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Original article

Vol. 143 No. 3536 (2013)

The expression of hypoxia-inducible factor-1α and its clinical significance in lung cancer: a systematic review and meta-analysis

  • Weiwei Ren
  • Denghai Mi
  • Kehu Yang
  • Nong Cao
  • Jinhui Tian
  • Zheng Li
  • Bin Ma
DOI
https://doi.org/10.4414/smw.2013.13855
Cite this as:
Swiss Med Wkly. 2013;143:w13855
Published
25.08.2013

Summary

BACKGROUND: Hypoxia-inducible factor-1α (HIF-1α) plays an important role in tumour progression and metastasis through activation of many target genes that are especially involved in pivotal aspects of cancer biology. However, the prognostic role of HIF-1α has been controversial in primary patients with lung cancer. This meta-analysis was performed to systematically evaluate whether HIF-1α expression is associated with the clinical outcomes in lung cancer patients.

METHODS: We retrieved relevant articles from Cochrane library, PubMed, EMbase, CNKI, CBM, VIP and Wan Fang Databases from inception to May 2012. Studies were selected using specific inclusion and exclusion criteria. A systematic review and meta-analysis was performed on the association between HIF-1α expression and clinical outcomes in lung cancer patients. All analyses were performed using the Revman 5.1 software.

RESULTS: A total of 30 studies were identified as eligible for the systematic review and meta-analysis. The expression of HIF-1α was significantly higher than those in normal lung tissue; and III‒IV stage, lymph node metastasis, poorly differentiation, squamous cell carcinoma and small cell lung cancer (SCLC) were significantly higher than those in I‒II stage, no lymph node metastasis, well differentiation, adenocarcinomas and non small cell lung cancer (NSCLC), respectively (odds ratio (OR) = 19.00, 95% confidence interval (CI):12.12–29.78, p <0.00001; OR = 0.23, 95% CI:0.14–0.36, p <0.00001; OR = 3.72, 95% CI:2.38–5.80, p <0.00001; OR = 0.47, 95% CI:0.31–0.70, p <0.00002, OR = 0.24, 95% CI:0.07–0.77, p = 0.02; OR = 0.78, 95% CI:0.63–0.98, p = 0.03). VEGF and CA IX positive expression in HIF-1α positive tumour tissues were significantly higher than those in HIF-1α negative tumour tissues, respectively (OR = 3.23, 95% CI: 1.90–5.46, p <0.0001; OR = 3.84, 95% CI: 2.10–7.03, p <0.0001). The positive HIF-1α tumour tissues of patients had lower 5-year survival rates (OR = 0.13, 95% CI: 0.03–0.47, p = 0.002) and overall survival (relative risk (RR) = 1.68, 95% CI: 1.12–2.50, p = 0.01).

CONCLUSIONS: HIF-1α is related to a differing degree of lung cancer cell, lymph node metastasis, post-operative survival time and histology (NSCLC vs. SCLC, adenocarcinomas vs. squamous cell carcinoma). HIF-1 α , which combines other proteins, such as vascular endothelial growth factor (VEGF) or CA IX, might serve as important parameters in evaluating biological behaviour and prognosis of lung cancer; it will be of benefit to clinical treatment and prognostic evaluation.

