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Pathological and prognostic significance of hypoxia-inducible factor 1α expression in epithelial ovarian cancer: a meta-analysis

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Tumor Biology

Abstract

Hypoxia-inducible factor-1α (HIF-1α) plays an important role in tumour progression and metastasis. However, the association between HIF-1α and clinicopathological characteristics of epithelial ovarian cancers is controversial. We searched articles on the association between HIF-1α expression and clinicopathological variables of epithelial ovarian cancer in Cochrane Library, Pubmed, Web of Knowledge and China National Knowledge Infrastructure (CNKI) from inception to February 2014. Twenty-five studies were included in the final review. The expression of HIF-1α in cancer or borderline tissue was significantly higher than that in benign tissue (cancer vs. benign, odds ratio (OR) = 9.73 (95 % confidence interval (CI), 4.90, 19.32); P < 0.00001; borderline vs. benign, OR = 6.29 (95 % CI, 2.69–14.73); P < 0.0001; cancer vs. borderline, OR = 2.31 (95 % CI, 1.04, 5.09); P = 0.04). The expression of HIF-1α in stages III–IV or lymph node metastasis was significantly higher than that in stages I–II or that without lymph node metastasis, respectively (OR = 3.01 (95 % CI, 1.92–4.74); P < 0.00001; OR = 5.20 (95 % CI, 2.10–12.89); P = 0.0004). HIF-1α was associated with histological grade of cancer (grades 3 vs. 1, OR = 4.52 (95 % CI, 2.79–7.31); P < 0.00001; grades 3 vs. 2, OR = 2.02 (95 % CI, 1.27–3.19); P = 0.003; grades 3 vs. 1, OR = 2.43 (95 % CI), 1.65–3.59; P < 0.00001) and lower 5-year survival rates (OR = 11.46 (95 % CI, 3.43–38.29); P < 0.0001). However, histological types and the age of patients were not associated with HIF-1α expression (OR = 1.01 (95 % CI, 0.72, 1.42); P = 0.94; OR = 1.06 (95 % CI, 0.73–1.55); P = 0.75). In conclusion, HIF-1α is related to the malignant degree, FIGO stage, histological grade, lymph node metastasis and 5-year survival rate of epithelial ovarian cancer. It may play an important role in clinical treatment and prognostic evaluation.

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References

  1. Kurokawa T, Miyamoto M, Kato K, Cho Y, Kawarada Y, Hida Y, et al. Overexpression of hypoxia-inducible-factor 1alpha(HIF-1alpha) in oesophageal squamous cell carcinoma correlates with lymph node metastasis and pathologic stage. Br J Cancer. 2003;89(6):1042–7.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  2. Le QT, Denko NC, Giaccia AJ. Hypoxic gene expression and metastasis. Cancer Metastasis Rev. 2004;23(3–4):293–310.

    Article  CAS  PubMed  Google Scholar 

  3. Richard DE, Berra E, Pouyssegur J. Angiogenesis: how a tumor adapts to hypoxia. Biochem Biophys Res Commun. 1999;266(3):718–22.

    Article  CAS  PubMed  Google Scholar 

  4. Wang GL, Jiang BH, Rue EA, Semenza GL. Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci U S A. 1995;92(12):5510–4.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  5. Vajkoczy P, Farhadi M, Gaumann A, Heidenreich R, Erber R, Wunder A, et al. Microtumor growth initiates angiogenic sprouting with simultaneous expression of VEGF, VEGF receptor-2, and angiopoietin-2. J Clin Invest. 2002;109(6):777–85.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  6. Zhong H, De Marzo AM, Laughner E, Lim M, Hilton DA, Zagzag D, et al. Overexpression of hypoxia-inducible factor 1alpha in common human cancers and their metastases. Cancer Res. 1999;59(22):5830–5.

    CAS  PubMed  Google Scholar 

  7. Murdoch WJ. Ovarian surface epithelium, ovulation and carcinogenesis. Biol Rev Camb Philos Soc. 1996;71(4):529–43.

    Article  CAS  PubMed  Google Scholar 

  8. Osada R, Horiuchi A, Kikuchi N, Yoshida J, Hayashi A, Ota M, et al. Expression of hypoxia-inducible factor 1alpha, hypoxia-inducible factor 2alpha, and von Hippel–Lindau protein in epithelial ovarian neoplasms and allelic loss of von Hippel–Lindau gene: nuclear expression of hypoxia-inducible factor 1alpha is an independent prognostic factor in ovarian carcinoma. Hum Pathol. 2007;38(9):1310–20.

