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Stromal control of oncogenic traits expressed in response to the overexpression of GLI2, a pleiotropic oncogene

Oncogene volume 28, pages 625–637 (2009)Cite this article

Abstract

Hedgehog signaling is often activated in tumors, yet it remains unclear how GLI2, a transcription factor activated by this pathway, acts as an oncogene. We show that GLI2 is a pleiotropic oncogene. The overexpression induces genomic instability and blocks differentiation, likely mediated in part by enhanced expression of the stem cell gene SOX2. GLI2 also induces transforming growth factor (TGF)B1-dependent transdifferentiation of foreskin and tongue, but not gingival fibroblasts into myofibroblasts, creating an environment permissive for invasion by keratinocytes, which are in various stages of differentiation having downregulated GLI2. Thus, upregulated GLI2 expression is sufficient to induce a number of the acquired characteristics of tumor cells; however, the stroma, in a tissue-specific manner, determines whether certain GLI2 oncogenic traits are expressed.

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Acknowledgements

We thank Drs Gillian Hall and Richard Shaw, University of Liverpool for providing oral SCC 1300C2, Dr Fritz Aberger, University of Salzburg for providing the HaCaT Tet cells, HaCaT GLI2 cells and the 6xHis-GLI2ΔN pcDNA4/TO vector construct and Dr Rosemary Akhurst, UCSF Helen Diller Family Comprehensive Cancer Center (HDFCCC) and Dr J Yingling (Eli Lilly and Company, Indianapolis, IN) for providing the transforming growth factor β receptor kinase inhibitor, LY2109761. The UCSF HDFCCC Microarray, Tissue, Immunohistochemistry/Molecular Pathology and Genome Analysis Shared Resources provided assistance. This work was supported by NIH Grant CA118323. AMS was the recipient of a postdoctoral fellowship from the California Tobacco-Related Disease Research Program (14FT-0011) and a trainee of the NCI-sponsored Tumor Microenvironment Training Program: Techniques in the Establishment and Manipulation of Organotypic Model Systems. BLS is an appointee of the Western Oral Research Consortium (NIH K12 DE14609).

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Authors and Affiliations

  1. Cancer Research Institute, University of California San Francisco, San Francisco, CA, USA

    A M Snijders & D G Albertson

  2. Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA

    A M Snijders, B Huey, R Roy, R C K Jordan, B L Schmidt & D G Albertson

  3. Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA, USA

    B Huey & D G Albertson

  4. Department of Orofacial Sciences, University of California San Francisco, San Francisco, CA, USA

    S T Connelly & R C K Jordan

  5. Department of Oral and Maxillofacial Surgery, University of California San Francisco, San Francisco, CA, USA

    B L Schmidt

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  1. A M Snijders
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Correspondence to D G Albertson.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Snijders, A., Huey, B., Connelly, S. et al. Stromal control of oncogenic traits expressed in response to the overexpression of GLI2, a pleiotropic oncogene. Oncogene 28, 625–637 (2009). https://doi.org/10.1038/onc.2008.421

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