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Clinicopathological significance of cathepsin D expression in non-small cell lung cancer is conditional on apoptosis-associated protein phenotype: an immunohistochemistry study

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Tumor Biology

Abstract

Cathepsin D is a well-known peptidase which belongs to the family of aspartic peptidases. It has been found to be overexpressed in many malignant tumors and associated with cancer metastasis and clinical outcome. However, its function in cancers remains controversial. Recently, increasing evidence shows that cathepsin D may play important roles in cell apoptosis. In the current study, we examined the expression of cathepsin D and a group of apoptosis-associated proteins including bcl-2, caspase 3, fas, fasL, p53, and survivin in non-small cell lung cancer (NSCLC) tissues to investigate the possible association between cathepsin D and these apoptosis-associated proteins and the clinicopathological features using immunohistochemistry. Cathepsin D expression was detected in cancer tissues including cancer cells (positive rate 64.5% (49/76)) and stromal parts including leukocytes, fibroblasts, capillary endothelial cells, and the matrix. No significant difference was found between the expression of cathepsin D in cancer cells and the corresponding non-tumor portions including bronchial epithelia and submucosal glands (positive rate 53.3% (8/15)) (p > 0.05). Immunofluorescence study on formalin-fixed, paraffin-embedded specimens confirmed the cytoplasmic expression of cathepsin D in cancer cells and non-tumor portions. Western blot study detected both mature and immature forms of cathepsin D in lung and NSCLC tissues, while the expression level of neither form showed a significant difference between these tissues (p > 0.05). Positive association was found between cathepsin D expression and fas status (p < 0.01) but not with the other apoptosis-associated proteins (p > 0.05) in cancer cells. Cathepsin D expression alone was not associated with any of the clinicopathological features (p > 0.05), while multiple-marker analysis revealed that two immunostaining phenotypes based on the expression of cathepsin D and one of the apoptosis-associated proteins, namely, cathepsin D+/caspase 3− and cathepsin D+/p53+ showed clinicopathological significance. The cathepsin D+/caspase 3− group was associated with advanced tumor node metastasis stages (III and IV) (p < 0.05), while the cathepsin D+/p53+ group was associated with lymph node metastasis (p < 0.05). The present findings indicate that the expression of cathepsin D in non-small cell lung cancer may have possible contributions to cancer development which is conditional on apoptosis-associated protein phenotype.

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References

  1. Fusek M, Vetvicka V. Dual role of cathepsin D: ligand and protease. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2005;149(1):43–50.

    Article  CAS  Google Scholar 

  2. Petr B, Vaclav V, Martin F. Cathepsin D—many functions of one aspartic protease. Crit Rev Oncol Hematol. 2008;68:12–28.

    Article  Google Scholar 

  3. Rochefort H, Garcia M, Glondu M, Laurent V, Liaudet E, Rey JM, Roger P. Cathepsin D in breast cancer: mechanisms and clinical applications, a 1999 overview. Clin Chim Acta. 2000;291(2):157–70.

    Article  CAS  Google Scholar 

  4. Leto G, Tumminello FM, Crescimanno M, Flandina C, Gebbia N. Cathepsin D expression levels in nongynecological solid tumors: clinical and therapeutic implications. Clin Exp Metastasis. 2004;21:91–106.

    Article  CAS  Google Scholar 

  5. Liaudet-Coopman E, Beaujouin M, Derocq D, Garcia M, Glondu-Lassis M, Laurent-Matha V, Prébois C, Rochefort H, Vignon F. Cathepsin D: newly discovered functions of a long-standing aspartic protease in cancer and apoptosis. Cancer Lett. 2006;237(2):167–79.

    Article  CAS  Google Scholar 

  6. Minarowska A, Minarowski L, Karwowska A, Gacko M. Regulatory role of cathepsin D in apoptosis. Folia Histochem Cytobiol. 2007;45(3):159–63.

    CAS  PubMed  Google Scholar 

  7. Olivier M, Anne-Sophie B, Danielle D, Christine P, Valérie LM, Pattingre S, Emmanuelle LC. Pathophysiological functions of cathepsin D: targeting its catalytic activity versus its protein binding activity? Biochimie. 2010;92:1635–43.

    Article  Google Scholar 

  8. Sobin DHWC. International Union Against Cancer (UICC): TNM classification of malignant tumors. New York: Wiley; 2002.

    Google Scholar 

  9. Travis WDBE, Muller-Hermelink HK, Harris CC. World Health Organization classification of tumors: pathology and genetics of tumors of the lung, pleura, thymus and heart. Lyon: IARC; 2004.

    Google Scholar 

  10. Dunn BM, Scarborough PE, Lowther WT, Rao-Naik C. Comparison of the active site specificity of the aspartic proteinases based on a systematic series of peptide substrates. Adv Exp Med Biol. 1995;362:1–9.

    Article  CAS  Google Scholar 

  11. Dunn BM, Hung S. The two sides of enzyme–substrate specificity: lessons from the aspartic proteinases. Biochim Biophys Acta. 2000;1477:231–40.