    Article  CAS  PubMed  Google Scholar 

  9. Miyazawa M, Yasuda M, Fujita M, Hirasawa T, Kajiwara H, Hirabayashi K, et al. Association of hypoxia-inducible factor-1 expression with histology in epithelial ovarian tumors: a quantitative analysis of HIF-1. Arch Gynecol Obstet. 2009;279(6):789–96.

    Article  CAS  PubMed  Google Scholar 

  10. Lee S, Garner EI, Welch WR, Berkowitz RS, Mok SC. Over-expression of hypoxia-inducible factor 1 alpha in ovarian clear cell carcinoma. Gynecol Oncol. 2007;106(2):311–7.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. Wong C, Wellman TL, Lounsbury KM. VEGF and HIF-1alpha expression are increased in advanced stages of epithelial ovarian cancer. Gynecol Oncol. 2003;91(3):513–7.

    Article  CAS  PubMed  Google Scholar 

  12. Iida T, Yasuda M, Miyazawa M, Fujita M, Osamura RY, Hirasawa T, et al. Hypoxic status in ovarian serous and mucinous tumors: relationship between histological characteristics and HIF-1alpha/GLUT-1 expression. Arch Gynecol Obstet. 2008;277(6):539–46.

    Article  CAS  PubMed  Google Scholar 

  13. Shimogai R, Kigawa J, Itamochi H, Iba T, Kanamori Y, Oishi T, et al. Expression of hypoxia-inducible factor 1alpha gene affects the outcome in patients with ovarian cancer. Int J Gynecol Cancer. 2008;18(3):499–505.

    Article  CAS  PubMed  Google Scholar 

  14. Nakai H, Watanabe Y, Ueda H, Hoshiai H. Hypoxia inducible factor 1-alpha expression as a factor predictive of efficacy of taxane/platinum chemotherapy in advanced primary epithelial ovarian cancer. Cancer Lett. 2007;251(1):164–7.

    Article  CAS  PubMed  Google Scholar 

  15. Birner P, Schindl M, Obermair A, Breitenecker G, Oberhuber G. Expression of hypoxia-inducible factor 1alpha in epithelial ovarian tumors: its impact on prognosis and on response to chemotherapy. Clin Cancer Res. 2001;7(6):1661–8.

    CAS  PubMed  Google Scholar 

  16. Konac E, Onen HI, Metindir J, Alp E, Biri AA, Ekmekci A. An investigation of relationships between hypoxia-inducible factor-1 alpha gene polymorphisms and ovarian, cervical and endometrial cancers. Cancer Detect Prev. 2007;31(2):102–9.

    Article  CAS  PubMed  Google Scholar 

  17. Duyndam MC, van Berkel MP, Dorsman JC, Rockx DA, Pinedo HM, Boven E. Cisplatin and doxorubicin repress vascular endothelial growth factor expression and differentially down-regulate hypoxia-inducible factor I activity in human ovarian cancer cells. Biochem Pharmacol. 2007;74(2):191–201.

    Article  CAS  PubMed  Google Scholar 

  18. Bardos JI, Ashcroft M. Negative and positive regulation of HIF-1: a complex network. Biochim Biophys Acta. 2005;1755(2):107–20.

    CAS  PubMed  Google Scholar 

  19. O’Donnell JL, Joyce MR, Shannon AM, Harmey J, Geraghty J, Bouchier-Hayes D. Oncological implications of hypoxia inducible factor-1alpha (HIF-1alpha) expression. Cancer Treat Rev. 2006;32(6):407–16.

    Article  PubMed  Google Scholar 

  20. Seeber LM, Horree N, Vooijs MA, Heintz AP, van der Wall E, Verheijen RH, et al. The role of hypoxia inducible factor-1alpha in gynecological cancer. Crit Rev Oncol Hematol. 2011;78(3):173–84.

