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  • Original Paper
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STAT3 activation is required for interleukin-6 induced transformation in tumor-promotion sensitive mouse skin epithelial cells

Oncogene volume 21, pages 3949–3960 (2002)Cite this article

Abstract

STAT3, a member of signal transducers and activators of transcription (STATs) originally discovered as mediators in cytokine signaling pathways, plays an active role in oncogenesis. However, the function of STAT3 in signaling multistage carcinogenesis, especially in transformation of tumor-promotion sensitive epithelial cells has not been elucidated. The present study demonstrates that STAT3 is activated in interleukin-6 induced transformation in mouse skin epithelial cells. DNA binding and transcriptional activities of STAT3 were significantly increased by interleukin-6. This induced anchorage-independent transformation in tumor-promotion sensitive JB6 mouse skin P+ cells but not in the resistant variant P− cells. Two forms of dominant negative STAT3 (mutant of transcriptional domain, mF, or DNA-binding domain, mD) were stably transfected into P+ cells. Activation of STAT3 was abolished and importantly, interleukin-6 induced anchorage-independent growth was absent in both mutant STAT3 transfectants. To determine the genes targeted by STAT3, three matrix metalloproteinase proteins linked with carcinogenesis of epithelial cells were analysed. Both basal and interleukin-6 induced expression of collagenase I and stromelysin I, but not gelatinase A, were inhibited in the mutant STAT3 transfectants. Furthermore, transfection of a wild type STAT3 restored STAT3 transactivation and response to interleukin-6 induced transformation in mutant STAT3 transfectants, which up-regulated collagenase I and stromelysin I as well. Together, these results provide the first evidence that STAT3 activation is required in the progression of multistage carcinogenesis of mouse skin epithelial cells, and matrix metalloproteinases are actively involved in STAT3-mediated cell transformation.

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Abbreviations

AP-1:

activator protein 1

EGF:

epithelial growth factor

GAPDH:

glyceraldehyde-3-phosphate dehydrogenase

IL-6:

Interleukin-6

Janus kinase:

Jak

PKC:

protein kinase C

MMPs:

matrix metalloproteinases

Manganese-containing superoxide dismutase:

MnSOD

NF-κB:

nuclear factor kappaB

STATs:

signal transducers and activators of transcription

TNF:

tumor necrosis factor

TPA:

12-O-tetradecanoylphorbol-13-acetate

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Acknowledgements

We thank Dr JE Darnell at Rockefeller University for critical comments and suggestions. We are grateful to Dr T Hirano at NIH for providing the wild type HA-STAT3, mutated HA-STAT3F and HA-STAT3D, and control vectors; Drs J Shively and T LeBon at City of Hope for insightful reading and editorial help; and Mrs V Boore for assistance in preparing the manuscript. By acceptance of this article, the publisher or recipient acknowledges the right of the US Government to retain a non-exclusive, royalty-free license in and to any copyright covering the article. The contents of this publication do not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government.

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Author notes

  1. Cheng-Yong Yu

    Present address: Molecular Immunology Section, Laboratory of Immunology, NEI, NIH, Bethesda, 20892, MD, USA

  2. Cheng-Yong Yu and Lihua Wang: C-Y Yu and L Wang have contributed equally to this work

Authors and Affiliations

  1. Laboratory of Experimental Immunology, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, Maryland, USA

    Cheng-Yong Yu

  2. Cytokine Molecular Mechanisms Section, Laboratory of Molecular Immunoregulation, National Cancer Institute, National Institutes of Health, Frederick, 21702, Maryland, MD, USA

    Lihua Wang & William L Farrar

  3. Laboratory of Basic Research, National Cancer Institute, National Institutes of Health, Frederick, 21702, Maryland, MD, USA

    Nancy H Colburn

  4. Department of Immunology, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, 44106, Ohio, OH, USA

    Andrew Larner

  5. Division of Radiation Oncology, Radiation Biology, Beckman Research Institute, City of Hope National Medical Center, Duarte, 91010, California, CA, USA

    Alexander Khaletskiy & Jian Jian Li

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Yu, CY., Wang, L., Khaletskiy, A. et al. STAT3 activation is required for interleukin-6 induced transformation in tumor-promotion sensitive mouse skin epithelial cells. Oncogene 21, 3949–3960 (2002). https://doi.org/10.1038/sj.onc.1205499

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