It has been demonstrated previously that E7 oncogene expression of human papillomavirus (HPV) type 8 in keratinocytes induces cell invasion and accelerated differentiation. Looking for cellular genes deregulated by HPV-8 E7, lipocalin-2 was identified as being upregulated in these cells by cDNA microarray analysis. Lipocalin-2 is known to be overexpressed in many human cancers and is implicated in the regulation of cell proliferation, differentiation and apoptosis. In this study, increased levels of lipocalin-2 were observed in extracts from HPV-8 E7-positive keratinocytes and from keratinocytes expressing E7 of HPV-1, -4, -5, -15, -20 and -38, but not of HPV-16. Similar results were obtained when measuring secreted lipocalin-2 in the supernatants of the cell cultures. Lipocalin-2 expression was associated with cell differentiation in keratinocyte monolayers and in organotypic skin cultures. It was found in the uppermost layers of HPV-5, -8, -15, -16, -20 and 38 E7-expressing but not low-risk HPV-1 and -4 E7-expressing keratinocytes. Immunohistochemical staining of HPV-positive and -negative human skin squamous cell carcinomas (SCCs) revealed lipocalin-2 expression mostly in differentiated, filaggrin-positive areas of 15 out of 17 HPV-positive and three out of nine HPV-negative SCCs. These data indicate that lipocalin-2 expression correlates with HPV positivity of cutaneous SCCs.


Article metrics loading...

Loading full text...

Full text loading...



