Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Oncogenomics
  • Published:

Genome-wide comparison of human keratinocyte and squamous cell carcinoma responses to UVB irradiation: implications for skin and epithelial cancer

Abstract

To gain insight into the transformation of epidermal cells into squamous carcinoma cells (SCC), we compared the response to ultraviolet B radiation (UVB) of normal human epidermal keratinocytes (NHEK) versus their transformed counterpart, SCC, using biological and molecular profiling. DNA microarray analyses (Affymetrix®, 12 000 genes) indicated that the major group of upregulated genes in keratinocytes fall into three categories: (i) antiapoptotic and cell survival factors, including chemokines of the CXC/CC subfamilies (e.g. IL-8, GRO-1, -2, -3, SCYA20), growth factors (e.g. HB-EGF, CTGF, INSL-4), and proinflammatory mediators (e.g. COX-2, S100A9), (ii) DNA repair-related genes (e.g. GADD45, ERCC, BTG-1, Histones), and (iii) ECM proteases (MMP-1, -10). The major downregulated genes are ΔNp63 and PUMILIO, two potential markers for the maintenance of keratinocyte stem cells. NHEK were found to be more resistant than SCC to UVB-induced apoptosis and this resistance was mainly because of the protection from cell death by secreted survival factors, since it can be transferred from NHEK to SCC cultures by the conditioned medium. Whereas the response of keratinocytes to UVB involved regulation of key checkpoint genes (p53, MDM2, p21Cip1, ΔNp63), as well as antiapoptotic and DNA repair-related genes – no or little regulation of these genes was observed in SCC. The effect of UVB on NHEK and SCC resulted in upregulation of 251 and 127 genes, respectively, and downregulation of 322 genes in NHEK and 117 genes in SCC. To further analyse these changes, we used a novel unsupervised coupled two-way clustering method that allowed the identification of groups of genes that clearly partitioned keratinocytes from SCC, including a group of genes whose constitutive expression levels were similar before UVB. This allowed the identification of discriminating genes not otherwise revealed by simple static comparison in the absence of UVB irradiation. The implication of the changes in gene profile in keratinocytes for epithelial cancer is discussed.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7

Similar content being viewed by others

Abbreviations

NHEK:

normal human epidermal keratinocyte

SCC:

squamous cell carcinoma

UVB:

ultraviolet B

NER:

nucleotide excision repair

CTWC:

coupled two-way clustering

SPC:

super paramagnetic clustering

References

  • Ahmad N, Gilliam AC, Katiyar SK, O'Brien TG and Mukhtar H . (2001). Am. J. Pathol., 159, 885–892.

  • Armstrong BK and Kricker A . (2001). J. Photochem. Photobiol. B, 63, 8–18.

  • Bassing CH, Chua KF, Sekiguchi J, Suh H, Whitlow SR, Fleming JC, Monroe BC, Ciccone DN, Yan C, Vlasakova, Livingston DM, Ferguson DO, Scully R and Alt FW . (2002). Proc. Natl. Acad. Sci. USA, 99, 8173–8178.

  • Blatt M, Wiseman S and Domany E . (1996). Phys. Rev. Lett., 76, 3251–3254.

  • Brash DE . (1997). Trends Genet., 13, 410–414.

  • Brinkmann U, Brinkmann E, Gallo M, Scherf U and Pastan I . (1996). Biochemistry, 35, 6891–6899.

  • Brune B and von Knethen A . (2002). J. Environ. Pathol. Toxicol. Oncol., 21, 103–112.

  • Buckman SY, Gresham A, Hale P, Hruza G, Anast J, Masferrer J and Pentland AP . (1998). Carcinogenesis, 19, 723–729.

  • Burns JE, Baird MC, Clark LJ, Burns PA, Edington K, Chapman C, Mitchell R, Robertson G, Soutar D and Parkinson EK . (1993). Br. J. Cancer, 67, 1274–1284.

