, Pedersen PL (2001) Glucose catabolism in cancer cells: identification and characterization of a marked activation response of the type II hexokinase gene to hypoxic conditions. J Biol Chem 276:43407–43412

    Article  CAS  PubMed  Google Scholar 

  36. Kilic M, Kasperczyk H, Fulda S et al (2007) Role of hypoxia inducible factor-1 alpha in modulation of apoptosis resistance. Oncogene 26:2027–2038

    Article  CAS  PubMed  Google Scholar 

  37. Bhattacharya S, Michels CL, Leung MK et al (1999) Functional role of p35srj, a novel p300/CBP binding protein, during transactivation by HIF-1. Genes Dev 13:64–75

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  38. Masson N, Willam C, Maxwell PH et al (2001) Independent function of two destruction domains in hypoxia-inducible factor-alpha chains activated by prolyl hydroxylation. EMBO J 20:5197–5206

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  39. Nardinocchi L, Puca R, Guidolin D et al (2009) Transcriptional regulation of hypoxia-inducible factor 1alpha by hipk2 suggests a novel mechanism to restrain tumor growth. Biochim Biophys Acta 1793:368–377

    Article  CAS  PubMed  Google Scholar 

  40. Yee KM, Spivak-Kroizman TR, Powis G (2008) Hif-1 regulation: not so easy come, easy go. Trends Biochem Sci 33:526–534

  41. Bae SH, Jeong JW, Park JA et al (2004) Sumoylation increases HIF-1alpha stability and its transcriptional activity. Biochem Biophys Res Commun 324:394–400

    Article  CAS  PubMed  Google Scholar 

  42. Loboda A, Jozkowicz A, Dulak J (2010) HIF-1 and HIF-2 transcription factors—similar but not identical. Mol Cells 29:435–442

    Article  CAS  PubMed  Google Scholar 

  43. Giaccia A, Siim BG, Johnson RS (2003) HIF-1 as a target for drug development. Nat Rev Drug Discov 2:803–811

    Article  CAS  PubMed  Google Scholar 

  44. Chau NM, Rogers P, Aherne W et al (2005) Identification of novel small molecule inhibitors of hypoxia-inducible factor-1 that differentially block hypoxia-inducible factor-1 activity and hypoxia-inducible factor-1alpha induction in response to hypoxic stress and growth factors. Cancer Res 65:4918–4928

    Article  CAS  PubMed  Google Scholar 

  45. Yonekura S, Itoh M, Okuhashi Y et al (2013) Effects of the HIF1 inhibitor, echinomycin, on growth and notch signalling in leukaemia cells. Anticancer Res 33:3099–3103

    CAS  PubMed  Google Scholar 

Download references

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Hongmei Liu.

Electronic supplementary material

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhao, H., Wu, Y., Chen, Y. et al. Clinical significance of hypoxia-inducible factor 1 and VEGF-A in osteosarcoma. Int J Clin Oncol 20, 1233–1243 (2015). https://doi.org/10.1007/s10147-015-0848-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10147-015-0848-x

Keywords

Navigation