References

  1. Herbst RS, Heymach JV, Lippman SM. Lung cancer. N Engl J Med. 2008;359(13):1367–80. doi: 10.1056/NEJMra0802714.
  2. Maxwell PH, Wiesener MS, Chang GW, Clifford SC, Vaux EC, Cockman ME, et al. The tumor suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature. 1999;399(6733):271–5.
  3. Semenza GL, Wang GL. A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation. Mol Cell Biol. 1992;12(12):5447–54.
  4. Birner P, Schindl M, Obermair A, Plank C, Breitenecker G, Oberhuber G. Overexpression of hypoxia-inducible factor 1alpha is a marker for an unfavorable prognosis in early-stage invasive cervical cancer. Cancer Res. 2000;60(17):4693–6.
  5. Mizukami Y, Li J, Zhang X, Zimmer MA, Iliopoulos O, Chung DC. Hypoxia-inducible factor-1- independent regulation of vascular endothelial growth factor by hypoxia in colon cancer. Cancer Res. 2004;64(5):1765–72.
  6. Bos R, van der Groep P, Greijer AE, Shvarts A, Meijer S, Pinedo HM, et al. Levels of hypoxia-inducible factor-1 alpha independently predict prognosis in patients with lymph node negative breast carcinoma. Cancer. 2003;97(6):1573–81.
  7. Buchler P, Reber HA, Buchler M, Shrinkante S, Buchler MW, Friess H, et al. Hypoxia-inducible factor-1 regulates vascular endothelial growth factor expression in human pancreatic cancer. Pancreas. 2003;26(1):56–64.
  8. 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.
  9. GA Wells, B Shea, D O’Connell, J Peterson, V Welch, M Losos, et al. The Newcastle – Ottawa Scale (NOS) for assessing the quality of non randomized studies in meta-analyses. 2012. Available at: http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp
  10. Steels E, Paesmans M, Berghmans T, Branle F, Lemaitre F, Mascaux C, et al. Role of p53 as a prognostic factor for survival in lung cancer: a systematic review of the literature with a meta-analysis. Eur Respir J. 2001;18(4):705–19.
  11. Gould Rothberg BE, Bracken MB. E-cadherin immunohistochemical expression as a prognostic factor in infiltrating ductal carcinoma of the breast: a systematic review and meta-analysis. Breast Cancer Res Treat. 2006;100(2):139–48.
  12. Wu Y, Liu HB, Ding M, Liu JN, Zhan P, Fu XS, et al. The impact of E-cadherin expression on non-small cell lung cancer survival: a meta-analysis. Mol Biol Rep. 2012;39(10):9621–8.
  13. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002; 21(11):1539–58.
  14. Giatromanolaki A, Koukourakis MI, Sivridis E, Turley H, Talks K, Pezzella F, et al. Relation of hypoxia inducible factor 1α and 2α in operable non-small cell lung cancer to angiogenic/molecular profile of tumours and survival. Br J Cancer. 2001;85(6):881–90.
  15. Giatromanolaki A, Koukourakis MI, Sivridis E, Pastorek J, Wykoff CC, Gatter KC, et al. Expression of hypoxia-inducible carbonic anhydrase-9 relates to angiogenic pathways and independently to poor outcome in non-small cell lung cancer. Cancer Res. 2001;61(21):7992–8.
  16. Wu X, Qian C, Yuan K. Correlation of hypoxia-inducible factor-1α/hypoxia-inducible factor-2α expression with angiogenesis factors expression and prognosis in non-small cell Iung cancer. Chin Med J (Engl). 2011;124(1):11–8.
  17. Chen Y, Zhao C, Li W. Effect of hypoxia-inducible factor-1α on transcription of survivin in non-small cell lung cancer. J Exp Clin Cancer Res. 2009;28(1):29.
  18. Kim SJ, Rabbani ZN, Dewhirst MW, Vujaskovic Z, Vollmer RT, Schreiber EG, et al. Expression of HIF-1alpha, CA IX, VEGF, and MMP-9 in surgically resected non-small cell lung cancer. Lung Cancer. 2005;49(3):325–35.
