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Keratin 17 promotes epithelial proliferation and tumor growth by polarizing the immune response in skin

Nature Genetics volume 42, pages 910–914 (2010)Cite this article

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Abstract

Basaloid skin tumors, including basal cell carcinoma (BCC) and basaloid follicular hamartoma, are associated with aberrant Hedgehog (Hh) signaling1 and, in the case of BCC, an expanding set of genetic variants including keratin 5 (encoded by KRT5)2, an intermediate filament-forming protein. We here show that genetic ablation of keratin 17 (Krt17) protein, which is induced in basaloid skin tumors3,4 and co-polymerizes with Krt5 in vivo5, delays basaloid follicular hamartoma tumor initiation and growth in mice with constitutive Hh signaling in epidermis6,7. This delay is preceded by a reduced inflammation and a polarization of inflammatory cytokines from a Th1- and Th17-dominated profile to a Th2-dominated profile. Absence of Krt17 also attenuates hyperplasia and inflammation in models of acute dermatitis. Re-expression of Krt17 in Gli2tg; Krt17−/− keratinocytes induces select Th1 chemokines that have established roles in BCC. Our findings establish an immunomodulatory role for Krt17 in Hh driven basaloid skin tumors that could impact additional tumor settings, psoriasis and wound repair.

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Figure 1: Absence of Krt17 delays the onset of ear lesions and epidermal hyperplasia in Gli2tg mice.
Figure 2: Role of inflammation in the onset of ear lesions.
Figure 3: Absence of Krt17 blunts epidermal hyperplasia and alters inflammation in a chemical model of dermatitis.

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Acknowledgements

We thank M. Han for technical support and J. Seykora for expertise. These studies were supported in part by grants CA123530 and AR44232 to P.A.C., fellowship grant F32 CA110618 to D.D. and grant CA087837 to A.A.D., all from the US National Institutes of Health.

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA

    Daryle DePianto, Michelle L Kerns & Pierre A Coulombe

  2. Department of Dermatology, University of Michigan School of Medicine, Ann Arbor, Michigan, USA

    Andrzej A Dlugosz

  3. Department of Cell and Developmental Biology, University of Michigan School of Medicine, Ann Arbor, Michigan, USA

    Andrzej A Dlugosz

  4. Department of Biological Chemistry, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA

    Pierre A Coulombe

  5. Department of Dermatology, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA

    Pierre A Coulombe

Authors
  1. Daryle DePianto
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  2. Michelle L Kerns
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  3. Andrzej A Dlugosz
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  4. Pierre A Coulombe
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Contributions

D.D. conceived and led the execution of all experiments and participated in the interpretation of the results and manuscript production. M.L.K. contributed expertise about inflammatory and immune cytokines and assisted D.D. in the execution and interpretation of many experiments.

A.A.D. contributed expertise on mouse skin tumor models and skin tumor histology and participated in manuscript production. P.A.C. conceived the experiments along with D.D. and participated in the interpretation of the results and manuscript production.

Corresponding author

Correspondence to Pierre A Coulombe.

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The authors declare no competing financial interests.

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Supplementary Figures 1–5 and Supplementary Table 1 (PDF 1237 kb)

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DePianto, D., Kerns, M., Dlugosz, A. et al. Keratin 17 promotes epithelial proliferation and tumor growth by polarizing the immune response in skin. Nat Genet 42, 910–914 (2010). https://doi.org/10.1038/ng.665

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