Skip to main content

Advertisement

SpringerLink
Log in

The Role of Lipocalin 2 and its Concernment With Human Nonmetastatic Clone 23 Type 1 and p53 in Carcinogenesis of Uterine Cervix

  • Original Articles
  • Published:
Reproductive Sciences Aims and scope Submit manuscript

Abstract

To investigate the novel role of lipocalin 2 and its concernment with human nonmetastatic clone 23 type 1 (nm23-H1) and p53 in cervical carcinogenesis, SiHa cervical cancer cells were knocked down for nm23-H and lipocalin 2 or overexpressed by lipocalin 2 genes. We found that the overexpression of lipocalin 2 or knockdown of nm23-H1 genes increased the proliferation of SiHa cancer cells, while knocking down of lipocalin 2 decreased the proliferation of SiHa. Furthermore, knockdown of nm23-H1 or overexpression of lipocalin 2 was associated with reduced expression of p53 and its downstream gene p21. Using tissue microarrays, lipocalin 2 immunoreactivity was significantly elevated in cancer tissues as compared with it in high- or low-grade dysplasia or normal tissues. Serum secreted form lipocalin 2 from patients with cervical cancer increased in comparison with normal controls. Conclusively, secreted form lipocalin 2 reflects its implication in cervical cancer tissues and may be utilized as an adjuvant biomarker.

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

Similar content being viewed by others

References

  1. Rosengard AM, Krutzsch HC, Shearn A, et al. Reduced Nm23/Awd protein in tumour metastasis and aberrant Drosophila development. Nature. 1989;342(6246):177–180.

    Article  CAS  PubMed  Google Scholar 

  2. Wallet V, Mutzel R, Troll H, et al. Dictyostelium nucleoside diphosphate kinase highly homologous to Nm23 and Awd proteins involved in mammalian tumor metastasis and Drosophila development. J Natl Cancer Inst. 1889;82(14):1199–1202.

    Article  Google Scholar 

  3. Kimura N, Shimada N, Nomura K, Watanabe K. Isolation and characterization of a cDNA clone encoding rat nucleoside diphosphate kinase. J Biol Chem. 1990;265(26):15744–15749.

    CAS  PubMed  Google Scholar 

  4. Lacombe ML, Milon L, Munier A, Mehus JG, Lambeth DO. The human Nm23/nucleoside diphosphate kinases. J Bioenerg Biomembr. 2000;32(3):247–258.

    Article  CAS  PubMed  Google Scholar 

  5. Ouatas T, Salerno M, Palmieri D, Steeg PS. Basic and translational advances in cancer metastasis: Nm23. J Bioenerg Biomembr. 2003;35(1):73–79.

    Article  CAS  PubMed  Google Scholar 

  6. Crawford RM, Treharne KJ, Best OG, Muimo R, Riemen CE, Mehta A. A novel physical and functional association between nucleoside diphosphate kinase A and AMP-activated protein kinase alpha1 in liver and lung. Biochem J. 2005;392(pt 1):201–209.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Wang PH, Chang H, Ko JL, Lin LY. Nm23-H1 immunohistochemical expression in multisteps of cervical carcinogenesis. Int J Gynecol Cancer. 2003;13(3):325–330.

    Article  PubMed  Google Scholar 

  8. Ravazoula P, Aletra C, Kourounis G, Ladopoulos I, Tzigounis V. Immunohistochemical analysis of nm23-H1 expression in human cervical lesions. Eur J Gynaecol Oncol. 2000;21(5):51–52.

    Google Scholar 

  9. Branca M, Giorgi C, Ciotti M, et al. Down-regulated nucleoside diphosphate kinase nm23-H1 expression is unrelated to high-risk human papillomavirus but associated with progression of cervical intraepithelial neoplasia and unfavourable prognosis in cervical cancer. J Clin Pathol. 2006;59(10):1044–1051.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Kjeldsen L, Johnsen AH, Sengelov H, Borregaard N. Isolation and primary structure of NGAL, a novel protein associated with human neutrophil gelatinase. J Biol Chem. 1993;268(14):10425–10432.

    CAS  PubMed  Google Scholar 

  11. Bratt T. Lipocalins and cancer. Biochim Biophys Acta. 2000;1482(1–2):318–326.

    Article  CAS  PubMed  Google Scholar 

  12. Goetz DH, Willie ST, Armen RS, Bratt T, Borregaard N, Strong RK. Ligand preference inferred from the structure of neutrophil gelatinase associated lipocalin. Biochemistry. 2000;39(8):1935–1941.