  19. Andersen S, Eilertsen M, Donnem T, Al-Shibli K, Al-Saad S, Busund LT, et al. Diverging prognostic impacts of hypoxic markers according to NSCLC histology. Lung Cancer. 2011; 72(3):294–302.
  20. Hirami Y, Aoe M, Tsukuda K, Hara F, Otani Y, Koshimune R, et al. Relation of epidermal growth factor receptor, phosphorylated-Akt, and hypoxia-inducible factor-1alpha in non-small cell lung cancers. Cancer Letters. 2004;214(2):157–64.
  21. Park S, Ha SY, Cho HY, Chung DH, Kim NR, Hong J, et al. Prognostic implications of hypoxia-inducible factor-1α in epidermal growth factor receptor-negative non-small cell lung cancer. Lung Cancer. 2011;72(1):100–7.
  22. Swinson DE, Jones JL, Cox G, Richardson D, Harris AL, O’Byrne KJ. Hypoxia-inducible factor-1 alpha in non small cell lung cancer: relation to growth factor, protease and apoptosis pathways. Int J Cancer. 2004;111(1):43–50.
  23. Li H, Li J, Wang J, Zhang H, Huang J, Wang H. Expression of HIF-1α, VEGF in non-small cell lung cancer. Journal of Hebei Medical University. 2011;32(4):455–8 [Article in Chinese].
  24. Xiang F, Wu C, Yang D, Niu Z, Shen Y. Prognostic significance of HIF-1α in pulmonary carcinoma and its relationship to proliferative activity of cancer cells. China Journal of Modern Medicine. 2008;18(1):28–32 [Article in Chinese].
  25. Yang D, Xiang F. Expression of vascular endothelial growth factor in patients with pulmonary carcinoma and relationship with biological behavior of hypoxia and tumor and prognosis. Chinese Journal of Clinical Rehabilitation. 2005;9(10):115–8 [Article in Chinese].
  26. Zhu L, Chen P, Jiang Y. Expression of COX-2 and HIF-1 in non-small cell lung cancer and the relationship between them and tumor angiogenesis. Journal of Chinese Physician. 2007;9(10):1340–2 [Article in Chinese].
  27. Wang X, Yin L. Expression of HIF-lα, P-gp and COX-2 in non-small cell lung cancer. Ning xia Med J. 2011;33(5):411–4 [Article in Chinese].
  28. Wang Q. Expression of hypoxia-inducible factor-1α and BNIP3 in human non-small cell lung cancer and their correlation. China: Nan Chang University Press. 2009;1–48 [Article in Chinese].
  29. Wu S, Cheng Z, Yu L, Song W, Tao Y. Expression of CD28/KAI1 and HIF-1α in non-small cell lung cancer and their relationship to vasculogenic mimicry. Chin J Lung Cancer. 2011;14(12):918–25 [Article in Chinese].
  30. Qin J. Study on the effect and mechanism of HIF-1α on the expressions of COX-2 and E-cadherin in lung adenocarcinoma cell during hypoxia. China: Tian Jin Medical University Press. 2008; 1–90 [Article in Chinese].
  31. Liu J, Zhang N, Xu C, Li Z, Liu J, Sun Y. Co-expression of hypoxia-inducible factor-1α and hepatocyte growth factor in non-small-cell lung cancer and their association with lymphangiogenesis. Journal of Shan Dong University (Health Sciences). 2011;49(11):112–6 [Article in Chinese].
  32. Jiang X, Dai P, Song D, Wu J, Li S. Expressions of HIF-1α、VEGF and VEGFR2 in non-small cell lung cancer and their clincical significance. Journal of Clinical Pulmonary Medicine. 2011;16(3):386–8 [Article in Chinese].
  33. Ding Y, Da C, Li Y, Wu J. Expression of HIF-1α and VEGF-C and the relationship of lymphatic metastasis in non small cell lung cancer. Journal of Qing Hai Medical College. 2009;30(2):93–8 [Article in Chinese].
  34. Deng S, Nie W, Wang C. The Expressions of HIF-1α and COX-2 in non-small cell lung carcinoma and its clinical significance. Journal of Basic and Clinical Oncology. 2010;23(5):369–71 [Article in Chinese].
