Skip to main content

Advertisement

SpringerLink
Log in

Lactate Dehydrogenase-5 (LDH-5) Expression in Human Gastric Cancer: Association with Hypoxia-Inducible Factor (HIF-1α) Pathway, Angiogenic Factors Production and Poor Prognosis

  • Gastrointestinal Oncology
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background

Lactate-dehydrogenase-5 (LDH-5) is an important isoenzyme converting pyruvate to lactate under hypoxic conditions and might play an important role in the development and progression of malignancies. However, the role of LDH-5 in gastric cancer is still unclear. In this study, we investigated the clinical significance of LDH-5 expression in gastric carcinoma.

Methods

LDH-5 expression in 152 patients with different grade and stage gastric carcinoma was analyzed by immunohistochemistry. In addition, hypoxia-inducible factor 1α (HIF-1α) as a marker of tumor hypoxia, as well as vascular endothelial growth factor (VEGF) and cyclooxygenase-2 (COX-2) as angiogenesis parameters were also assessed in this study. Correlations between the expression of investigated proteins and various clinicopathological factors including survival were determined.

Results

There were 94 cases (61.8%) showing high LDH-5 expression, and 95 patients (62.5%) had high HIF-1α expression. Positive correlation was found between LDH-5 expression and HIF-1α, VEGF, and COX-2. The overexpression of LDH-5 was more prevalent in advanced tumors having positive vessel invasion. Patients with overexpression of LDH-5 showed far lower disease-free (63.5% vs 82.7%) and overall (56.3% vs 78.4%) survival rates compared with patients with low LDH-5 expression. HIF-1α expression was shown to have no significance on survival. In multivariate analysis, high LDH-5 expression kept its independence as a negative prognostic indicator.

Conclusion

The results of the current study show that LDH-5 expression may be a useful prognostic factor for patients with gastric carcinoma.

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

Access this article

Log in via an institution

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

Similar content being viewed by others

References

  1. Dicken BJ, Bigam DL, Cass C, et al. Gastric adenocarcinoma: review and considerations for future directions. Ann Surg 2005; 241:27–39.

    PubMed  Google Scholar 

  2. Warburg O. On the origin of cancer cells. Science 1965; 123:309–14.

    Article  Google Scholar 

  3. Holbrook JJ, Liljas A, Steindel SJ, et al. (1975) Lactate dehydrogenase. In: Boyer PD (ed) The enzymes, 3rd edition, vol. XI, part A. New York: Academic Press, pp 191–2

  4. Markert CL. Lactate dehydrogenase isozymes: dissociation and recombination of subunits. Science 1963; 140:1329–30.

    Article  PubMed  CAS  Google Scholar 

  5. Koukourakis MI, Giatromanolaki A, Sivridis E. Lactate dehydrogenase isoenzymes 1 and 5: differential expression by neoplastic and stromal cells in non-small cell lung cancer and other epithelial malignant tumors. Tumour Biol 2003; 24:199–202.

    Article  PubMed  CAS  Google Scholar 

  6. Hockel M, Vaupel P. Tumor hypoxia: definitions and current clinical, biological, and molecular aspects. J Natl Cancer Inst 2001; 93:266–76.

    Article  PubMed  CAS  Google Scholar 

  7. Semenza GL. HIF-1: mediator of physiological and pathophysiological responses to hypoxia. J Appl Physiol 2000; 88:1474–80.

    PubMed  CAS  Google Scholar 

  8. Semenza GL, Nejfelt MK, Chi SM, Antonarakis SE. Hypoxia-inducible nuclear factors bind to an enhancer element located 3′ to the human erythropoietin gene. Proc Natl Acad Sci USA 1991; 88:5680–4.

    Article  PubMed  CAS  Google Scholar 

  9. Semenza G. Signal transduction to hypoxia-inducible factor 1. Biochem Pharmacol 2002; 64:993–8.

    Article  PubMed  CAS  Google Scholar 

  10. Zhong H, De Marzo AM, Laughner E, et al. Overexpression of hypoxia-inducible factor 1α in common human cancers and their metastases. Cancer Res 1999; 59:5830–5.

    PubMed  CAS  Google Scholar 

  11. Maxwell PH, Wiesener MS, Chang GW, et al. The tumour suppressor protein VHL targets hypoxia inducible factors for oxygen dependent proteolysis. Nature 1999; 399:271–5.

    Article  PubMed  CAS  Google Scholar 

  12. Maxwell PH, Dachs GU, Gleadle JM, et al. Hypoxia-inducible factor-1 modulates gene expression in solid tumors and influences both angiogenesis and tumor growth. Proc Natl Acad Sci USA 1997; 94:8104–9.

    Article  PubMed  CAS  Google Scholar 

  13. Semenza GL. Regulation of mammalian O2 homeostasis by hypoxia-inducible factor 1. Annu Rev Cell Dev Biol 1999; 15:551–78.

    Article  PubMed  CAS  Google Scholar 

  14. Japanese Gastric Cancer Association. Japanese classification of gastric carcinoma—2nd English edition. Gastric Cancer 1998; 1:10–24

    Google Scholar 

  15. Kolev YV, Uetake H, Iida S, Ishikawa T, Kawano T, Sugihara K. Prognostic significance of VEGF expression in correlation with COX-2, microvessel density, and clinicopathological characteristics in human gastric carcinoma. Ann Surg Oncol 2007; 14:2738–47.

