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Systemic Interferon-α (IFN-α) Treatment Leads to Stat3 Inactivation in Melanoma Precursor Lesions

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Abstract

Background

In the setting of familial melanoma, the presence of atypical nevi, which are the precursors of melanoma, is associated with a nearly 100% risk of developing primary melanoma by age 70. In patients with sporadic melanoma, it is estimated that 40–60% of melanomas develop in contiguous association with atypical nevi. Currently, the only way to prevent atypical nevi from progressing to melanoma is to monitor and excise them as soon as they exhibit changes in their clinical features. Activation of the transcription factor, Stat3, has been linked to abnormal cell growth and transformation as well as to interferon α (IFN-α)-mediated growth suppression in vitro.

Materials and Methods

To determine whether IFN-α, used for adjuvant therapy of high-risk, resected melanoma, induces changes in Stat3 in atypical nevi, patients with a clinical history of melanoma who have multiple atypical nevi were treated for 3 months with low-dose IFN-α. Thereupon, the new technology of microscopic spectral imaging and biochemical assays such as electrophoretic mobility shift assays (EMSAs) and immunoblot analysis were used for the study of atypical nevi, obtained before and after IFN-α treatment.

Results

The results of the investigations provided evidence that, as a result of systemic IFN-α treatment, Stat1 and Stat3, which are constitutively activated in melanoma precursor lesions, lose their ability to bind DNA, and as shown in the case of Stat3, become dephosphorylated.

Conclusions

Unlike primary and metastatic melanomas, melanoma precursor lesions cannot be established as cell cultures. Thus, the only way to explore pathways and treatment regimens that might help prevent progression to melanoma is within the context of a melanoma precursor lesion study conducted prospectively. The findings presented here suggest that down-regulation of the transcription factors Stat1 and Stat3 by systemic IFN-α treatment may represent a potential pathway to prevent the activation of gene(s) whose expression may be required for atypical nevus cells to progress to melanoma.

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Acknowledgments

This work was supported by grants from the National Institutes of Health (D.B. and D.J.T.), the National Science Foundation (D.L.F.), and the Cancer Treatment Research Foundation (D.B.).

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Authors and Affiliations

  1. Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA

    John M. Kirkwood, Arup Chakraborty, Kevin F. Dyer, David J. Tweardy & Sandra S. Donnelly

  2. Department of Bioengineering, University of Pittsburgh, Pittsburgh, Pennsylvania, USA

    Daniel L. Farkas

  3. Department of Pathology, University of Pittsburgh, BST, E1057, 211 Lothrop Street, Pittsburgh, Pennsylvania, 15213, USA

    John L. Abernethy &  Dorothea Becker

  4. Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA

    Howard D. Edington

  5. Center for Light Microscope Imaging and Biotechnology, Carnegie Mellon University, Pittsburgh, Pennsylvania, USA

    Daniel L. Farkas

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  1. John M. Kirkwood
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  2. Daniel L. Farkas
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  3. Arup Chakraborty
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  4. Kevin F. Dyer
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  5. David J. Tweardy
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  6. John L. Abernethy
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  8. Sandra S. Donnelly
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  9. Dorothea Becker
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Correspondence to Dorothea Becker.

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Kirkwood, J.M., Farkas, D.L., Chakraborty, A. et al. Systemic Interferon-α (IFN-α) Treatment Leads to Stat3 Inactivation in Melanoma Precursor Lesions. Mol Med 5, 11–20 (1999). https://doi.org/10.1007/BF03402135

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  • DOI: https://doi.org/10.1007/BF03402135

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