  35. Lu P, Zhang D, Cai C, Chang J. Expression and significance of HIF-1αand P300／CBP in squamous cell carcinoma and adenocarcinoma of lung. Modem Oncology. 2009;17(1):55–7 [Article in Chinese].
  36. Cheng C, Pan T, Chen T, Xu Q, Gao S. Relationship of hypoxia-inducible factor-1 alpha (HIF-1α) expression with vascular endothelial growth factor (VEGF) and microvessel density (MVD) in human non-small cell lung cancer. China Journal of Modern Medicine. 2005;15(15):2285–8 [Article in Chinese].
  37. Han Y, Wang J, Wang G, Ao Q. Vasculogenic mimicry and HIF-1α expression in lung cancer and their significance. J Clin Exp Pathol. 2008;24(3):269–72 [Article in Chinese].
  38. Zuo S, Wang J, Guo J. Expressions and correlation of HIF-1α and VEGF-C in non-small cell lung cancer. The Journal of Practical Medicine. 2009;25(1):59–61 [Article in Chinese].
  39. Fan L, Diao L, Chen D, Liu X, Zhu L, Li H, et al. Expression of HIF-1α and its relationship to apoptosis and proliferation in lung cancer. Chinese Journal of Cancer. 2002;21(3):254–8 [Article in Chinese].
  40. Huo R, Teng L, Zhang X, Liu Q. Expression and significance of HIF-lα and MMP-9 in non-small cell lung cancer. Modern Medicine &Health. 2010;26(6):802–3 [Article in Chinese].
  41. Zhao J, Yang J, Li Y. Expressions and clinical significance of PTEN and HIF-1α proteins in human lung carcinoma using tissue microarray. Medical Journal of Wu han University. 2005;26(4):399–442 [Article in Chinese].
  42. Wang X, Wan Y, Zhang Q. Expression and Significance of HIF-1α and VEGF in non-small cell lung cancer. Cancer Research on Prevention and Treatment. 2005;32(8):487–9 [Article in Chinese].
  43. Yuan Y, Zhong H, Mei J, Zhang P, Bao C, Li B, et al. Expression and clinical significance of HIF-1αin non-small cell lung cancer. Progress in Modern Biomedicine. 2010;10(15):2814–7 [Article in Chinese].
  44. Harris AL. Hypoxia: a key regulatory factor in tumour growth. Nat Rev Cancer. 2002;2(1):38–47.
  45. Bottaro DP, Liotta LA. Cancer: Out of air is not out of action. Nature. 2003;423(6940):593–5.
  46. 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.
  47. Nordmann AJ, Kasenda B, Briel M. Meta-analyses: what they can and cannot do. Swiss Med Wkly. 2012;142:w13518. doi: 10.4414/smw.2012.13518.
  48. Lee CH, Lee MK, Kang CD, Kim YD, Park DY, Kim JY, et al. Differential expression of hypoxia inducible factor-1 alpha and tumor cell proliferation between squamous cell carcinomas and adenocarcinomas among operable non-small cell lung carcinomas. J Korean Med Sci. 2003;18(2):196–203.
  49. Semenza GL. Targeting HIF-1 for cancer therapy. Nat Rev Cancer. 2003;3(10):721–32.
  50. Koukourakis MI, Giatromanolaki A, Brekken RA, Sivridis E, Gatter KC, Harris AL, et al. Enhanced expression of SPARC/osteonectin in the tumor-associated stroma of non-small cell lung cancer is correlated with markers of hypoxia/acidity and with poor prognosis of patients. Cancer Res. 2003;63(17):5376–80.
  51. Giatromanolaki A, Koukourakis MI, Sowter HM, Sivridis E, Gibson S, Gatter KC, et al. BNIP3 expression Is linked with hypoxia-regulated protein expression and with poor prognosis in non-small cell lung cancer. Clin Cancer Res. 2004;10(16):5566–71.
  52. VanDiest PJ, vanDam P, Henzen-Logmans SC, Berns E, vanderBurg ME, Green J, et al. A scoring system for immunohistochemical staining: consensus report of the task force for basic research of the EORTC-GCCG. European organization for research and treatment of cancer-gynaecological cancer cooperative group. J Clin Pathol. 1997;50(10):801–4.