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Tumorigenic conversion of immortal human skin keratinocytes (HaCaT) by elevated temperature

Oncogene volume 18, pages 5638–5645 (1999)Cite this article

Abstract

UV-radiation is a major risk factor for non-melanoma skin cancer causing specific mutations in the p53 tumor suppressor gene and other genetic aberrations. We here propose that elevated temperature, as found in sunburn areas, may contribute to skin carcinogenesis as well. Continuous exposure of immortal human HaCaT skin keratinocytes (possessing UV-type p53 mutations) to 40°C reproducibly resulted in tumorigenic conversion and tumorigenicity was stably maintained after recultivation of the tumors. Growth at 40°C was correlated with the appearance of PARP, an enzyme activated by DNA strand breaks and the level corresponded to that seen after 5 Gy γ-radiation. Concomitantly, comparative genomic hybridization (CGH) analyis demonstrated that chromosomal gains and losses were present in cells maintained at 40°C while largely absent at 37°C. Besides individual chromosomal aberrations, all tumor-derived cells showed gain of chromosomal material on 11q with the smallest common region being 11q13.2 to q14.1. Cyclin D1, a candidate gene of that region was overexpressed in all tumor-derived cells but cyclinD1/cdk4/cdk6 kinase activity was not increased. Thus, these data demonstrate that long-term thermal stress is a potential carcinogenic factor in this relevant skin cancer model, mediating its effect through induction of genetic instability which results in selection of tumorigenic cells characterized by gain of 11q.

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Acknowledgements

We would like to thank H Steinbauer for excellent technical help in tumorigenicity studies, Dirk Breitkreutz for critical discussions, and Brigitte Plagens for stylistic improvements. We also wish to extend our thanks to Brigitte Engelhardt and coworkers for their excellent photo work. This work was in part supported by grants from EC (ENV4-CT96-01272 to P Boukamp) (Bio4 CT 96o464 to NE Fusenig), Sander Stiftung Nr. 98.013.1 (to P Boukamp), and the DFG (Bo 1246 3-1 to P Boukamp).

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  1. Division of Carcinogenesis and Differentiation, Deutsches Krebsforschungszentrum (DKFZ), Im Neuenheimer Feld 280, Heidelberg, D-69120, Germany

    P Boukamp, S Popp, K Bleuel, E Tomakidi & N E Fusenig

  2. Division of Applied Tumor Virology, Deutsches Krebsforschungszentrum (DKFZ), Im Neuenheimer Feld 280, Heidelberg, D-69120, Germany

    A Bürkle

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  1. P Boukamp
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Boukamp, P., Popp, S., Bleuel, K. et al. Tumorigenic conversion of immortal human skin keratinocytes (HaCaT) by elevated temperature. Oncogene 18, 5638–5645 (1999). https://doi.org/10.1038/sj.onc.1202934

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