    Article  CAS  Google Scholar 

  12. Nousheen Z, Andreas M, Sebastian N, Hubert K. Cathepsin D: a cellular roadmap. Biochem Biophys Res Commun. 2008;376:5–9.

    Article  Google Scholar 

  13. Schulte T, Böhringer S, Schöls L, Müller T, Fischer C, Riess O, Przuntek H, Berger K, Epplen JT, Krüger R. Modulation of disease risk according to a cathepsin D / apolipoprotein E genotype in Parkinson's disease. J Neural Transm. 2003;110(7):749–55.

    Article  CAS  Google Scholar 

  14. Sato Y, Suzuki Y, Ito E, Shimazaki S, Ishida M, Yamamoto T, Yamamoto H, Toda T, Suzuki M, Suzuki A, Endo T. Identification and characterization of an increased glycoprotein in aging: age-associated translocation of cathepsin D. Mech Ageing Dev. 2006;127(10):771–8.

    Article  CAS  Google Scholar 

  15. Awano T, Katz ML, O'Brien DP, Taylor JF, Evans J, Khan S, Sohar I, Lobel P, Johnson GS. A mutation in the cathepsin D gene (CTSD) in American bulldogs with neuronal ceroid lipofuscinosis. Mol Genet Metab. 2006;87:341–8.

    Article  CAS  Google Scholar 

  16. Siintola E, Partanen S, Stromme P, Haapanen A, Haltia M, Maehlen J, Lehesjoki AE, Tyynela J. Cathepsin D deficiency underlies congenital human neuronal ceroid-lipofuscinosis. Brain. 2006;129:1438–45.

    Article  Google Scholar 

  17. Cullen V, Lindfors M, Ng J, Paetau A, Swinton E, Kolodziej P, Boston H, Saftig P, et al. Cathepsin D expression level affects alpha-synuclein processing, aggregation, and toxicity in vivo. Mol Brain. 2009;2:5.

    Article  Google Scholar 

  18. Rochefort H. Cathepsin D in breast cancer: a tissue marker associated with metastasis. Eur J Cancer. 1992;28A:1780–3.

    Article  CAS  Google Scholar 

  19. Rochefort H, Liaudet-Coopman E. Cathepsin D in cancer metastasis: a protease and a ligand. APMIS. 1999;107:86–95.

    Article  CAS  Google Scholar 

  20. Mirza AN, Mirza NQ, Vlastos G, Singletary SE. Prognostic factors in node-negative breast cancer: a review of studies with sample size more than 200 and follow-up more than 5 years. Ann Surg. 2002;235:10–26.

    Article  Google Scholar 

  21. Alina M, Lukasz M, Alicja K, Marek G. Regulatory role of cathepsin D in apoptosis. Folia Histochem Cytobiol. 2007;45(3):159–63.

    Google Scholar 

  22. Johansson AC, Steen H, Ollinger K, Roberg K. Cathepsin D mediates cytochrome c release and caspase activation in human fibroblast apoptosis induced by staurosporine. Cell Death Differ. 2003;10:1253–9.

    Article  CAS  Google Scholar 

  23. Roberg K, Kagedal K, Ollinger K. Microinjection of cathepsin D induces caspase-dependent apoptosis in fibroblasts. Am J Pathol. 2002;161:89–96.

    Article  CAS  Google Scholar 

  24. Heinrich M, Neumeyer J, Jakob M. Cathepsin D links TNF-induced acid sphingomyelinase to Bid-mediated caspase-9 and -3 activation. Cell Death Differ. 2004;11:550–63.

    Article  CAS  Google Scholar 

  25. Deiss LP, Galinka H, Berissi H, Cohen O, Kimchi A. Cathepsin D protease mediates programmed cell death induced by interferon-gamma, Fas/APO-1 and TNF-alpha. EMBO J. 1996;15:3861–70.

    Article  CAS  Google Scholar 

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Acknowledgment

This work was supported by the National Natural Science Foundation of China (no. 81071905 to Enhua Wang, MD).

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Authors and Affiliations

  1. Department of Pathology, First Affiliated Hospital and College of Basic Medical Sciences, China Medical University, 110001, Shenyang, China

    Chuifeng Fan, Xuyong Lin & Enhua Wang

  2. Institute of Pathology and Pathophysiology, China Medical University, 110001, Shenyang, China

    Chuifeng Fan, Xuyong Lin & Enhua Wang

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  1. Chuifeng Fan
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  2. Xuyong Lin
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  3. Enhua Wang
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Correspondence to Enhua Wang.

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Fan, C., Lin, X. & Wang, E. Clinicopathological significance of cathepsin D expression in non-small cell lung cancer is conditional on apoptosis-associated protein phenotype: an immunohistochemistry study. Tumor Biol. 33, 1045–1052 (2012). https://doi.org/10.1007/s13277-012-0338-y

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  • DOI: https://doi.org/10.1007/s13277-012-0338-y

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