  1. Akgül, B., García-Escudero, R., Ghali, L., Pfister, H. J., Fuchs, P. G., Navsaria, H. & Storey, A.(2005). The E7 protein of cutaneous human papillomavirus type 8 causes invasion of human keratinocytes into the dermis in organotypic cultures of skin. Cancer Res 65, 2216–2223.[CrossRef] [Google Scholar]
  2. Akgül, B., Cooke, J. C. & Storey, A.(2006). HPV-associated skin disease. J Pathol 208, 165–175.[CrossRef] [Google Scholar]
  3. Bouwes Bavinck, J. N., Plasmeijer, E. I. & Feltkamp, M. C.(2008).β-Papillomavirus infection and skin cancer. J Invest Dermatol 128, 1355–1358.[CrossRef] [Google Scholar]
  4. de Koning, M., Quint, W., Struijk, L., Kleter, B., Wanningen, P., van Doorn, L. J., Weissenborn, S. J., Feltkamp, M. & ter Schegget, J.(2006). Evaluation of a novel highly sensitive, broad-spectrum PCR-reverse hybridization assay for detection and identification of beta-papillomavirus DNA. J Clin Microbiol 44, 1792–1800.[CrossRef] [Google Scholar]
  5. Dell'Oste, V., Azzimonti, B., De Andrea, M., Mondini, M., Zavattaro, E., Leigheb, G., Weissenborn, S. J., Pfister, H., Michael, K. M. & other authors(2009). High β-HPV DNA loads and strong seroreactivity are present in epidermodysplasia verruciformis. J Invest Dermatol 129, 1026–1034.[CrossRef] [Google Scholar]
  6. Devarajan, P.(2007). Neutrophil gelatinase-associated lipocalin: new paths for an old shuttle. Cancer Ther 5, 463–470. [Google Scholar]
  7. Devireddy, L. R., Gazin, C., Zhu, X. & Green, M. R.(2005). A cell-surface receptor for lipocalin 24p3 selectively mediates apoptosis and iron uptake. Cell 123, 1293–1305.[CrossRef] [Google Scholar]
  8. Iannetti, A., Pacifico, F., Acquaviva, R., Lavorgna, A., Crescenzi, E., Vascotto, C., Tell, G., Salzano, A. M., Scaloni, A. & other authors(2008). The neutrophil gelatinase-associated lipocalin (NGAL), a NF-κB-regulated gene, is a survival factor for thyroid neoplastic cells. Proc Natl Acad Sci U S A 105, 14058–14063.[CrossRef] [Google Scholar]
  9. Lee, J. H., Kye, K. C., Seo, E. Y., Lee, K., Lee, S. K., Lim, J. S., Seo, Y. J., Kim, C. D. & Park, J. K.(2008). Expression of neutrophil gelatinase-associated lipocalin in calcium-induced keratinocyte differentiation. J Korean Med Sci 23, 302–306.[CrossRef] [Google Scholar]
  10. Leng, X., Ding, T., Lin, H., Wang, Y., Hu, L., Hu, J., Feig, B., Zhang, W., Pusztai, L. & other authors(2009). Inhibition of lipocalin 2 impairs breast tumorigenesis and metastasis. Cancer Res 69, 8579–8584.[CrossRef] [Google Scholar]
  11. Mallbris, L., O'Brien, K. P., Hulthen, A., Sandstedt, B., Cowland, J. B., Borregaard, N. & Stahle-Backdahl, M.(2002). Neutrophil gelatinase-associated lipocalin is a marker for dysregulated keratinocyte differentiation in human skin. Exp Dermatol 11, 584–591.[CrossRef] [Google Scholar]
  12. Orth, G.(2006). Genetics of epidermodysplasia verruciformis: insights into host defense against papillomaviruses. Semin Immunol 18, 362–374.[CrossRef] [Google Scholar]
  13. Pfister, H., Fuchs, P. G., Majewski, S., Jablonska, S., Pniewska, I. & Malejczyk, M.(2003). High prevalence of epidermodysplasia verruciformis-associated human papillomavirus DNA in actinic keratoses of the immunocompetent population. Arch Dermatol Res 295, 273–279.[CrossRef] [Google Scholar]
  14. Saiki, R. K., Chang, C.-A., Levenson, C. H., Warren, T. C., Boehm, C. D., Kazazian, H. H., Jr & Erlich, H. A.(1988). Diagnosis of sickle cell anemia and β-thalassemia with enzymatically amplified DNA and nonradioactive allele-specific oligonucleotide probes. N Engl J Med 319, 537–541.[CrossRef] [Google Scholar]
  15. Seo, E.-Y., Lee, W.-H., Piao, Y.-J., Kim, K.-H., Lee, K.-M., Ahn, K.-S., Yang, J.-M., Seo, Y.-J., Kim, C. D. & other authors(2004). Identification of calcium-inducible genes in primary keratinocytes using suppression-subtractive hybridization. Exp Dermatol 13, 163–169.[CrossRef] [Google Scholar]
  16. Seo, S. J., Ahn, J.-Y., Hong, C.-K., Seo, E.-Y., Kye, K.-C., Lee, W.-H., Lee, S.-K., Lim, J.-S., Hahn, M.-J. & other authors(2006). Expression of neutrophil gelatinase-associated lipocalin in skin epidermis. J Invest Dermatol 126, 510–512.[CrossRef] [Google Scholar]
  17. Syrjänen, S., Naud, P., Sarian, L., Derchain, S., Roteli-Martins, C., Tatti, S., Branca, M., Erzen, M., Hammes, L. S. & other authors(2010). 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 134, 50–59.[CrossRef] [Google Scholar]
  18. Tong, Z., Wu, X., Ovcharenko, D., Zhu, J., Chen, C. S. & Kehrer, J. P.(2005). Neutrophil gelatinase-associated lipocalin as a survival factor. Biochem J 391, 441–448.[CrossRef] [Google Scholar]
  19. Weissenborn, S. J., Nindl, I., Purdie, K., Harwood, C., Proby, C., Breuer, J., Majewski, S., Pfister, H. & Wieland, U.(2005). Human papillomavirus-DNA loads in actinic keratoses exceed those in non-melanoma skin cancers. J Invest Dermatol 125, 93–97.[CrossRef] [Google Scholar]
  20. Westphal, K., Akgül, B., Storey, A. & Nindl, I.(2009). Cutaneous human papillomavirus E7 type-specific effects on differentiation and proliferation of organotypic skin cultures. Cell Oncol 31, 213–226. [Google Scholar]
  21. Zhang, H., Xu, L., Xiao, D., Xie, J., Zeng, H., Wang, Z., Zhang, X., Niu, Y., Shen, Z. & other authors(2007). Upregulation of neutrophil gelatinase-associated lipocalin in oesophageal squamous cell carcinoma: significant correlation with cell differentiation and tumour invasion. J Clin Pathol 60, 555–561. [Google Scholar]
  22. zur Hausen, H.(2002). Papillomaviruses and cancer: from basic studies to clinical application. Nat Rev Cancer 2, 342–350.[CrossRef] [Google Scholar]

Data & Media loading...

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error