  • Celeste A, Petersen S, Romanienko PJ, Fernandez-Capetillo O, Chen HT, Sedelnikova OA, Reina-San-Martin B, Coppola V, Meffre E, Difilippantonio MJ, Redon C, Pilch DR, Olaru A, Eckhaus M, Camerini-Otero RD, Tessarollo L, Livak F, Manova K, Bonner WM, Nussenzweig MC and Nussenzweig A . (2002). Science, 296, 922–927.

  • Chazal M, Marionnet C, Michel L, Mollier K, Dazard JE, Della Valle V, Larsen CJ, Gras MP and Basset-Seguin N . (2002). Oncogene, 21, 2652–2661.

  • Chiarugi A and Moskowitz MA . (2002). Science, 297, 200–201.

  • Chung HT, Pae HO, Choi BM, Billiar TR and Kim YM . (2001). Biochem. Biophys. Res. Commun., 282, 1075–1079.

  • Cleaver JE and Crowley E . (2002). Front. Biosci., 7, d1024–d1043.

  • Coussens LM, Raymond WW, Bergers G, Laig-Webster M, Behrendtsen O, Werb Z, Caughey GH and Hanahan D . (1999). Genes Dev., 13, 1382–1397.

  • Coussens LM and Werb Z . (2002). Nature, 420, 860–867.

  • Dazard JE, Piette J, Basset-Seguin N, Blanchard JM and Gandarillas A . (2000). Oncogene, 19, 3693–3705.

  • Decraene D, Agostinis P, Bouillon R, Degreef H and Garmyn M . (2002). J. Biol. Chem., 277, 32587–32595.

  • Evan GI and Vousden KH . (2001). Nature, 411, 342–348.

  • Fang L, Li G, Liu G, Lee SW and Aaronson SA . (2001). EMBO J., 20, 1931–1939.

  • Garssen J and van Loveren H . (2001). Crit. Rev. Immunol., 21, 359–397.

  • Getz G, Levine E and Domany E . (2000). Proc. Natl. Acad. Sci. USA, 97, 12079–12084.

  • Gloster Jr HM and Brodland DG . (1996). Dermatol. Surg., 22, 217–226.

  • Green DR and Evan GI . (2002). Cancer Cell, 1, 19–30.

  • Greinert R, Boguhn O, Harder D, Breitbart EW, Mitchell DL and Volkmer B . (2000). Photochem. Photobiol., 72, 701–708.

  • Gupta RA and Dubois RN . (2001). Nat. Rev. Cancer, 1, 11–21.

  • Han JA, Kim JI, Ongusaha PP, Hwang DH, Ballou LR, Mahale A, Aaronson SA and Lee SW . (2002). EMBO J., 21, 5635–5644.

  • Hanson KM and Clegg RM . (2002). Photochem. Photobiol., 76, 57–63.

  • Kannan K, Amariglio N, Rechavi G, Jakob-Hirsch J, Kela I, Kaminski N, Getz G, Domany E and Givol D . (2001). Oncogene, 20, 2225–2234.

  • Karin M, Cao Y, Greten FR and Li ZW . (2002). Nat. Rev. Cancer, 2, 301–310.

  • Li D, Turi TG, Schuck A, Freedberg IM, Khitrov G and Blumenberg M . (2001). FASEB J., 15, 2533–2535.

  • Liefer KM, Koster MI, Wang XJ, Yang A, McKeon F and Roop DR . (2000). Cancer Res., 60, 4016–4020.

  • Lotem J, Kama R and Sachs L . (1999). Proc. Natl. Acad. Sci. USA, 96, 12016–12020.

  • Loukinova E, Chen Z, Van Waes C and Dong G . (2001). Int. J. Cancer, 94, 637–644.

  • Martini EM, Keeney S and Osley MA . (2002). Genetics, 160, 1375–1387.

  • Michael D and Oren M . (2002). Curr. Opin. Genet. Dev., 12, 53–59.

  • Notterman DA, Alon U, Sierk AJ and Levine AJ . (2001). Cancer Res., 61, 3124–3130.