    Article  CAS  PubMed  Google Scholar 

  13. Wojnar P, Lechner M, Redl B. Antisense down-regulation of lipocalin-interacting membrane receptor expression inhibits cellular internalization of lipocalin-1 in human NT2 cells. J Biol Chem. 2003;278(18):16209–16215.

    Article  CAS  PubMed  Google Scholar 

  14. Kjeldsen L, Johnsen AH, Sengeløv H, Borregaard N. Isolation and primary structure of NGAL, a novel protein associated with human neutrophil gelatinase. Biol Chem. 1993;268(14):10425–10432.

    CAS  Google Scholar 

  15. Xu S, Venge P. Lipocalins as biochemical markers of disease. Biochim Biophys Acta. 2000;1482(1–2):298–307.

    Article  CAS  PubMed  Google Scholar 

  16. Stoesz SP, Friedl A, Haag JD, Lindstrom MJ, Clark GM, Gould MN. Heterogeneous expression of the lipocalin NGAL in primary breast cancers. Int J Cancer. 1998;79(6):565–572.

    Article  CAS  PubMed  Google Scholar 

  17. Cho H, Kim JH. Lipocalin2 expressions correlate significantly with tumor differentiation in epithelial ovarian cancer. J Histochem Cytochem. 2009;57(5):513–521.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Syrjänen S, Naud P, Sarian L, et al. Up-regulation of lipocalin 2 is associated with high-risk human papillomavirus and grade of cervical lesion at baseline but does not predict outcomes of infections or incident cervical intraepithelial neoplasia. Am J Clin Pathol. 2010;134(1):50–59.

    Article  PubMed  Google Scholar 

  19. Choudhuri T, Murakami M, Kaul R, et al. Nm23-H1 can induce cell cycle arrest and apoptosis in B cells. Cancer Biol Ther. 2010;9(12):1065–1078.

    Article  CAS  PubMed  Google Scholar 

  20. Olaussen KA, Dunant A, Fouret P, et al. DNA repair by ERCC1 in non-small-cell lung cancer and cisplatin-based adjuvant chemotherapy. N Engl J Med. 2006;355(10):983–991.

    Article  CAS  PubMed  Google Scholar 

  21. Al-Haddad S, Zhang Z, Leygue E, et al. Psoriasin (S100A7) expression and invasive breast cancer. Am J Pathol. 1999;155(6):2057–2066.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Handra-Luca A, Bilal H, Bertrand JC, Fouret P. Extra-cellular signal regulated ERK-1/ERK-2 pathway activation in human salivary gland mucoepidermoid carcinoma: Association to aggressive tumor behavior and tumor cell proliferation. Am J Pathol. 2003;163(3):957–967.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Hsu CG, Lin LY, Ko JL, et al. High expression of human nonmetastatic clone 23 type 1 in cancer of uterine cervix and its association with poor cell differentiation and worse overall survival. J Surg Oncol. 2008;98(6):448–456.

    Article  PubMed  Google Scholar 

  24. Jung H, Seong HA, Ha H. Nm23-H1 tumor suprressor and its interacting partner STRAP activated p53 function. J Biol Chem. 2007;282(48):35293–35307.

    Article  CAS  PubMed  Google Scholar 

  25. Jung H, Seong HA, Ha H. Direct interaction between NM23-H1 and macrophage migration inhibitory factor (MIF) is critical for alleviation of MIF-mediated suppression of p53 activity. J Biol Chem. 2008;283(47):32669–32679.

    Article  CAS  PubMed  Google Scholar 

  26. Bedelbaeva K, Snyder A, Gourevitch D, et al. Lack of p21 expression links cell cycle control and appendage regeneration in mice. Proc Natl Acad Sci U S A. 2010;107(13):5845–5850.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Iannetti A, Pacifico F, Acquaviva R, et al. The neutrophil gelatinase-associated lipocalin (NGAL), a NF-kappaB-regulated gene, is a survival factor for thyroid neoplastic cells. Proc Natl Acad Sci U S A. 2008;105(37):14058–14063.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Bolignano D, Donato V, Lacquaniti A, et al. Neutrophil gelatinase-associated lipocalin (NGAL) in human neoplasias: a new protein enters the scene. Cancer Lett. 2010;288(1):10–16.

    Article  CAS  PubMed  Google Scholar 

  29. Ak P, Levine AJ. p53 and NF-{kappa}B: different strategies for responding to stress lead to a functional antagonism. FASEB J. 2010;24(10):3643–3652.

    Article  CAS  PubMed  Google Scholar 

  30. Ogawara Y, Kishishita S, Obata T, et al. Akt enhances Mdm2-mediated ubiquitination and degradation of p53. J Biol Chem. 2002;277(24):21843–21850.