    Article  PubMed  Google Scholar 

  16. Giatromanolaki A, Sivridis E, Kouskoukis C, Gatter KC, Harris AL Koukourakis MI. Hypoxia-inducible factors 1alpha and 2alpha are related to vascular endothelial growth factor expression and a poorer prognosis in nodular malignant melanomas of the skin. Melanoma Res 2003; 13:493–501.

    Article  PubMed  CAS  Google Scholar 

  17. Yuce K, Baykal C, Genc C, Al A, Ahyan A. Diagnostic and prognostic value of serum and peritoneal fluid lactate dehydrogenase in epithelial ovarian cancer. Eur J Gynaecol Oncol 2001; 22:228–32.

    PubMed  CAS  Google Scholar 

  18. Brizel DM, Schroeder T, Sher RL, et al. Elevated tumor lactate concentrations predict for an increased risk of metastases in head-and-neck cancer. Int J Radiat Oncol Biol Phys 2001; 51:349–53.

    PubMed  CAS  Google Scholar 

  19. Taz F, Aykan F, Alici S, et al. Prognostic factors in pancreatic carcinoma: serum LDH levels predict survival in metastatic disease. Am J Clin Oncol 2001; 24:547–50.

    Article  Google Scholar 

  20. Koukourakis MI, Giatromanolaki A, Sivridis E, et al. Lactate dehydrogenase-5 (LDH-5) overexpression in non-small-cell lung cancer tissues is linked to tumour hypoxia, angiogenic factor production and poor prognosis. Br J Cancer 2003; 89:877–85.

    Article  PubMed  CAS  Google Scholar 

  21. Giatromanolaki A, Sivridis E, Gatter KC, Turley H, Harris AL, Koukourakis MI. Lactate dehydrogenase 5 (LDH-5) expression in endometrial cancer relates to the activated VEGF/VEGFR2(KDR) pathway and prognosis. Gynecol Oncol 2006; 103:912–18.

    Article  PubMed  CAS  Google Scholar 

  22. Koukourakis MI, Giatromanolaki A, Sivridis E, Gatter KC, Harris AL. Lactate dehydrogenase 5 expression in operable colorectal cancer: strong association with survival and activated vascular endothelial growth factor pathway—A report of the Tumour Angiogenesis Research Group. J Clin Oncol 2006; 24:4301–8.

    Article  PubMed  CAS  Google Scholar 

  23. Song YL, Yang GL, Dong YM. Immunohistochemical study of lactate dehydrogenase isoenzymes in gastric cancer. China Natl J New Gastroenterol 1995; 1:13–7.

    Google Scholar 

  24. Stubbs M, McSheehy PM, Griffiths JR, Bashford CL. Causes and consequences of tumour acidity and implications for treatment. Mol Med Today 2000; 6:15–1.

    Article  PubMed  CAS  Google Scholar 

  25. Urano N, Fujiwara Y, Doki Y, et al. Overexpression of hypoxia-inducible factor-1 alpha in gastric adenocarcinoma. Gastric Cancer 2006; 9:44–9.

    Article  PubMed  CAS  Google Scholar 

  26. Griffiths EA, Pritchard SA, Welch IM, Price PM, West CM. Is the hypoxia-inducible factor pathway important in gastric cancer? Eur J Cancer 2005; 41:2792–805.

    Article  PubMed  CAS  Google Scholar 

  27. Wang W, Davis DA, Haque M, Huang LE, Yarchoan R. Differential gene up-regulation by hypoxia-inducible factor-1alpha and hypoxia-inducible factor-2alpha in HEK293T cells. Cancer Res 2005; 65:3299–306.

    PubMed  CAS  Google Scholar 

  28. Carmeliet P, Dor Y, Herbert JM, et al. Role of HIF-1α in hypoxia-mediated apoptosis, cell proliferation, and tumour angiogenesis. Nature 1998; 394:485–90.

    Article  PubMed  CAS  Google Scholar 

  29. Griffiths EA, Pritchard SA, Valentine HR, et al. Hypoxia-inducible factor-1α expression in the gastric carcinogenesis sequence and its prognostic role in gastric and gastro-oesophageal adenocarcinomas. Br J Cancer 2007; 96:95–103.

    Article  PubMed  CAS  Google Scholar 

  30. Lu H, Forbes RA, Verma A. Hypoxia-inducible factor 1 activation by aerobic glycolysis implicates the Warburg effect in carcinogenesis. J Biol Chem 2002; 277:23111–5.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Surgical Oncology Department, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan

    Yanislav Kolev MD, PhD, Hiroyuki Uetake MD, PhD, Yoko Takagi & Kenichi Sugihara MD, PhD

Authors
  1. Yanislav Kolev MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hiroyuki Uetake MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yoko Takagi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kenichi Sugihara MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yanislav Kolev MD, PhD.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kolev, Y., Uetake, H., Takagi, Y. et al. Lactate Dehydrogenase-5 (LDH-5) Expression in Human Gastric Cancer: Association with Hypoxia-Inducible Factor (HIF-1α) Pathway, Angiogenic Factors Production and Poor Prognosis. Ann Surg Oncol 15, 2336–2344 (2008). https://doi.org/10.1245/s10434-008-9955-5

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1245/s10434-008-9955-5

Keywords

Search

Navigation