    Article  PubMed  Google Scholar 

  21. Quintero M, Mackenzie N, Brennan PA. Hypoxia-inducible factor 1 (HIF-1) in cancer. Eur J Surg Oncol. 2004;30(5):465–8.

    Article  CAS  PubMed  Google Scholar 

  22. Jiang H, Feng Y. Hypoxia-inducible factor 1alpha (HIF-1alpha) correlated with tumor growth and apoptosis in ovarian cancer. Int J Gynecol Cancer. 2006;16 Suppl 1:405–12.

    Article  PubMed  Google Scholar 

  23. Chen Y, Zhang L, Pan Y, Ren XB, Hao Q. Over-expression of semaphorin4D, hypoxia-inducible factor-1 alpha and vascular endothelial growth factor is related to poor prognosis in ovarian epithelial cancer. Int J Mol Sci. 2012;13(10):13264–74.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  24. Daponte A, Ioannou M, Mylonis I, Simos G, Minas M, Messinis IE, et al. Prognostic significance of hypoxia-inducible factor 1 alpha(HIF-1 alpha) expression in serous ovarian cancer: an immunohistochemical study. BMC Cancer. 2008;8:335.

    Article  PubMed Central  PubMed  Google Scholar 

  25. Ji F, Wang Y, Qiu L, Li S, Zhu J, Liang Z, et al. Hypoxia inducible factor 1alpha-mediated LOX expression correlates with migration and invasion in epithelial ovarian cancer. Int J Oncol. 2013;42(5):1578–88.

    CAS  PubMed Central  PubMed  Google Scholar 

  26. Nakayama K, Kanzak A, Hata K, Katabuchi H, Okamura H, Miyazaki K, et al. Hypoxia-inducible factor 1 alpha (HIF-1 alpha) gene expression in human ovarian carcinoma. Cancer Lett. 2002;176(2):215–23.

    Article  CAS  PubMed  Google Scholar 

  27. Yasuda M, Miyazawa M, Fujita M, Kajiwara H, Iida T, Hirasawa T, et al. Expression of hypoxia inducible factor-1alpha (HIF-1alpha) and glucose transporter-1 (GLUT-1) in ovarian adenocarcinomas: difference in hypoxic status depending on histological character. Oncol Rep. 2008;19(1):111–6.

    CAS  PubMed  Google Scholar 

  28. Luo J, Peng Z, Yang K, Wang H, Yang H, Dong D, et al. Relation between the expression of hypoxia inducible factor-1alpha and angiogenesis in ovarian cancer using tissue microarray. Zhonghua Fu Chan Ke Za Zhi. 2005;40(1):38–41.

    PubMed  Google Scholar 

  29. Li SY, Yang WW, Wen QT, Xu L, Meng HM, Chen M, et al. Expression and significance of HIF-1alpha and PTEN in epithelial ovarian carcinoma and their correlation. Chin J Clin Exp Pathol. 2009;25(4):361–3.

    Google Scholar 

  30. Su M, Zhang Y, Huang H. Expression of HIF-1alpha and MMP-2 in vasculogenic mimicry of ovarian cancer. Curr Adv Obstet Gynecol. 2011;20(2):83–7.

    Google Scholar 

  31. Tong XG, Xu HM, Liu YP, Hou KZ. Role of hypoxia-inducible factor-1alpha(HIF-1alpha) and angiogenic factors in peritoneal metastases and prognosis of advanced serous ovarian cancer. Chin J Clin Oncol. 2008;35(5):272–6.

    CAS  Google Scholar 

  32. Yu L, Wu S, Zhou L, Song W. Correlation between bacterial L-form infection, expression of HIF-1alpha/MMP-9 and vasculogenic mimicry in epithelial ovarian cancer. Sheng Li Xue Bao. 2012;64(6):657–65.

    CAS  PubMed  Google Scholar 

  33. Chen Y, Zhang L, Liu X. The expression and clinical significance of semaphorin4D, hypoxia-inducible factor-1α and vascular endothelial growth factor in ovarian epithelial cancer. Chin J Obstet Gynecol. 2011;46(10):786–8.

    CAS  Google Scholar 

  34. Fu L, Feng W, Zhao YH, Wang AH, Wang BB, Yang LX, et al. Expression and significance of hypoxia inducible factor-la in ovarian epithelial cancer. Chin J Lab Diagn. 2008;11:1373–5.