    Article  CAS  PubMed  Google Scholar 

  31. Bai D, Ueno L, Vogt PK. Akt-mediated regulation of NFkappaB and the essentialness of NFkappaB for the oncogenicity of PI3K and Akt. Int J Cancer. 2009;125(12):2863–2870.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Berger T, Cheung CC, Elia AJ, Mak TW. Disruption of the Lcn2 gene in mice suppresses primary mammary tumor formation but does not decrease lung metastasis. Proc Natl Acad Sci U S A. 2010;107(7):2995–3000.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Yang J, Bielenberg DR, Rodig SJ, et al. Lipocalin 2 promotes breast cancer progression. Proc Natl Acad Sci USA. 2009;106(10):3913–3918.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Kubben FJ, Sier CF, Hawinkels LJ, et al. Clinical evidence for a protective role of lipocalin-2 against MMP-9 autodegradation and the impact for gastric cancer. European J Cancer. 2007;43(12):1869–1876.

    Article  CAS  Google Scholar 

  35. Moniaux N, Chakraborty S, Yalniz M, et al. Early diagnosis of pancreatic cancer: neutrophil gelatinase-associated lipocalin as a marker of pancreatic intraepithelial Neoplasia. Br J Cancer. 2008;98(9):1540–1547.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Niitsu N, Okamoto M, Honma Y, et al. Serum levels of the nm23-H1 protein and their clinical implication in extranodal NK/T-cell lymphoma. Leukemia. 2003;17(5):987–990.

    Article  CAS  PubMed  Google Scholar 

  37. Niitsu N, Honma Y, Iijima K, et al. Clinical significance of nm23-H1 proteins expressed on cell surface in non-Hodgkin’s lymphoma. Leukemia. 2003;17(1):196–202.

    Article  CAS  PubMed  Google Scholar 

  38. Okabe-Kado J, Kasukabe T, Honma Y, Kobayashi H, Maseki N, Kaneko Y. Extracellular NM23 protein promotes the growth and survival of primary cultured human acute myelogenous leukemia cells. Cancer Sci. 2009;100(10):1885–1894.

    Article  CAS  PubMed  Google Scholar 

  39. Rumjahn SM, Javed MA, Wong N, Law WE, Buxton IL. Purinergic regulation of angiogenesis by human breast carcinoma-secreted nucleoside diphosphate kinase. Br J Cancer. 2007;97(10):1372–1380.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Provatopoulou X, Gounaris A, Kalogeraj E, et al. Circulating levels of matrix metalloproteinase-9 (MMP-9), neutrophil gelatinase-associated lipocalin (NGAL) and their complex MMP-9/NGAL in breast cancer disease. BMC Cancer. 2009;9:390–396.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Lim R, Ahmed N, Borregaard N, et al. Neutrophil gelatinase-associated lipocalin (NGAL) an early-screening biomarker for ovarian cancer: NGAL is associated with epidermal growth factor-induced epithelio-mesenchymal transition. Int J Cancer. 2007;120(11):2426–2434.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Institute of Medicine, Chung Shan Medical University, 110, Section 1, Chien-Kuo North Road, Taichung, 40201, Taiwan

    Po-Hui Wang MD, PhD, Shun-Fa Yang PhD, Jiunn-Liang Ko PhD & Long-Yau Lin MD, DSc

  2. School of Medicine, Chung Shan Medical University, Taichung, Taiwan

    Po-Hui Wang MD, PhD, Chih-Jen Tseng MD, Tsung-Ho Ying MD, PhD & Long-Yau Lin MD, DSc

  3. Department of Obstetrics and Gynecology, Chung Shan Medical University Hospital, Taichung, Taiwan

    Po-Hui Wang MD, PhD, Chih-Jen Tseng MD, Tsung-Ho Ying MD, PhD & Long-Yau Lin MD, DSc

  4. Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan

    Shun-Fa Yang PhD

  5. Institute of Medical and Molecular Toxicology, Chung Shan Medical University, Taichung, Taiwan

    Jiunn-Liang Ko PhD

Authors
  1. Po-Hui Wang MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shun-Fa Yang PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chih-Jen Tseng MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tsung-Ho Ying MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jiunn-Liang Ko PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Long-Yau Lin MD, DSc
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Po-Hui Wang MD, PhD, Jiunn-Liang Ko PhD or Long-Yau Lin MD, DSc.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wang, PH., Yang, SF., Tseng, CJ. et al. The Role of Lipocalin 2 and its Concernment With Human Nonmetastatic Clone 23 Type 1 and p53 in Carcinogenesis of Uterine Cervix. Reprod. Sci. 18, 447–455 (2011). https://doi.org/10.1177/1933719110395407

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1177/1933719110395407

Keywords

Search

Navigation