  • Parsa R, Yang A, McKeon F and Green H . (1999). J. Invest. Dermatol., 113, 1099–1105.

  • Pellegrini G, Dellambra E, Golisano O, Martinelli E, Fantozzi I, Bondanza S, Ponzin D, McKeon F and De Luca M . (2001). Proc. Natl. Acad. Sci. USA, 98, 3156–3161.

  • Pfeiffer GP . (1997). Photochem. and Photobiol., 65, 270–283.

  • Richmond A . (2002). Nat. Rev. Immunol., 2, 664–674.

  • Sage E, Lamolet B, Brulay E, Moustacchi E, Chteauneuf A and Drobetsky EA . (1996). Proc. Natl. Acad. Sci. USA, 93, 176–180.

  • Selgrade MK, Smith MV, Oberhelman-Bragg LJ, LeVee GJ, Koren HS and Cooper KD . (2001). Photochem. Photobiol., 74, 88–95.

  • Sesto A, Navarro M, Burslem F and Jorcano JL . (2002). Proc. Natl. Acad. Sci. USA, 99, 2965–2970.

  • Singh RK, Varney ML, Bucana CD and Johansson SL . (1999). Melanoma Res., 9, 383–387.

  • Soehnge H, Ouhtit A and Ananthaswamy ON . (1997). Front. Biosci., 2, D538–D551.

  • Soufir N, Moles JP, Vilmer C, Moch C, Verola O, Rivet J, Tesniere A, Dubertret L and Basset-Seguin N . (1999). Oncogene, 18, 5477–5481.

  • Tsujii M and DuBois RN . (1995). Cell, 83, 493–501.

  • Turini ME and DuBois RN . (2002). Annu. Rev. Med., 53, 35–57.

  • Wickens M, Bernstein DS, Kimble J and Parker R . (2002). Trends Genet., 18, 150–157.

  • Xie K . (2001). Cytokine Growth Factor Rev., 12, 375–391.

  • Xing PX, Apostolopoulos V, Pietersz G and McKenzie IF . (2001). Front. Biosci., 6, D1284–D1295.

  • Yang A, Kaghad M, Wang Y, Gillett E, Fleming MD, Dotsch V, Andrews NC, Caput D and McKeon F . (1998). Mol. Cell, 305–316.

  • Yang A, Schweitzer R, Sun D, Kaghad M, Walker N, Bronson RT, Tabin C, Sharpe A, Caput D, Crum C and McKeon I . (1999). Nature, 398, 714–718.

  • Zhao R, Gish K, Murphy M, Yin Y, Notterman D, Hoffman WH, Tom E, Mack DH and Levine AJ . (2000). Genes Dev., 1, 981–993.

  • Ziegler A, Jonason AS, Leffell DJ, Simon JA, Sharma HW, Kimmelman J, Remington L, Jacks T and Brash DE . (1994). Nature, 372, 773–776.

Download references

Acknowledgements

We are grateful to the family of Arison Dorsman for their donation to the Center for DNA Chips in the Pediatric Oncology Department, The Chaim Sheba Medical Center, Tel-Aviv. This study was supported in part by the Yad Abraham Research Center for Cancer Diagnosis and Therapy, and grants from the Irwin Green Alzheimer's Research Fund, the Israel Science Foundation (ISF) and the Germany–Israel Science Foundation (GIF). We thank M Oren for monoclonal antibodies against p53 and MDM2, A Jetten for the polyclonal antibody against Cornifin, G de Murcia for the polyclonal antibody against PARP, and N Fusenig for HaCaT cells.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to David Givol.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Dazard, JE., Gal, H., Amariglio, N. et al. Genome-wide comparison of human keratinocyte and squamous cell carcinoma responses to UVB irradiation: implications for skin and epithelial cancer. Oncogene 22, 2993–3006 (2003). https://doi.org/10.1038/sj.onc.1206537

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1206537

Keywords

This article is cited by

Search

Quick links