    Google Scholar 

  35. Guo LL, Liu ZQ, Zhang LP, Guo GL. Expression and clinical significance of human leucocyte antigen protein G and hypoxia inducible factor-lα in epithelial ovarian carcinoma. J Hainan Med Univ. 2010;04:421–,8.

    Google Scholar 

  36. Li GL, Wang Z, Han RF. Expression of mitogen activated protein kinase p38 and hypoxia-inducible factor la in epithefial ovarian cancer. Clin Med Eng. 2011;04:507–9.

    Google Scholar 

  37. Liu LX, Liu GM, Sun YH, He XP. Analysis of the relationship between HIF-1а gene expression and drug resistance of chemotherapy in ovarian cancer. Progress Modern Biomed. 2012;02:276–9.

    Google Scholar 

  38. Shen Y, Zhang XY, Shi YQ, Wang Y, Guo DH. Significance of Glut-1, HIF-1 and P53 expression in ovarian cancer. J Tianjin Med Univ. 2013;05:383–6,437.

    Google Scholar 

  39. Wang XC, Li XY, Li SQ. Expression of HIF-1A and VEGF and their relationship in ovarian neoplasms. Chin J Misdiagn. 2008;20:4795–7.

    Google Scholar 

  40. Yu J, Huang YC, Zhang LJ, Lu YB. Expression and significance of hypoxia-inducible factor-1α and glucose transporter protein-1 in epithelial ovarian tumor. Chin Clin Oncol. 2009;03:207–11.

    Google Scholar 

  41. Attia J, Thakkinstian A, D’Este C. Meta-analyses of molecular association studies: methodologic lessons for genetic epidemiology. J Clin Epidemiol. 2003;56(4):297–303.

    Article  PubMed  Google Scholar 

  42. Nordmann AJ, Kasenda B, Briel M. Meta-analyses: what they can and cannot do. Swiss Med Wkly. 2012;142:w13518.

    PubMed  Google Scholar 

  43. Ren W, Mi D, Yang K, Cao N, Tian J, Li Z, et al. The expression of hypoxia-inducible factor-1alpha and its clinical significance in lung cancer: a systematic review and meta-analysis. Swiss Med Wkly. 2013;143:w13855.

    PubMed  Google Scholar 

  44. van Diest PJ, van Dam P, Henzen-Logmans SC, Berns E, van der Burg ME, Green J, et al. A scoring system for immunohistochemical staining: consensus report of the task force for basic research of the EORTC-GCCG. Eur Organ Res Treat Cancer-Gynaecol Cancer Coop Group J Clin Pathol. 1997;50(10):801–4.

    Google Scholar 

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Authors and Affiliations

  1. Department of Gynecology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 1630 S. Dongfang Road, Shanghai, 200127, China

    Yue Jin, Jun Ma & Yu Wang

  2. Department of General Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 1630 S. Dongfang Road, Shanghai, 200127, China

    Haolu Wang

  3. Therapeutics Research Centre, School of Medicine, Princess Alexandra Hospital, The University of Queensland, Woolloongabba, QLD, 4102, Australia

    Haolu Wang & Xiaowen Liang

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  1. Yue Jin
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  4. Jun Ma
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Correspondence to Yu Wang.

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Yue Jin and Haolu Wang contributed equally to this work and should be considered co-first authors.

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Supplementary Fig. 1

Forest plot of association between HIF-1α expression and the age of patients with epithelial ovarian cancer (I 2 = 39 %) (PDF 24 kb)

Supplementary Fig. 2

Forest plot of association between HIF-1α expression and histological type of epithelial ovarian cancer. a The expression of HIF-1α in serous cancer vs. that in other types (I 2 = 0 %). b The expression of HIF-1α in clear cell cancer vs. that in other types (I 2 = 0 %) (PDF 28 kb)

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Jin, Y., Wang, H., Liang, X. et al. Pathological and prognostic significance of hypoxia-inducible factor 1α expression in epithelial ovarian cancer: a meta-analysis. Tumor Biol. 35, 8149–8159 (2014). https://doi.org/10.1007/s13277-014-2059-x

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  • DOI: https://doi.org/10.1007/s13277-014-2059-x

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